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1.
PLoS One ; 15(1): e0227637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929574

RESUMO

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Antiobesidade/farmacologia , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Fármacos Antiobesidade/química , Dieta Hiperlipídica , Modelos Animais de Doenças , Quimioterapia Combinada , Hesperidina/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Inflamação/metabolismo , Inflamação/patologia , Leptina/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Obesidade/metabolismo , Obesidade/patologia , Orlistate/química , Orlistate/farmacologia , Ratos Wistar
3.
J Chromatogr A ; 1609: 460443, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31416624

RESUMO

In the present study, during removal of minor impurities by twin-column recycling chromatography with a solvent gradient, a compressing band effect was generated to offset band spreading and retain the principal component band within one column. For real-time monitoring, a detector was mounted on-line after the upstream column to monitor when the tail of the principal component was eluted from this column. When the conditions fluctuated, the column were switched to ensure successful separation without the need to determine the adsorption equilibrium in advance. Optimization of the operating conditions revealed that increasing the solvent gradient improved pre-impurity separation but impeded post-impurity removal. Changing the feed volume within a certain range hardly affected separation of the impurities, and increasing the number of cycles enhanced separation of the impurities.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Solventes/química , Adsorção , Orlistate/análise , Análise de Componente Principal , Água/química
4.
Mar Drugs ; 17(9)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540318

RESUMO

This study investigated the anti-obesity effect of a polysaccharide-rich red algae Gelidium amansii hot-water extract (GHE) in high-fat (HF) diet-induced obese hamsters. GHE contained 68.54% water-soluble indigestible carbohydrate polymers. Hamsters were fed with a HF diet for 5 weeks to induce obesity, and then randomly divided into: HF group, HF with 3% guar gum diet group, HF with 3% GHE diet group, and HF with orlistat (200 mg/kg diet) group for 9 weeks. The increased weights of body, liver, and adipose in the HF group were significantly reversed by GHE supplementation. Lower plasma leptin, tumor necrosis factor-α, and interleukin-6 levels were observed in the GHE+HF group compared to the HF group. GHE also increased the lipolysis rate and decreased the lipoprotein lipase activity in adipose tissues. GHE induced an increase in the phosphorylation of AMP-activated protein kinase (AMPK) and the protein expressions of peroxisome proliferator-activated receptor alpha (PPARα) and uncoupling protein (UCP)-2 in the livers. The decreased triglyceride and total cholesterol in the plasma and liver were also observed in obese hamsters fed a diet with GHE. These results suggest that GHE exerts a down-regulation effect on hepatic lipid metabolism through AMPK phosphorylation and up-regulation of PPARα and UCP-2 in HF-induced obese hamsters.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Suplementos Nutricionais , Obesidade/dietoterapia , Extratos Vegetais/administração & dosagem , Rodófitas/química , Adenilato Quinase/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mesocricetus , Obesidade/etiologia , Orlistate/administração & dosagem , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Proteína Desacopladora 2/metabolismo , Regulação para Cima/efeitos dos fármacos , Água/química
5.
Int J Clin Pract ; 73(11): e13399, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397946

RESUMO

AIMS: To evaluate in a real-world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. METHODS: Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with at least a weight-related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification. The co-primary end-points, assessed at 3-6 months and at the end of the follow-up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs. RESULTS: Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included. Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low-density lipoprotein-cholesterol and alanine transaminase over a median follow-up period of 7 months. WL with liraglutide (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. CONCLUSIONS: In this real-world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Adulto , Estudos de Coortes , Feminino , Humanos , Lactonas/uso terapêutico , Estilo de Vida , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Orlistate/efeitos adversos , Sobrepeso/tratamento farmacológico , Estudos Retrospectivos , Perda de Peso/efeitos dos fármacos
6.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398944

RESUMO

The inhibition of recombinant CpLIP2 lipase/acyltransferase from Candida parapsiolosis was considered a key model for novel antifungal drug discovery and a potential therapeutic target for candidiasis. Lipases have identified recently as potent virulence factors in C. parapsilosis and some other yeasts. The inhibition effects of orlistat and four flavonols (galangin, kaempferol, quercetin and myricetin) characterized by an increasing degree of hydroxylation in B-ring, were investigated using ethyl oleate hydrolysis as the model reaction. Orlistat and kaempferol (14 µM) strongly inhibited CpLIP2 catalytic activity within 1 min of pre-incubation, by 90% and 80%, respectively. The relative potency of flavonols as inhibitors was: kaempferol > quercetin > myricetin > galangin. The results suggested that orlistat bound to the catalytic site while kaempferol interacted with W294 on the protein lid. A static mechanism of interactions between flavonols and CpLIP2 lipase was confirmed by fluorescence quenching analyses, indicating that the interactions were mainly driven by hydrophobic bonds and electrostatic forces. From the Lehrer equation, fractions of tryptophan accessibility to the quencher were evaluated, and a relationship with the calculated number of binding sites was suggested.


