RAUL CAVALCANTE MARANHAO
Projetos de Pesquisa
Unidades Organizacionais
FBC, FCF - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
37 resultados
Resultados de Busca
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- Plasma kinetics of an LDL-like nanoemulsion and lipid transfer to HDL in subjects with glucose intolerance(2012) BERTATO, Marina P.; OLIVEIRA, Carolina P.; WAJCHENBERG, Bernardo L.; LERARIO, Antonio C.; MARANHAO, Raul C.OBJECTIVE: Glucose intolerance is frequently associated with an altered plasma lipid profile and increased cardiovascular disease risk. Nonetheless, lipid metabolism is scarcely studied in normolipidemic glucose-intolerant patients. The aim of this study was to investigate whether important lipid metabolic parameters, such as the kinetics of LDL free and esterified cholesterol and the transfer of lipids to HDL, are altered in glucose-intolerant patients with normal plasma lipids. METHODS: Fourteen glucose-intolerant patients and 15 control patients were studied; none of the patients had cardiovascular disease manifestations, and they were paired for age, sex, race and co-morbidities. A nanoemulsion resembling a LDL lipid composition (LDE) labeled with C-14-cholesteryl ester and H-3-free cholesterol was intravenously injected, and blood samples were collected over a 24-h period to determine the fractional clearance rate of the labels by compartmental analysis. The transfer of free and esterified cholesterol, triglycerides and phospholipids from the LDE to HDL was measured by the incubation of the LDE with plasma and radioactivity counting of the supernatant after chemical precipitation of non-HDL fractions. RESULTS: The levels of LDL, non-HDL and HDL cholesterol, triglycerides, apo A1 and apo B were equal in both groups. The 14 C-esterified cholesterol fractional clearance rate was not different between glucose-intolerant and control patients, but the H-3-free- cholesterol fractional clearance rate was greater in glucose-intolerant patients than in control patients. The lipid transfer to HDL was equal in both groups. CONCLUSION: In these glucose-intolerant patients with normal plasma lipids, a faster removal of LDE free cholesterol was the only lipid metabolic alteration detected in our study. This finding suggests that the dissociation of free cholesterol from lipoprotein particles occurs in normolipidemic glucose intolerance and may participate in atherogenic signaling.
- Organic effects of associating paclitaxel with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella(2017) FEIO, Danielle Cristinne Azevedo; OLIVEIRA, Nayara Cristina Lima de; PEREIRA, Edmundo Luis Rodrigues; MORIKAWA, Aleksandra Tiemi; MUNIZ, Jose Augusto Pereira Carneiro; MONTENEGRO, Raquel Carvalho; ALVES, Ana Paula Negreiros Nunes; LIMA, Patricia Danielle Lima de; MARANHAO, Raul Cavalcante; BURBANO, Rommel RodriguezLipid-based nanoparticle systems have been used as vehicles for chemotherapeutic agents in experimental cancer treatments. Those systems have generally been credited with attenuating the severe toxicity of chemotherapeutic agents. This study aimed to investigate the effects of associating paclitaxel (PTX) with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella, documenting the toxicity as measured by serum biochemistry, which is a detailed analysis of blood and tissue. Eighteen C. apella were studied: three animals were treated with cholesterol-rich nanoemulsion (LDE) only, without PTX, administered intravenously every 3 weeks, during six treatment cycles; six animals were treated with PTX associated with LDE at the same administration scheme, three with lower (175 mg/m(2)) and three with higher (250 mg/m(2)) PTX doses; and six animals were treated with commercial PTX, three with the lower and three with the higher doses. In the LDE-PTX group, no clinical toxicity appeared, and the weight-food consumption curve was similar to that of the controls. Two animals treated with commercial PTX presented weight loss, nausea and vomiting, diarrhea, skin flaking, 70% loss of body hair, and decreased physical activity. The use of LDE as a carrier at both lower and higher doses reduced the toxicity of the drug in this species, which is closely related to human subjects. This was observed not only by clinical, biochemical, and hematological profiles but also by the histopathological analysis. The results of this study support the assumption that lipid-based nanoparticle systems used as drug carriers can serve as valuable tools to decrease the toxicity and increase the safety of chemotherapeutic agents.
- Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine lymphoma(2015) LUCAS, S. R. R.; MARANHAO, R. C.; GUERRA, J. L.; COELHO, B. M. P.; BARBOZA, R.; POZZI, D. H. B.A lipid nanoemulsion (LDE) resembling low-density lipoprotein can target malignant tumours. In in vivo and clinical studies, association of chemotherapeutic agents to LDE decreased their toxicity and increased pharmacological action. Here, safety of LDE as carmustine carrier (50 mg m(-2), intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone. In five dogs from LDE-carmustine and six from commercial carmustine, complete remission was achieved (P > 0.05). Partial remission occurred in two dogs from each group. In both groups, the median progression-free intervals (119 and 199 days) and overall survival times (207 and 247 days) were equal. Neutropenia was observed in both groups, but no other major toxicities occurred. Therefore, no difference was observed between the treatments. LDE-carmustine was shown to be safe and effective in a drug combination protocol, which encourages larger studies to investigate the use of this novel formulation to treat canine lymphomas.
- Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions(2011) TAVARES, Elaine R.; FREITAS, Fatima R.; DIAMENT, Jayme; MARANHAO, Raul C.Objectives: Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated. Methods: Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections. Results: LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase II alpha and tubulin). Conclusion: The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.
- Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles(2016) SHIOZAKI, Afonso A.; SENRA, Tiago; MORIKAWA, Aleksandra T.; DEUS, Debora F.; PALADINO-FILHO, Antonio T.; PINTO, Ibraim M. F.; MARANHAO, Raul C.OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m(2) body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.
- Lipoprotein removal mechanisms and aging: implications for the cardiovascular health of the elderly(2020) MARANHAO, Raul C.; PALA, Daniela; FREITAS, Fatima R.Purpose of review The speed of removal from the plasma of apolipoprotein B-containing lipoproteins, for example, chylomicrons, VLDL and LDL is determinant of the plasma concentration of these lipoproteins, is influenced by genetic features and ambient factors, and has implications in atherogenesis. As aging increases the clinical complications of atherosclerosis, it is important to appraise the status of the removal mechanisms in elderly individuals. Recent findings Removal of triglyceride-rich lipoproteins remnants is delayed but the triglyceride breakdown is unchanged in elderly individuals. The discovery of PCSK9, enzyme that degrades LDL receptors, and the recent observation that PCSK9 is elevated in the elderly raises another hypothesis to account for the increased LDL-cholesterol levels in the elderly. The removal of cholesterol from cells by HDL, the first step of cholesterol reverse transport is also less efficient in the elderly, which may compromise the body cholesterol homeostasis. Aging determines reduction of the efficiency of lipoprotein plasma removal mechanisms, which is implicated in increased incidence of cardia complications. Moreover, aging is frequently accompanied by physical activity reduction, weight gain, and metabolic disturbances that can further decrease the efficacy of the removal mechanisms. This knowledge is important for promoting cardiovascular health in the elderly and prolonging survival.
