Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 555
Filtrar
1.
Trials ; 21(1): 902, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126910

RESUMO

OBJECTIVES: To assess the impact of adding statin (atorvastatin) and/or aspirin on clinical deterioration in patients infected with SARS-CoV-2 who require hospitalisation. The safety of these drugs in COVID-19 patients will also be evaluated. TRIAL DESIGN: This is a single-centre, prospective, four-arm parallel design, open-label, randomized control trial. PARTICIPANTS: The study will be conducted at National Cancer Institute (NCI), Jhajjar, Haryana, which is a part of All India Institute of Medical Sciences (AIIMS), New Delhi, and has been converted into a dedicated COVID-19 management centre since the outbreak of the pandemic. All RT-PCR confirmed cases of SARS-CoV-2 infection with age ≥ 40 years and < 75 years requiring hospital admission (patients with WHO clinical improvement ordinal score 3 to 5) will be included in the trial. Written informed consent will be taken for all recruited patients. Patients with a critical illness (WHO clinical improvement ordinal score > 5), documented significant liver disease/dysfunction (aspartate transaminase [AST] / alanine aminotransferase [ALT] > 240), myopathy and rhabdomyolysis (creatine phosphokinase [CPK] > 5x normal), allergy or intolerance to statins or aspirin, prior statin or aspirin use within 30 days, history of active gastrointestinal bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, or inability to take oral or nasogastric medications will be excluded. Patients refusing to give written consent and taking drugs that are known to have a significant drug interaction with statin or aspirin [including cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor, telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole), clarithromycin and colchicine] will also be excluded from the trial. INTERVENTION AND COMPARATOR: In this study, the benefit and safety of atorvastatin (statin) and/or aspirin as adjuvant therapy will be compared with the control group receiving usual care for management of COVID-19. Atorvastatin will be prescribed as 40 mg oral tablets once daily for ten days or until discharge, whichever is earlier. The dose of aspirin will be 75 mg once daily for ten days or until discharge, whichever is earlier. All other therapies will be administered according to the institute's COVID-19 treatment protocol and the treating physician's clinical judgment. MAIN OUTCOMES: All study participants will be prospectively followed up for ten days or until hospital discharge, whichever is longer for outcomes. The primary outcome will be clinical deterioration characterized by progression to WHO clinical improvement ordinal score ≥ 6 (i.e., endotracheal intubation, non-invasive mechanical ventilation, pressor agents, renal replacement therapy, ECMO requirement, and mortality). The secondary outcomes will be change in serum inflammatory markers (C-reactive protein and Interleukin-6), Troponin I, and creatine phosphokinase (CPK) from time zero to 5th day of study enrolment or 7th day after symptom onset, whichever is later. Other clinical outcomes that will be assessed include progression to Acute Respiratory Distress Syndrome (ARDS), shock, ICU admission, length of ICU admission, length of hospital admission, and in-hospital mortality. Adverse drug effects like myalgia, myopathy, rhabdomyolysis, hepatotoxicity, and bleeding will also be examined in the trial to assess the safety of the interventions. RANDOMISATION: The study will use a four-arm parallel-group design. A computer-generated permuted block randomization with mixed block size will be used to randomize the participants in a 1:1:1:1 ratio to group A (atorvastatin with conventional therapy), group B (aspirin with conventional therapy), group C (aspirin + atorvastatin with conventional therapy), and group D (control; only conventional therapy). BLINDING (MASKING): The study will be an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): As there is no existing study that has evaluated the role of aspirin and atorvastatin in COVID-19 patients, formal sample size calculation has not been done. Patients satisfying the inclusion and exclusion criteria will be recruited during six months of study period. Once the first 200 patients are included in each arm (i.e., total 800 patients), the final sample size calculation will be done on the basis of the interim analysis of the collected data. TRIAL STATUS: The institutional ethical committee has approved the study protocol (Protocol version 3.0 [June 2020]). Participant recruitment starting date: 28th July 2020 Participant recruitment ending date: 27th January 2021 Trial duration: 6 months TRIAL REGISTRATION: The trial has been prospectively registered in Clinical Trial Registry - India (ICMR- NIMS): Reference no. CTRI/2020/07/026791 (registered on 25 July 2020)]. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Aspirina/uso terapêutico , Atorvastatina/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Aspirina/efeitos adversos , Atorvastatina/efeitos adversos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Índia , Masculino , Pessoa de Meia-Idade , Pandemias , Inibidores da Agregação de Plaquetas/efeitos adversos , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(40): e22572, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019469