Assuntos
Aciltransferases/antagonistas & inibidores , Aciltransferases/química , Flavonóis/química , Flavonóis/farmacologia , Algoritmos , Flavonoides , Hidrólise , Hidroxilação , Quempferóis , Modelos Teóricos , Estrutura Molecular , Orlistate/química , Orlistate/farmacologia , Ligação Proteica , Quercetina , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Termodinâmica
7.
Biomater Sci ; 7(10): 4273-4282, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31407729

RESUMO

Only a limited amount of orally administered lipid nanoparticles are absorbed as intact particles due to lipolysis by lipases in the gastrointestinal tract. It is hypothesized that by counteracting lipolysis, more particles will survive gastrointestinal digestion and be absorbed as intact particles. In this study, incorporation of a lipase inhibitor orlistat (OLST), as well as polyethylene glycol (PEG) coating, is employed to slow down the lipolysis using solid lipid nanoparticles (SLNs) as model particles. To explore the in vivo behaviors of the particles, near-infrared fluorescent probes with absolute aggregation-caused quenching (ACQ) properties are used to label and track the unmodified, PEG-coated and OLST-loaded SLNs. The in vitro lipolysis study indicates very fast first-order degradation of unmodified SLNs and significantly decreased degradation of OLST-SLNs. Live imaging reveals the same trend of slowed-down lipolysis in vivo which correlates well with the in vitro lipolysis. The scanning of ex vivo gastrointestinal segments confirms the considerably prolonged residence time of OLST-SLNs, mirroring the significantly decreased lipolysis rate. The observation of fluorescence in the blood, though very weak, and in the liver speaks of the oral absorption of intact SLNs. The substantially higher hepatic levels of OLST-SLNs than unmodified SLNs should be attributed to the significantly enhanced survival rate because both particles exhibit similar cellular recognition as well as similar physicochemical properties except for the survival rate. Similarly, slowing down lipolysis also contributes to the significantly enhanced cumulative lymphatic transport of OLST-SLNs (7.56% vs. 1.27% for the unmodified SLNs). The PEG coating slows down the lipolysis rate as well but not to the degree as done by OLST. As a result, the gastrointestinal residence time of PEG-SLNs has been moderately prolonged and the hepatic levels moderately increased. The weakened cellular recognition of PEG-SLNs implies that the enhanced oral absorption is solely ascribed to the slowed-down lipolysis and enhanced mucus penetration. In conclusion, the oral absorption of intact SLNs can be significantly enhanced by slowing down lipolysis, especially by OLST, showing potential as carriers for the oral delivery of labile biomacromolecules.


Assuntos
Reguladores do Metabolismo de Lipídeos/administração & dosagem , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Orlistate/administração & dosagem , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Reguladores do Metabolismo de Lipídeos/química , Reguladores do Metabolismo de Lipídeos/farmacocinética , Lipídeos/química , Lipídeos/farmacocinética , Lipólise/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/química , Orlistate/química , Orlistate/farmacocinética
8.
Acta Pharm ; 69(1): 1-16, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259721

RESUMO

Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT.


Assuntos
Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Pâncreas/metabolismo , Preparações Farmacêuticas/química , Animais , Orlistate/farmacologia , Relação Estrutura-Atividade , Suínos
9.
Anticancer Res ; 39(7): 3815-3822, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262909

RESUMO

BACKGROUND/AIM: Fatty acid synthase (FASN) provides palmitate for cell membrane formation in colorectal cancer (CRC) cells, however, palmitate is also available in the blood of CRC patients. The aim of this study was to examine whether orlistat, a FASN inhibitor, is able to attenuate CRC cell growth despite the availability of extracellular palmitate. MATERIALS AND METHODS: Palmitate concentrations were measured in serum from CRC patients and healthy controls. HT-29 CRC cells were treated with orlistat and palmitate. RESULTS: Treatment of CRC cells with orlistat caused a dose-dependent inhibition of cell proliferation. In turn, delivery of extracellular palmitate at doses lower than those found in the serum of CRC patients reversed inhibition by orlistat concentrations of up to 10 µM. CONCLUSION: Inhibition of CRC cell proliferation by orlistat is reversed by palmitate which is present at high levels in the serum. Therefore, orlistat may be effective in vivo only at high concentrations.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Orlistate/farmacologia , Palmitatos/sangue , Adulto , Idoso , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/sangue , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/genética , Feminino , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade
10.
Eur J Pharm Sci ; 135: 1-11, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067495