- Human Paraoxonase-1 Activity Is Related to the Number of CD4+T-Cells and Is Restored by Antiretroviral Therapy in HIV-1-Infected Individuals(2014) MASELLI, Luciana Morganti Ferreira; CUNHA, Joel da; GUTIERREZ, Eliana Battaggia; MARANHAO, Raul Cavalcante; SPADA, Celso; BYDLOWSKI, Sergio PauloBackground. Paraoxonase-1 (PON1) activity is suggested to be altered in individuals infected with human immunodeficiency virus type-1 (HIV-1). We investigated PON1 activity in individuals receiving different regimens of highly active antiretroviral therapy (HAART). Methods. PON1 activity was evaluated in 91 HIV-1 seronegative and 624 HIV-1 infected individuals (115 were not undergoing therapy (ART-naive), and 509 were receiving HAART). HIV-1 infected individuals were treated with the following: efavirenz (EFV;n = 195) or nevirapine (NVP;n = 95) or lopinavir/ritonavir (LOP/r; n = 219). Serum levels of total cholesterol (TC), HDL, and low-density lipoprotein (LDL) fractions and the atherogenic indices (AI, TC : HDL, and LDL : HDL ratios) were determined. Results. PON1 activity (U/L) was lower in the ART-naive group compared with the other groups. PON1 activity correlated with CD4+ T-cell number of ART-naive group (r = 0, 121; P = 0, 014). The LOP/r group showed a reduction in HDL and an increase in AI (TC: HDL ratio) in comparison with other groups. Conclusion. PON1 activity was reduced in untreated individuals, but not in individuals receiving HAART. PON1 activity correlated with the number of CD4+ T-cells. The findings suggest that the activity of PON1 is associated with the immune status of HIV-1 infected individuals.
- An artificial nanoemulsion carrying paclitaxel decreases the transplant heart vascular disease: A study in a rabbit graft model(2011) LOURENCO-FILHO, Domingos D.; MARANHAO, Raul C.; MENDEZ-CONTRERAS, Carlos A.; TAVARES, Elaine R.; FREITAS, Fatima R.; STOLF, Noedir A.Objective: In previous studies cholesterol-rich nanoemulsions (LDE) resembling low-density lipoprotein were shown to concentrate in atherosclerotic lesions of rabbits. Lesions were pronouncedly reduced by treatment with paclitaxel associated with LDE. This study aimed to test the hypothesis of whether LDE-paclitaxel is able to concentrate in grafted hearts of rabbits and to ameliorate coronary allograft vasculopathy after the transplantation procedure. Methods: Twenty-one New Zealand rabbits fed 0.5% cholesterol were submitted to heterotopic heart transplantation at the cervical position. All rabbits undergoing transplantation were treated with cyclosporin A (10 mg . kg(-1) . d(-1) by mouth). Eleven rabbits were treated with LDE-paclitaxel (4 mg/kg body weight paclitaxel per week administered intravenously for 6 weeks), and 10 control rabbits were treated with 3 mL/wk intravenous saline. Four control animals were injected with LDE labeled with [(14)C]-cholesteryl oleate ether to determine tissue uptake. Results: Radioactive LDE uptake by grafts was 4-fold that of native hearts. In both groups the coronary arteries of native hearts showed no stenosis, but treatment with LDE-paclitaxel reduced the degree of stenosis in grafted hearts by 50%. The arterial luminal area in grafts of the treated group was 3-fold larger than in control animals. LDE-paclitaxel treatment resulted in a 7-fold reduction of macrophage infiltration. In grafted hearts LDE-paclitaxel treatment reduced the width of the intimal layer and inhibited the destruction of the medial layer. No toxicity was observed in rabbits receiving LDE-paclitaxel treatment. Conclusions: LDE-paclitaxel improved posttransplantation injury to the grafted heart. The novel therapeutic approach for heart transplantation management validated here is thus a promising strategy to be explored in future clinical studies. (J Thorac Cardiovasc Surg 2011;141:1522-8)