RESUMO

RATIONALE: Atorvastatin is the most common drug used in therapy for cardiovascular diseases. The most common adverse side effects associated with statins are myopathy and hypertransaminasemia. Here, we report a rare case of gamma glutamyl transpeptidase (GGT) elevation induced by atorvastatin. PATIENT CONCERNS: A 47-year-old male was admitted to our hospital with dyslipidemia, he had been taking pitavastatin 2 mg/day for 2 months. The levels of total cholesterol (265.28 mg/dL) and low-density lipoprotein-cholesterol (LDL) (179.15 mg/dL) were also high. DIAGNOSIS: Blood lipid test showed mixed dyslipidemia. INTERVENTION: Atorvastatin 10 mg/day was given to the patient. OUTCOMES: The patient came back to our hospital for blood tests after 4 weeks. Although no symptoms were detectable, the patient's GGT level was markedly elevated (up to 6-fold over normal level) with less marked increases in alkaline phosphatase (ALP) and alanine aminotransferase (ALT). The serum GGT level returned to normal within 6 weeks of cessation of atorvastatin. LESSONS: This is a case of GGT elevation without hyperbilirubinemia, hypertransaminasemiam, or serum creatine phosphokinase (CPK) abnormalities despite an atorvastatin regimen. This case highlights GGT elevation caused by atorvastatin, a rare but serious condition. Clinicians should be aware of these possible adverse effects and monitor liver function tests in patients on statin therapy.


Assuntos
Atorvastatina/efeitos adversos , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Quinolinas/efeitos adversos , gama-Glutamiltransferase/efeitos dos fármacos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Atorvastatina/administração & dosagem , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/diagnóstico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Suspensão de Tratamento , gama-Glutamiltransferase/sangue
3.
Medicine (Baltimore) ; 99(40): e22616, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019482

RESUMO

RATIONALE: Neuromyelitis optica spectrum disorders (NMOSDs) are inflammatory demyelinating disorders of the central nervous system; they are characterized by severe optic neuritis and transverse myelitis. Intravenous methylprednisolone pulse (IVMP) therapy is an effective treatment that is administered to patients in the acute phase of NMOSD; this therapy has achieved remarkable results in clinical practice. However, there are no reports on NMOSD patients who have experienced an acute bilateral cerebral infarction while undergoing IVMP treatment. PATIENT CONCERNS: We report on a 62-yr-old woman who was undergoing IVMP therapy for the primary diagnosis of NMOSD. Unexpectedly, the patient's existing limb weakness worsened, and she developed motor aphasia on the second day of IVMP treatment. Additionally, brain magnetic resonance imaging revealed acute bilateral cerebral infarction. DIAGNOSIS: The patient's clinical manifestations, medical imaging results, and laboratory test results were taken into consideration; the final diagnosis was acute bilateral cerebral infarction in the presence of NMOSD. INTERVENTIONS: Subsequent to the onset of acute cerebral infarction, the patient was immediately treated with oral aspirin, atorvastatin, and intravenous butylphthalide. The hormone dose was adjusted to an oral 60-mg/d dose for maintenance; this was followed by immunoadsorption plasmapheresis for 3 days, and double-filtration plasmapheresis for 2 days. OUTCOMES: Following treatment onset, the patient's ocular symptoms significantly improved, and her limb muscle strength gradually recovered. Two months after discharge, the patient's husband reported that she was able to walk with the help of others and take care of herself, and that there was no recurrence. LESSONS: Medical professionals must be aware of the possibility of NMOSD patients with cerebrovascular risk factors suffering an acute cerebral infarction while undergoing high-dose IVMP therapy, as this therapy can exacerbate existing problems.


Assuntos
Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Doença Aguda , Administração Intravenosa , Administração Oral , Anticolesterolemiantes/uso terapêutico , Afasia de Broca/induzido quimicamente , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Atorvastatina/uso terapêutico , Benzofuranos/administração & dosagem , Benzofuranos/uso terapêutico , Infarto Cerebral/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Plasmaferese/métodos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Resultado do Tratamento
4.
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
5.
PLoS One ; 15(9): e0238575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941476

RESUMO

OBJECTIVE: Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. DESIGN: Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. METHODS: We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. RESULTS: Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. CONCLUSIONS: The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. CLINICAL TRIALS REGISTRATION: NCT02577042.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Imunossenescência/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Raltegravir Potássico/administração & dosagem
9.
Cochrane Database Syst Rev ; 7: CD013268, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668027