RESUMO

Obesity is a rapidly growing epidemic, with over one-third of the global population classified as overweight or obese. Consequently, an urgent need exists to develop innovative approaches and technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions of commercial clay platelets (Veegum® HS and LAPONITE® XLG), were delivered as complimentary, bioactive excipients with the potent lipase inhibitor, orlistat, for the inhibition of fat (lipid) hydrolysis. Simulated intestinal lipolysis studies were performed by observing changes in free fatty acid concentration and revealed that a combinatorial effect existed when NSC particles were co-administered with orlistat, as evidenced by a 1.2- to 1.6-fold greater inhibitory response over 60 min, compared to dosing orlistat alone. Subsequently, it was determined that a multifaceted approach to lipolysis inhibition was presented, whereby NSC particles adsorbed high degrees of lipid (up to 80% of all lipid species present in lipolysis media) and thus physically shielded the lipid-in-water interface from lipase access, while orlistat covalently attached and blocked the lipase enzyme active site. Thus, the ability for NSC particles to enhance the biopharmaceutical performance and potency of orlistat is hypothesised to translate into promising in vivo pharmacodynamics, where this novel approach is predicted to lead to considerably greater weight reductions for obese patients, compared to dosing orlistat alone.


Assuntos
Fármacos Antiobesidade/química , Argila/química , Lipase/antagonistas & inibidores , Lipídeos/química , Nanopartículas/química , Obesidade/tratamento farmacológico , Orlistate/química , Compostos de Alumínio/química , Fármacos Antiobesidade/administração & dosagem , Suplementos Nutricionais , Digestão , Ácidos Graxos/metabolismo , Humanos , Hidrólise , Absorção Intestinal , Lipase/química , Lipólise , Compostos de Magnésio/química , Orlistate/administração & dosagem , Tamanho da Partícula , Silicatos/química , Propriedades de Superfície
11.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(3): 140-149, mar. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-182613

RESUMO

La prevalencia de la obesidad se ha incrementado mundialmente en las últimas décadas. La obesidad se asocia a múltiples comorbilidades, como la diabetes tipo 2, que generan un gran impacto en la salud y en la economía. La pérdida de peso en este colectivo favorece el control glucémico, por lo que es uno objetivo a lograr. Los cambios en el estilo de vida son poco efectivos por sí solos, y en los últimos años se han desarrollado otras opciones terapéuticas como la cirugía bariátrica/metabólica, así como fármacos para la diabetes tipo 2 y fármacos para reducir peso en la obesidad. El objetivo de la revisión es la comparación de los resultados en reducción de peso y control glucémico de los distintos tipos de fármacos con los resultados de la cirugía bariátrica/metabólica en diabetes tipo 2


The prevalence of obesity has increased worldwide over the past decades. Obesity is associated with multiple comorbidities, such as type 2 diabetes, that generates a great impact on health and economy. Weight loss in these patients leads to glycemic control so it is a target to achieve. Lifestyle changes are not effective enough and recently other treatments have been developed such as bariatric/metabolic surgery, as well as drugs for type 2 diabetes and antiobesity drugs. The aim of this review is to compare the results in weight reduction and glycemic control of the different kinds of drugs with bariatric / metabolic surgery's results in type 2 diabetes


Assuntos
Humanos , Diabetes Mellitus Tipo 2/terapia , Obesidade/epidemiologia , Perda de Peso , Índice Glicêmico , Terapia Combinada/tendências , Cirurgia Bariátrica , Obesidade/tratamento farmacológico , Simportadores/administração & dosagem , Orlistate/administração & dosagem , Liraglutida/administração & dosagem , Naltrexona/administração & dosagem , Obesidade/fisiopatologia
12.
Int J Pharm ; 560: 377-384, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30790612