- Treatment With Methotrexate Associated With Lipid Core Nanoparticles Prevents Aortic Dilation in a Murine Model of Marfan Syndrome(2022) GUIDO, Maria Carolina; LOPES, Natalia de Menezes; ALBUQUERQUE, Camila Inagaki; TAVARES, Elaine Rufo; JENSEN, Leonardo; CARVALHO, Priscila de Oliveira; TAVONI, Thauany Martins; DIAS, Ricardo Ribeiro; PEREIRA, Lygia da Veiga; LAURINDO, Francisco Rafael Martins; MARANHAO, Raul CavalcanteIn Marfan syndrome (MFS), dilation, dissection, and rupture of the aorta occur. Inflammation can be involved in the pathogenicity of aortic defects and can thus be a therapeutic target for MFS. Previously, we showed that the formulation of methotrexate (MTX) associated with lipid nanoparticles (LDE) has potent anti-inflammatory effects without toxicity. To investigate whether LDEMTX treatment can prevent the development of aortic lesions in the MFS murine model. Mg Delta loxPneo MFS (n = 40) and wild-type (WT, n = 60) mice were allocated to 6 groups weekly injected with IP solutions of: (1) only LDE; (2) commercial MTX; (3) LDEMTX (dose = 1mg/kg) between 3rd and 6th months of life. After 12 weeks of treatments, animals were examined by echocardiography and euthanatized for morphometric and molecular studies. MFS mice treated with LDEMTX showed narrower lumens in the aortic arch, as well as in the ascending and descending aorta. LDEMTX reduced fibrosis and the number of dissections in MFS but not the number of elastic fiber disruptions. In MFS mice, LDEMTX treatment lowered protein expression of pro-inflammatory factors macrophages (CD68), T-lymphocytes (CD3), tumor necrosis factor-alpha (TNF-alpha), apoptotic factor cleaved-caspase 3, and type 1 collagen and lowered the protein expression of the transforming growth factor-beta (TGF-beta), extracellular signal-regulated kinases 1/2 (ERK1/2), and SMAD3. Protein expression of CD68 and CD3 had a positive correlation with an area of aortic lumen (r(2) = 0.36; p < 0.001), suggesting the importance of inflammation in the causative mechanisms of aortic dilation. Enhanced adenosine availability by LDEMTX was suggested by higher aortic expression of an anti-adenosine A2a receptor (A2a) and lower adenosine deaminase expression. Commercial MTX had negligible effects. LDEMTX prevented the development of MFS-associated aortic defects and can thus be a candidate for testing in clinical studies.
- Nanotechnology for the treatment of deep endometriosis: uptake of lipid core nanoparticles by LDL receptors in endometriotic foci(2019) BEDIN, Alessandra; MARANHAO, Raul C.; TAVARES, Elaine R.; CARVALHO, Priscila O.; BARACAT, Edmund C.; PODGAEC, SergioOBJECTIVE: Rapidly dividing cells in multiple types of cancer and inflammatory diseases undergo high low density lipoprotein (LDL) uptake for membrane synthesis, and coupling an LDL-like nanoemulsion, containing lipid nanoparticles (LDE) to a chemotherapeutic agent efficiently targets these cells without significant systemic effects. This was a prospective exploratory study that evaluated the uptake of a radioactively labeled LDE emulsion by receptors of endometriotic foci and the capacity of the LDE for cellular internalization. METHODS: The lipid profile of each patient was determined before surgery, and labeled LDE were injected into fourteen patients with intestinal or nonintestinal endometriosis. The radioactivity of each tissue sample (intestinal endometriosis, nonintestinal endometriosis, healthy peritoneum, or topical endometrium) was measured. RESULTS: The group with intestinal endometriosis presented higher levels of plasma LDL but lower LDE uptake by foci than the nonintestinal group, suggesting less cell division and more fibrosis. The uptake of LDE was highest in the topical endometrium, followed by the healthy peritoneum, and lowest in the endometriotic lesion. Since the endometriotic foci showed significant LDE uptake, there was likely increased consumption of LDL by these cells, similar to cells in cancers and inflammatory diseases. Plasma cholesterol levels had no influence on LDE uptake, which showed that the direct delivery of the nanoemulsion to target tissues was independent of serum lipoproteins. There were no significant differences in the parameters (p > 0.01) because of the small sample size, but the findings were similar to those of previous studies. CONCLUSION: Nanotechnology is a promising therapeutic option for surgery and hormonal blockage for deep endometriosis, with a lower complication rate and no systemic side effects.