RESUMO

BACKGROUND: Asthma is a common chronic respiratory disease. People with asthma have inflammation of their airways that causes recurrent episodes of wheezing, breathlessness and chest tightness, with or without a cough. Statins possess multiple therapeutic effects, including lowering lipid levels in the blood. Statins are reported to have a potential role as an adjunct treatment in asthma. However, comprehensive evidence of the benefits and harms of using statins is required to facilitate decision making. OBJECTIVES: To assess the benefits and harms of statins as an adjunct therapy for asthma in adults and children. SEARCH METHODS: We searched for studies in the Cochrane Airways Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid SP and Embase Ovid SP, from their inception dates We handsearched the proceedings of major respiratory conferences. We also searched clinical trials registries for completed, ongoing and unpublished studies, and scanned the reference lists of included studies and relevant reviews to identify additional studies. The search is current to 7 February 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a parallel-group design that assessed statins for at least 12 weeks' duration. We considered all participants with a clinical diagnosis of asthma to be eligible, regardless of age, sex, disease severity and previous or current treatment. We planned to include studies reported as full text, those published as abstract only, and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected the studies, extracted outcome data and intervention characteristics from included studies, and assessed risk of bias according to standard Cochrane methodological procedures. We resolved any disagreement through discussion. MAIN RESULTS: We found only one trial involving a total of 60 people living with asthma. The trial compared the effect of atorvastatin with a placebo (dummy treatment containing lactose) in treating people with chronic asthma. The trial did not report data for the primary outcomes or adverse events. There was uncertainty about the relative effect on forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) in the atorvastatin group compared with the placebo group. The study did not report serious adverse effects for the interventions. The included study had internal discrepancies in its reported data. AUTHORS' CONCLUSIONS: The evidence was of very low certainty, so we are unable to draw conclusions about the effectiveness and safety of statins to treat asthma. High-quality RCTs are needed to assess the effect of statins on people with asthma. Well-designed multicentre trials with larger samples and longer duration of treatment are required, which assess outcomes such as adverse events, hospital utilisation and costs, to provide better quality evidence. Future studies that include subgroups of obese people with asthma are also required.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pico do Fluxo Expiratório/efeitos dos fármacos
11.
Arch Biochem Biophys ; 689: 108470, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32592802

RESUMO

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Ratos
12.
Nat Commun ; 11(1): 2622, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457361

RESUMO

Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.


Assuntos
Aterosclerose/tratamento farmacológico , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Macrófagos/metabolismo , Nanopartículas/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/metabolismo , Atorvastatina/uso terapêutico , Materiais Biomiméticos , Membrana Celular/metabolismo , Liberação Controlada de Fármacos , Feminino , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento
13.
PLoS One ; 15(5): e0233230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428019

RESUMO

INTRODUCTION: Atorvastatin-80mg/day and Rosuvastatin-40mg/day are the commonest high-dose statin (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) regimes for post-PCI (Percutaneous Coronary Interventions) patients to lower (by ≥50%) blood low-density-lipoprotein cholesterol (LDL-C). Dearth of conclusive evidence from developing world, regarding overall safety, tolerability and comparative effectiveness (outcome/safety/tolerability/endothelial inflammation control) of Rosuvastatin over Atorvastatin in high-dose, given its higher cost, called for an overall and comparative assessment among post-PCI patients in a tertiary cardiac-care hospital of Kolkata, India. METHODS: A record-based non-concurrent cohort study was conducted involving 942 post-PCI patients, aged 18-75 years, on high-dose statin for three months and followed up for ≥one year. Those on Atorvastatin-80mg (n = 321) and Rosuvastatin-40mg (n = 621) were compared regarding outcome (death/non-fatal myocardial infarction: MI/repeated hospitalization/target-vessel revascularisation/control of LDL and high-sensitivity C-reactive protein: hsCRP), safety (transaminitis/myopathy/myalgia/myositis/rhabdomyolysis), tolerability (gastroesophageal reflux disease: GERD/gastritis) and inflammation control adjusting for socio-demographics, tobacco-use, medications and comorbidities using SAS-9.4. RESULTS: Groups varied minimally regarding distribution of age/gender/tobacco-use/medication/comorbidity/baseline (pre-PCI) LDL and hs-CRP level. During one-year post-PCI follow up, none died. One acute MI and two target vessel revascularizations occurred per group. Repeated hospitalization for angina/stroke was 2.18% in Atorvastatin group vs. 2.90% in Rosuvastatin group. At three-months follow up, GERD/Gastritis (2.18% vs 4.83%), uncontrolled hs-CRP (22.74% vs 31.08%) and overall non-tolerability (4.67% vs. 8.21%) were lower for Atorvastatin group. Multiple logistic regression did show that compared to Atorvastatin-80mg, Rosuvastatin-40mg regime had poorer control of hs-CRP (A3OR = 1.45,p = 0.0202), higher (A3OR = 2.07) adverse effects, poorer safety profile (A3OR = 1.23), higher GERD/Gastritis (A3OR = 1.50) and poorer overall tolerability (A3OR = 1.50). CONCLUSION: Post-PCI high dose statins were effective, safe and well-tolerated. High dose Rosuvastatin as compared to high dose Atorvastatin were similar in their clinical efficacy. Patients treated with Atrovastatin had significantly lower number of patients with hs-CRP (high-sensitivity C-reactive protein)/C-reactive protein (CRP) level beyond comparable safe limit and relatively better tolerated as opposed to Rosuvastatin-40mg.Thus given the lower price, Atorvastatin 80mg/day appeared to be more cost-effective. A head-to-head cost-effectiveness as well as efficacy trial may be the need of the hour.