RESUMO

To face the challenges of oral delivery of peptide and protein (P/P) drugs, self-emulsifying drug delivery systems (SEDDSs) containing monoacyl phosphatidylcholine (MAPC), Labrasol (LAB) and medium-chain (MC) monoglycerides as permeation enhancers (PEs) were evaluated for their effect on intestinal absorption of insulin. In this study, insulin was complexed with phosphatidylcholine (SPC) to form an insulin-SPC complex (ins-SPC) with increased lipophilicity. The following three SEDDSs: MCT(MAPC) (MC triglycerides and MAPC included), MCT(RH40) (MC triglycerides and Kolliphor® RH40 included) and LCT(MAPC) (long-chain triglycerides and MAPC included) were loading with ins-SPC (4% or 8% w/w of SPC). Three SEDDSs generated emulsions with droplet sizes between 50 and 470 nm and with zeta potentials between -5 to -25 mV in a simulated intestinal medium. Mucus-secreting Caco-2/HT29-MTX-E12 co-culture and Caco-2 monolayers were used as in vitro cell transport models to investigate insulin permeability. In comparison to insulin HBSS solution, MCT(MAPC) significantly increased the insulin permeability across co-culture and Caco-2 monolayers (2.0-2.5 × 10-7 cm/s). In an intra-jejunal (i.j.) instillation model in rats, MCT(RH40) significantly decreased the rat blood glucose after 0.5 h by 17.0 ±â€¯2.5% and for MCT(MAPC), it was 23.6 ±â€¯10.6%. Furthermore, a lipase inhibitor orlistat was incorporated into MCT(MAPC) to evaluate the effect of lipid digestion on insulin absorption. Results indicated that the incorporation of orlistat did not significantly alter the in vivo insulin absorption. Overall, the SEDDS MCT(MAPC) composed of natural PEs (MAPC and MC glycerides) and synthetic PE (LAB) significantly increased the intestinal absorption of insulin upon i.j. instillation. Although it is not possible to conclude if a single PE is dominating the intestinal absorption of insulin, MCT(MAPC) seems to have the potential for oral insulin delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Excipientes/química , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Animais , Células CACO-2 , Técnicas de Cocultura , Emulsões , Glicerídeos/química , Células HT29 , Humanos , Hipoglicemiantes/farmacocinética , Insulina/farmacocinética , Absorção Intestinal , Jejuno/metabolismo , Masculino , Modelos Biológicos , Monoglicerídeos/química , Orlistate/administração & dosagem , Orlistate/farmacologia , Tamanho da Partícula , Permeabilidade , Fosfatidilcolinas/química , Ratos , Ratos Sprague-Dawley
13.
Mol Imaging ; 18: 1536012118821032, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799682

RESUMO

OBJECTIVE: To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs. METHODS: The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines. RESULTS: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions. CONCLUSIONS: PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Ácido Graxo Sintase Tipo I/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Neoplasias Hepáticas/diagnóstico por imagem , Metaloproteinase 2 da Matriz/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/farmacocinética , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Transplante de Neoplasias , Orlistate/administração & dosagem , Orlistate/farmacologia , Tomografia por Emissão de Pósitrons , Propionatos/administração & dosagem , Propionatos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Regulação para Cima
14.
Expert Opin Pharmacother ; 20(5): 585-593, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30614740

RESUMO

INTRODUCTION: Obesity is a growing health problem that has numerous comorbidities, including cardiovascular disease (CVD). The multi-disciplinary treatment of obesity now includes the use of pharmacotherapy. When treating patients with obesity and CVD, certain medications may be more appropriate than others. AREAS COVERED: Herein, the authors review the most commonly used FDA approved medications for the treatment of obesity, describing their mechanism of action, and the efficacy and safety of the medications as seen in recent studies, particularly in patients with CVD. EXPERT OPINION: In the population of patients with obesity and CVD, the medications orlistat, lorcaserin and liraglutide are considered the most appropriate options for their treatment, in terms of safety. Sympathomimetic medications, such as phentermine, should be avoided in this group. The recent CAMELLIA-TIMI 61 trial supports the safety of lorcaserin in patients with CVD. Until there are more studies, it is reasonable to extrapolate the findings of the LEADER trial, which found improved CV outcomes in subjects with type 2 diabetes taking liraglutide, to the population of nondiabetic patients being treated for obesity. Further cardiovascular outcomes trials (CVOT) are needed to assess the safety of other pharmacotherapeutic options for weight loss.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Obesidade/tratamento farmacológico , Fármacos Antiobesidade/efeitos adversos , Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Liraglutida/uso terapêutico , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Perda de Peso/efeitos dos fármacos
15.
Chem Res Toxicol ; 32(2): 255-264, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30667213

RESUMO

Orlistat has been proved to be an effective fatty acid synthase inhibitor that is able to inhibit the proliferation and induce apoptosis in many cancer cell types. However, the anticancer effects of orlistat on hepatocellular carcinoma are undefined. We found that orlistat inhibited cell growth and induced G0/G1 cell cycle arrest with increased cyclin D, cyclin E, and p21 expression in human hepatoma Hep3B cells. Furthermore, protein expression of cyclin A, cyclin B, Cdk1, Cdk2, and Cdk4 was reduced by orlistat. This study investigated the role of lipid metabolism on orlistat-induced human hepatoma Hep3B cell death. The decrease in the expression of key enzymes in fatty acid metabolism, including FASN, ACOT8, PPT1, FABP1, CPT1 and CPT2, was observed after orlistat treatment. We also demonstrated that peroxisomal activity was involved in the orlistat-induced Hep3B cell death. In this study, we established an in vitro model to investigate the effect of orlistat on lipid accumulation. We found that orlistat significantly inhibited the cellular lipid content when administered in fatty acid overload conditions in Hep3B cells. Combination treatment of orlistat and paclitaxel was able to induce a synergistic effect on growth inhibition and cell apoptosis in Hep3B cells. Our data suggested that orlistat displays antitumor activity and enhances the efficacy of paclitaxel in Hep3B cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Orlistate/farmacologia , Paclitaxel/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias Hepáticas/patologia , Palmitoil-CoA Hidrolase/genética , Palmitoil-CoA Hidrolase/metabolismo , Peroxissomos/metabolismo
17.
Adv Ther ; 36(1): 217-231, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30387022

RESUMO

INTRODUCTION: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat (VF) accumulation in Japanese individuals. Therefore, this study aimed to analyze the efficacy and safety of 52 weeks of orlistat administration in Japanese individuals. METHODS: Orlistat 60 mg was administered orally three times daily for 52 weeks to Japanese participants with excessive VF accumulation and without dyslipidemia, diabetes mellitus, and hypertension (metabolic diseases). Participants were also counseled to improve their diet and to maintain exercise habits. We defined excessive VF accumulation as a waist circumference (WC) of ≥ 85 cm for males and ≥ 90 cm for females, which corresponds to a VF area of 100 cm2. Adverse reactions, clinical laboratory tests, VF, WC, body weight (BW), etc., were monitored throughout the study period. RESULTS: VF, WC, and BW were significantly reduced at week 52 from baseline; the mean ± standard error rate of change was - 21.52% ± 1.89%, - 4.89% ± 0.45%, and - 5.36% ± 0.56%, respectively, and continued to reduce throughout the 52 weeks; these significantly reduced at whole term compared with baseline. Most adverse reactions were defecation-related symptoms such as oily spotting and flatus with discharge (flatus with small amounts of stool or oil) due to the pharmacologic effects of the lipase inhibitor. These symptoms were mostly mild, reversible, and recognizable by the participants; none were serious or severe. No participants discontinued by medical judgment about adverse reactions, and the drug could be administered continuously. CONCLUSION: VF, WC, and BW were reduced from week 4 to week 52, indicating the effect of long-term orlistat administration. Moreover, it was well tolerated with an acceptable safety profile. Long-term administration of orlistat may be efficacious in reducing VF accumulation with safety when used in combination with diet and exercise. TRIAL REGISTRATION: This study is registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-184004). FUNDING: Funding for this study was provided by Taisho Pharmaceutical Co., Ltd.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Gordura Intra-Abdominal , Lactonas/uso terapêutico , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Adulto , Antropometria , Peso Corporal , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
18.
Adv Ther ; 36(1): 86-100, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535651