Assuntos
Atorvastatina/uso terapêutico , Lipoproteínas LDL/efeitos dos fármacos , Rosuvastatina Cálcica/uso terapêutico , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Refluxo Gastroesofágico , Coração , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea/métodos , Resultado do Tratamento , Triglicerídeos/sangue
14.
Toxicol Appl Pharmacol ; 396: 114997, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259528

RESUMO

High-fat high-fructose diet (HFF) in obesity can induce dyslipidemia and lipid accumulation both in kidney and liver which related to insulin resistance and lipotoxicity-induced cellular damage. We investigated whether dapagliflozin with or without atorvastatin could improve lipid accumulation-induced kidney and liver injury in HFF-induced insulin resistant rats. Male Wistar rats were fed with HFF for 16 weeks and then received drug treatments for 4 weeks; vehicle, dapagliflozin, atorvastatin and dapagliflozin plus atorvastatin treatment groups. HFF rats demonstrated insulin resistance, dyslipidemia, liver injury and renal dysfunction associated with impaired renal lipid metabolism and lipid accumulation. Dapagliflozin and combination treatment could improve HFF-induced insulin resistance, lipogenesis and lipotoxicity-related renal oxidative stress, inflammation, fibrosis and apoptosis leading to kidney dysfunction recovery. Liver injury-associated inflammation was also improved by these two regimens. Notably, the reduced lipid accumulation in liver and kidney that linked to an improvement of lipid oxidation was prominent in the combination treatment. Therefore, dapagliflozin combined with atorvastatin treatment exert the beneficial effects on lipid metabolism and lipotoxicity in liver and kidney injury via the attenuation of oxidative stress, fibrosis and apoptosis in insulin resistant model.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Atorvastatina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Frutose/efeitos adversos , Glucosídeos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Animais , Atorvastatina/administração & dosagem , Compostos Benzidrílicos/administração & dosagem , Western Blotting , Carboidratos da Dieta/farmacologia , Quimioterapia Combinada , Frutose/farmacologia , Glucosídeos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Ratos , Ratos Wistar
15.
Epilepsia ; 61(3): 359-386, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32196665

RESUMO

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.


Assuntos
Anticonvulsivantes/uso terapêutico , Antioxidantes/uso terapêutico , Epilepsia Pós-Traumática/prevenção & controle , Epilepsia/prevenção & controle , GABAérgicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acetilcisteína/uso terapêutico , Animais , Atorvastatina/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Ceftriaxona/uso terapêutico , Dibenzazepinas/uso terapêutico , Reposicionamento de Medicamentos , Epilepsia/etiologia , Eritropoetina/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Isoflurano/uso terapêutico , Levetiracetam/uso terapêutico , Losartan/uso terapêutico , Estresse Oxidativo , Pregabalina/uso terapêutico , Pirrolidinonas/uso terapêutico , Sirolimo/uso terapêutico , Acidente Vascular Cerebral/complicações , Topiramato/uso terapêutico , Pesquisa Médica Translacional , Vigabatrina/uso terapêutico
16.
Eur J Clin Pharmacol ; 76(3): 419-430, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897532

RESUMO

PURPOSE: Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. METHODS: The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. RESULTS: There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). CONCLUSION: The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.