RESUMO

INTRODUCTION: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat accumulation in Japanese subjects. Therefore, this comparative, placebo-controlled, double-blind, randomized study aimed to evaluate the efficacy and safety of orlistat in Japanese participants with excessive visceral fat accumulation and without dyslipidemia, diabetes mellitus, and hypertension ("metabolic diseases"). METHODS: The study population included Japanese participants with excessive visceral fat accumulation (waist circumference ≥ 85 cm in males and ≥ 90 cm in females, which corresponds to a visceral fat area of 100 cm2) and without metabolic diseases. Following a 12-week observation term, participants were randomized to the orlistat 60 mg group (n = 100) or placebo group (n = 100). Both drugs were administered orally three times daily for 24 weeks. Participants were also counseled to improve their diet and to maintain exercise throughout the study. Visceral fat area, subcutaneous fat area, waist circumference, body weight, body mass index, adverse reactions, laboratory tests, and blood pressure were regularly assessed. RESULTS: Visceral fat area, waist circumference, and body weight were significantly reduced in the orlistat group (mean ± standard error, - 13.50 ± 1.52%, - 2.51 ± 0.25%, and - 2.79 ± 0.30%, respectively) compared to the placebo group (- 5.45 ± 1.50%, - 1.55 ± 0.26%, and - 1.22 ± 0.28%, respectively) at the last assessment. The main adverse reactions were defecation-related symptoms including oily spotting and flatus with discharge, resulting from the pharmacological effects of orlistat. Most adverse reactions were mild, and none were serious or severe. CONCLUSION: Orlistat administration reduced visceral fat area, waist circumference, and body weight in Japanese participants with excessive visceral fat and without metabolic diseases. In addition, safety was confirmed with a tolerable profile. Orlistat may be useful to reduce excessive visceral fat accumulation when used in combination with diet and exercise. TRIAL REGISTRATION: Japan Pharmaceutical Information Center identifier, JapicCTI-184005. FUNDING: Taisho Pharmaceutical Co., Ltd.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Exercício Físico , Gordura Intra-Abdominal/patologia , Obesidade/tratamento farmacológico , Adulto , Antropometria , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Obesidade/terapia , Orlistate , Resultado do Tratamento
19.
Naunyn Schmiedebergs Arch Pharmacol ; 392(2): 165-175, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30465055

RESUMO

Cancer is a broad term used to describe a large number of diseases characterized by uncontrolled cell proliferation that leads to tumor production. Cancer is associated with mutations in genes controlling proliferation and apoptosis, oxidative stress, fatty acid synthase (FAS) expression, and other mechanisms. Currently, most antineoplastic drugs have severe adverse effects and new effective and safe drugs are needed. This study aims to investigate the possible anticancer activity of rutin and orlistat which are both safely used clinically in humans against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (PANC-1). Our results have shown that both rutin and orlistat exerted an in vivo anticancer activity as evidenced by the decrease in tumor volume, CEA level, cholesterol content, FAS, and the exerted antioxidant action (reduced MDA level and increased GSH content) and through histopathological examination. In addition, both were cytotoxic to MCF-7 and Panc-1 cell lines by promoting apoptosis. In conclusion, the anticancer activity of rutin and orlistat makes them promising candidates for cancer treatment alone or in combination with other anticancer drugs specially that they are used clinically with an acceptable safety profile.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Orlistate/uso terapêutico , Rutina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Antígeno Carcinoembrionário/metabolismo , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Colesterol/metabolismo , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Camundongos , Orlistate/farmacologia , Rutina/farmacologia , Carga Tumoral/efeitos dos fármacos
20.
J Pharm Pharmacol ; 71(2): 281-291, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30362563

RESUMO

OBJECTIVES: To determine the efficacy of Corchorus olitorius (C. olitorius) leaf extract in the prevention of metabolic syndrome induced in rats by high-fat diet (HFD) and compare it with that of orlistat. METHODS: Phytochemical analysis was performed. Effect of orlistat and C. olitorius extract on lipase activity and acute food intake were investigated. Body weight, biochemical parameters and histopathological examination were demonstrated. KEY FINDINGS: Corchorus olitorius extract inhibited the pancreatic lipase activity, but orlistat was more potent. Cumulative food intake has not changed by the tested agents. In obese rats, C. olitorius or orlistat significantly decreased weight gain and visceral white adipose tissue. They exhibited a significant reduction in serum glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, IL-1ß, tumour necrosis factor-α (TNF-α), insulin and leptin levels of obese rat groups while high density lipoprotein cholesterol and adiponectin levels were significantly increased by them. Histopathological examination of the liver revealed that C. olitorius was more effective than orlistat in the alleviating of steatosis and adipocyte hypertrophy shown in obese control rats. CONCLUSIONS: Corchorus olitorius is effective as orlistat in preventing obesity, hyperlipidaemia, steatosis and insulin resistance. These actions may be mediated by inhibiting of lipase activity, TNF-α, IL-1ß and leptin resistance along with increasing of adiponectin.


Assuntos
Corchorus/química , Citocinas/metabolismo , Síndrome Metabólica/prevenção & controle , Extratos Vegetais/farmacologia , Adiponectina/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/prevenção & controle , Insulina/metabolismo , Resistência à Insulina , Leptina/metabolismo , Lipase/antagonistas & inibidores , Masculino , Síndrome Metabólica/etiologia , Obesidade/prevenção & controle , Orlistate/farmacologia , Folhas de Planta , Ratos , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
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