Assuntos
Atorvastatina/uso terapêutico , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Sistema Enzimático do Citocromo P-450/genética , Polimorfismo Genético/genética , Rosuvastatina Cálcica/uso terapêutico , Alelos , Anticolesterolemiantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Feminino , Genótipo , Humanos , Isoenzimas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/uso terapêutico
17.
Cancer Res ; 80(6): 1293-1303, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31969375

RESUMO

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. SIGNIFICANCE: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , MAP Quinase Quinase 5/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Colesterol/biossíntese , Técnicas de Silenciamento de Genes , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipidômica , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase 5/genética , Sistema de Sinalização das MAP Quinases/genética , Ácido Mevalônico/metabolismo , Camundongos , Proteína Quinase 7 Ativada por Mitógeno/genética , RNA-Seq , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Expert Opin Pharmacother ; 21(4): 435-444, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31957506

RESUMO

Introduction: Chronic subdural hematoma (CSDH) is a common neurosurgical disease, whose incidence has been steadily increasing with our aging population. While not common, CSDH can also occur in children. CSDH is often associated with traumatic head injury, but its underlying mechanism remains poorly understood. The first line treatment for CSDH is surgery. However, surgery is contraindicated in some patients and has a high rate of recurrence. Effective non-surgical treatment is therefore highly desirable.Areas covered: This review discusses the pathogenesis of CSDH and drugs that have been used to treat CSDH either as monotherapy or an adjuvant to surgery, including controlled clinical trials.Expert opinion: The pathophysiology of CSDH remains poorly understood. Developing effective drug treatments is therefore challenging. Most drugs discussed in this review are evaluated in small clinical studies without sufficient sample size and controls for confounding variables. More controlled clinical trials are therefore needed to carefully evaluate drugs for the non-surgical treatment of CSDH, especially for drugs targeting specific pathogenic pathways of CSDH.


Assuntos
Hematoma Subdural Crônico/tratamento farmacológico , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Atorvastatina/administração & dosagem , Atorvastatina/uso terapêutico , Diuréticos/administração & dosagem , Diuréticos/uso terapêutico , Hematoma Subdural Crônico/epidemiologia , Hematoma Subdural Crônico/etiologia , Humanos , Incidência , Recidiva , Resultado do Tratamento
19.
Life Sci ; 245: 117349, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981632

RESUMO

AIMS: To explore whether the combination of atorvastatins and resveratrol is superior to each individual drug alone regarding re-endothelialization after drug-eluting stents (DESs) implantation. MATERIALS AND METHODS: Ninety-four rabbits were randomized into control, atorvastatin, resveratrol, and combined medication groups. Abdominal aorta injury was induced via ballooning, followed by DES implantation. Neointimal formation and re-endothelialization after stent implantation were assessed via optical coherence tomography and scanning electron microscopy. The effects of resveratrol and atorvastatin on bone marrow-derived mesenchymal derived stem cells (BMSCs) were assessed. KEY FINDINGS: Compared with the findings in the resveratrol and atorvastatin groups, the neointimal area and mean neointimal thickness were greater in the combined medication group, which also exhibited improved re-endothelialization. Compared with the effects of monotherapy, combined treatment further protected BMSCs against rapamycin-induced apoptosis and improved cell migration. Combined medication significantly upregulated Akt, p-Akt, eNOS, p-eNOS, and CXCR4 expression in BMSCs compared with the effects of monotherapy, and these effects were abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. SIGNIFICANCE: The combination of atorvastatin and resveratrol has the potential of accelerating re-endothelialization after stent implantation, reducing the risk of thrombosis and improving the safety of DESs.


Assuntos
Atorvastatina/uso terapêutico , Implante de Prótese Vascular/métodos , Stents Farmacológicos , Endotélio Vascular/efeitos dos fármacos , Resveratrol/uso terapêutico , Animais , Aorta Abdominal/cirurgia , Aorta Abdominal/ultraestrutura , Atorvastatina/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/ultraestrutura , Hylobatidae , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Coelhos , Ratos , Ratos Sprague-Dawley , Resveratrol/administração & dosagem , Tomografia de Coerência Óptica
20.
Arterioscler Thromb Vasc Biol ; 40(3): 714-732, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996022

RESUMO

OBJECTIVE: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1ß (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1ß mRNA, and increased Rac1-dependent IL-1ß protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1ß expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2). CONCLUSIONS: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1ß signaling axis.


Assuntos
Aterosclerose/tratamento farmacológico , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Macrófagos/efeitos dos fármacos , Neuropeptídeos/metabolismo , Placa Aterosclerótica , Calcificação Vascular/enzimologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Idoso , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Camundongos Knockout para ApoE , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Prenilação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Calcificação Vascular/genética , Calcificação Vascular/patologia , Proteínas rac1 de Ligação ao GTP/deficiência , Proteínas rac1 de Ligação ao GTP/genética , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA