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1.
J Med Chem ; 63(1): 382-390, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31850759

RESUMO

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/uso terapêutico , Lipopeptídeos/uso terapêutico , Ocitocina/análogos & derivados , Ocitocina/uso terapêutico , Receptores de Ocitocina/agonistas , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Depressores do Apetite/síntese química , Depressores do Apetite/farmacocinética , Peso Corporal/efeitos dos fármacos , Humanos , Lipopeptídeos/síntese química , Lipopeptídeos/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Obesidade/tratamento farmacológico , Ocitocina/farmacocinética , Engenharia de Proteínas , Perda de Peso/efeitos dos fármacos
2.
Expert Opin Pharmacother ; 20(16): 1981-1991, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487204

RESUMO

Introduction: Obstructive sleep apneas are a frequent clinical condition in which there are momentary interruptions or reductions in breathing activity. To date, the gold standard therapy is the use of Continous Positive Airway Pressure (CPAP). But, due to the relatevely high frequency of poor compliant patients, there is the need to research possible pharmacological treatments for obstructive apnea (OSA). Areas covered: A recent study divided OSA into four major phenotypes. With this characterization in hand, the authors have reviewed the pharmacological treatments present to date according to the different phenotypes in which they could be used. Afterwards, they analyzed the efficacy of different medicaments for the therapy of the residual (despite CPAP treatment) excessive day-time sleepiness (EDS) that often afflicts OSA' patients. Expert opinion: Different drug classes have been evaluated, with some positive results. However, there is still the need to better define treatment strategies for every single phenotype. This underlines the importance to avoid considering the pathology like a single entity without any differences between each single form. The authors are concerned about the risk that, treating only EDS, patients could reduce their compliance to CPAP, thus not reducing the cardiovascular risk associated with OSA.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Apneia Obstrutiva do Sono/terapia , Antidepressivos/uso terapêutico , Depressores do Apetite/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Humanos , Mandíbula/anatomia & histologia , Fenótipo , Apneia Obstrutiva do Sono/tratamento farmacológico , Apneia Obstrutiva do Sono/patologia
3.
Nutrients ; 11(9)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533291

RESUMO

The prevalence of obesity is increasing worldwide. Bioactive phytochemicals in food supplements are a trending approach to facilitate dieting and to improve patients' adherence to reducing food and caloric intake. The aim of this systematic review was to assess efficacy and safety of the most commonly used bioactive phytochemicals with appetite/hunger-suppressing and/or satiety/fullness-increasing properties. To be eligible, studies needed to have included at least 10 patients per group aged 18 years or older with no serious health problems except for overweight or obesity. Of those studies, 32 met the inclusion criteria, in which 27 different plants were tested alone or as a combination, regarding their efficacy in suppressing appetite/hunger and/or increasing satiety/fullness. The plant extracts most tested were derived from Camellia sinensis (green tea), Capsicum annuum, and Coffea species. None of the plant extracts tested in several trials showed a consistent positive treatment effect. Furthermore, only a few adverse events were reported, but none serious. The findings revealed mostly inconclusive evidence that the tested bioactive phytochemicals are effective in suppressing appetite/hunger and/or increasing satiety/fullness. More systematic and high quality clinical studies are necessary to determine the benefits and safety of phytochemical complementary remedies for dampening the feeling of hunger during dieting.


Assuntos
Depressores do Apetite/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Obesidade/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Resposta de Saciedade/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Feminino , Humanos , Masculino , Obesidade/epidemiologia , Obesidade/fisiopatologia , Obesidade/psicologia , Compostos Fitoquímicos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
4.
Genes (Basel) ; 10(8)2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398921

RESUMO

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.


Assuntos
Adiposidade/efeitos dos fármacos , Depressores do Apetite/farmacologia , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Ocidental/efeitos adversos , Sobrepeso/prevenção & controle , Proantocianidinas/farmacologia , Tecido Adiposo/metabolismo , Animais , Depressores do Apetite/uso terapêutico , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Leptina/genética , Leptina/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Sobrepeso/tratamento farmacológico , Proantocianidinas/uso terapêutico , Ratos , Vitis/química
5.
Med Hypotheses ; 131: 109308, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443779

RESUMO

Adiposity is a chronic disease and one of the major modifiable risk factors for the development of type 2 diabetes mellitus (T2DM). Its prevalence in the world could be considered epidemic with 80% of patients with T2DM being obese. Novel antidiabetic drugs, such as glucagone-like peptide-1 (GLP-1) agonists have demonstrated benefitial effect on weight reduction. Nevertheless, in the last decades the need for new therapeutic strategies in the management of adiposity have emerged. Both adiposity and T2DM have negative effect on hypothalamic-pituitary-gonadal axis. Conversely, it has been known that sex hormone replacement therapy improves metabolic parameters in hypogonadal subjects. Recent research has found potential therapeutic effect of combination therapies with sex hormones and GLP-1 agonists in reducing body weight. Based on the aforementioned, we hypothesize that there is a possible synergistic effect of GLP-1 agonists and sex hormones on body mass reduction in patients with type 2 diabetes. The possible additional effect of sex hormones on weight loss could contribute to more effective treatment of T2DM and its complications.


Assuntos
Adiposidade/fisiologia , Fármacos Antiobesidade/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hormônios Esteroides Gonadais/farmacologia , Hipoglicemiantes/farmacologia , Modelos Biológicos , Perda de Peso , Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/farmacologia , Depressores do Apetite/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Sinergismo Farmacológico , Estradiol/sangue , Feminino , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Hormônios Esteroides Gonadais/fisiologia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Ciclo Menstrual/fisiologia , Sobrepeso/sangue , Sobrepeso/tratamento farmacológico , Sobrepeso/epidemiologia , Pâncreas/efeitos dos fármacos , Pâncreas/embriologia , Fatores de Risco , Taxa Secretória/efeitos dos fármacos , Testosterona/sangue , Perda de Peso/efeitos dos fármacos
6.
Metabolism ; 96: 83-91, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30902750

RESUMO

BACKGROUND: This pilot study evaluated whether adding phentermine to liraglutide would induce further weight loss in participants who had previously lost weight with liraglutide alone. SUBJECTS/METHODS: Participants were 45 adults with obesity (75.6% female, 55.6% white, body mass index = 34.3 ±â€¯4.7 kg/m2) who had lost an average of 12.6 ±â€¯6.8% of initial weight during a prior 1-year randomized trial with liraglutide and intensive behavioral treatment. Participants were re-randomized, in a double-blinded fashion, to liraglutide 3.0 mg plus phentermine 15.0 mg (liraglutide-phentermine) or liraglutide plus placebo (liraglutide-placebo). Participants also were provided with four, 15-minute counseling sessions during the 12-week extension study. RESULTS: At week 12, the liraglutide-phentermine and liraglutide-placebo groups lost a mean (±SEM) of 1.6 ±â€¯0.6% and 0.1 ±â€¯0.5% of re-randomization weight, respectively (p = 0.073). Two (9.1%) liraglutide-phentermine participants and one (4.3%) liraglutide-placebo participant lost ≥5% of re-randomization weight; 19 (86.4%) and 16 (69.9%) participants, respectively, maintained their full weight loss achieved in the prior 1-year trial (p = 0.125). Liraglutide-phentermine participants generally reported larger reductions in hunger and food preoccupation than liraglutide-placebo participants during the first 8 weeks of the extension study. CONCLUSIONS: The combination of liraglutide and phentermine appeared to be well-tolerated but did not produce additional clinically meaningful weight loss in individuals who had already lost 12.6% of initial weight with liraglutide alone. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02911818.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Fentermina/uso terapêutico , Adulto , Idoso , Fármacos Antiobesidade/efeitos adversos , Apetite/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Fome/efeitos dos fármacos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/psicologia , Fentermina/efeitos adversos , Projetos Piloto , Resultado do Tratamento , Perda de Peso
7.
J Consult Clin Psychol ; 87(1): 91-105, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30570304

RESUMO

OBJECTIVE: To provide a comprehensive meta-analysis on the efficacy of psychological and medical treatments for binge-eating disorder (BED), including those targeting weight loss. METHOD: Through a systematic search before March 2018, 81 published and unpublished randomized-controlled trials (RCTs), totaling 7,515 individuals with BED (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition [DSM-IV] and Fifth Edition [DSM-5]), were retrieved and analyzed using random-effect modeling. RESULTS: In RCTs with inactive control groups, psychotherapy, mostly consisting of cognitive-behavioral therapy, showed large-size effects for the reduction of binge-eating episodes and abstinence from binge eating, followed by structured self-help treatment with medium-to-large effects when compared with wait-list. Pharmacotherapy and pharmacological weight loss treatment mostly outperformed pill placebo conditions with small effects on binge-eating outcome. These results were confirmed for the most common treatments of cognitive-behavioral therapy, self-help treatment based on cognitive-behavioral therapy, and lisdexamfetamine. In RCTs with active control groups, there was limited evidence for the superiority of one treatment category or treatment. In a few studies, psychotherapy outperformed behavioral weight loss treatment in short- and long-term binge-eating outcome and led to lower longer-term abstinence than self-help treatment, while combined treatment revealed no additive effect on binge-eating outcome over time. Overall study quality was heterogeneous and the quality of evidence for binge-eating outcome was generally very low. CONCLUSIONS: This comprehensive meta-analysis demonstrated the efficacy of psychotherapy, structured self-help treatment, and pharmacotherapy for patients with BED. More high quality research on treatments for BED is warranted, with a focus on long-term maintenance of therapeutic gains, comparative efficacy, mechanisms through which treatments work, and complex models of care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Assuntos
Depressores do Apetite/uso terapêutico , Cirurgia Bariátrica/psicologia , Transtorno da Compulsão Alimentar/terapia , Psicoterapia/métodos , Grupos de Autoajuda , Adulto , Transtorno da Compulsão Alimentar/diagnóstico , Transtorno da Compulsão Alimentar/psicologia , Feminino , Seguimentos , Humanos , Masculino , Obesidade/psicologia , Obesidade/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Autocuidado , Resultado do Tratamento , Perda de Peso
8.
Circulation ; 139(3): 366-375, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30586726

RESUMO

BACKGROUND: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.


Assuntos
Depressores do Apetite/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Benzazepinas/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefropatias/epidemiologia , Rim/efeitos dos fármacos , Obesidade/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Depressores do Apetite/efeitos adversos , Benzazepinas/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Dieta Redutora , Progressão da Doença , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/mortalidade , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/mortalidade , Obesidade/fisiopatologia , Obesidade/psicologia , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Agonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
9.
Obes Facts ; 11(6): 440-453, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30537704

RESUMO

OBJECTIVE: This study evaluated the effect of a protein, the isolated Trypsin Inhibitor (TTI) from Tamarindus indica L. seed, as a CCK secretagogue and its action upon food intake and leptin in obese Wistar rats. METHODS: Three groups of obese rats were fed 10 days one of the following diets: Standard diet (Labina®) + water; High Glycemic Index and Load (HGLI) diet + water or HGLI diet + TTI. Lean animals were fed the standard diet for the 10 days. Food intake, zoometric measurements, plasma CCK, plasma leptin, relative mRNA expression of intestinal CCK-related genes, and expression of the ob gene in subcutaneous adipose tissue were assessed. RESULTS: TTI decreased food intake but did not increase plasma CCK in obese animals. On the other hand, TTI treatment decreased CCK-1R gene expression in obese animals compared with the obese group with no treatment (p = 0.027). Obese animals treated with TTI presented lower plasma leptin than the non-treated obese animals. CONCLUSION: We suggest that TTI by decreasing plasma leptin may improve CCK action, regardless of its increase in plasma from obese rats, since food intake was lowest.


Assuntos
Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Leptina/sangue , Obesidade , Proteínas de Vegetais Comestíveis/farmacologia , Receptores da Colecistocinina/genética , Tamarindus/química , Animais , Depressores do Apetite/isolamento & purificação , Depressores do Apetite/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Masculino , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/genética , Proteínas de Vegetais Comestíveis/isolamento & purificação , Ratos , Ratos Wistar , Receptores da Colecistocinina/metabolismo , Resposta de Saciedade/efeitos dos fármacos , Sementes/química
10.
Obesity (Silver Spring) ; 26(11): 1721-1726, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30358156

RESUMO

OBJECTIVE: The satiating effect of protein compared with other nutrients has been well described and is thought to be mediated, in part, by gut hormone release. Previously, it has been shown that oral L-arginine acts as a GLP-1 secretagogue both in vitro and in vivo in rodents. Here, the effect of L-arginine on gut hormone release in humans was investigated. METHODS: The hypothesis was tested in two separate studies. The first study assessed the tolerability of oral L-arginine in healthy human subjects. The second study assessed the effect of oral L-arginine on gut hormone release following an ad libitum meal. Subjects were given L-arginine, glycine (control amino acid), or vehicle control in a randomized double-blind fashion. RESULTS: At a dose of 17.1 mmol, L-arginine was well tolerated and stimulated the release of plasma GLP-1 (P < 0.05) and PYY (P < 0.001) following an ad libitum meal. Food diaries showed a trend toward lower energy intake and particularly fat intake following L-arginine treatment. CONCLUSIONS: L-arginine can significantly elevate GLP-1 and PYY in healthy human volunteers in combination with a meal. Further work is required to investigate whether L-arginine may have utility in the suppression of appetite and food intake.


Assuntos
Depressores do Apetite/uso terapêutico , Arginina/uso terapêutico , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Peptídeo YY/efeitos dos fármacos , Período Pós-Prandial/efeitos dos fármacos , Adulto , Depressores do Apetite/farmacologia , Arginina/farmacologia , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Masculino , Peptídeo YY/sangue
11.
Lancet ; 392(10161): 2269-2279, 2018 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-30293771

RESUMO

BACKGROUND: There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission. METHODS: In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m2) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264. FINDINGS: Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054). INTERPRETATION: Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. FUNDING: Eisai.


Assuntos
Depressores do Apetite/uso terapêutico , Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Idoso , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/prevenção & controle , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Estado Pré-Diabético/complicações , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/prevenção & controle , Indução de Remissão , Perda de Peso/efeitos dos fármacos
13.
Curr Nutr Rep ; 7(4): 329-334, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30168043

RESUMO

PURPOSE OF REVIEW: Obesity is a life-limiting disease that is associated with a number of co-morbidities. Bariatric surgery remains the most efficacious and durable weight loss method available to patients. However, a significant percentage of patients can regain weight resulting in frustration, depression, and return of obesity-related co-morbidities. The present review provides an overview of the most common therapeutic modalities available to combat weigh regain after weight loss surgery. RECENT FINDINGS: Given the high percentage of patients with weight regain after surgery, significant effort has been placed on developing treatment options in the last few years. Tremendous work has taken place in the realm of cognitive behavior therapy, appetite suppressants, and endoscopic procedures with the hope of reducing the need for revision surgery which can be associated with significant complications. Weight regain is unfortunately a common phenomenon associated with all weight loss modalities including bariatric surgery. We now have a number of treatment options that can reverse the weight loss trend.


Assuntos
Depressores do Apetite/uso terapêutico , Cirurgia Bariátrica/efeitos adversos , Terapia Cognitivo-Comportamental/métodos , Endoscopia Gastrointestinal/métodos , Obesidade/cirurgia , Ganho de Peso/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Endoscopia Gastrointestinal/efeitos adversos , Comportamento Alimentar/efeitos dos fármacos , Humanos , Obesidade/epidemiologia , Obesidade/fisiopatologia , Obesidade/psicologia , Prevalência , Recidiva , Reoperação , Fatores de Risco , Resultado do Tratamento
14.
Cell Metab ; 28(4): 619-630.e5, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30146485

RESUMO

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.


Assuntos
Depressores do Apetite/uso terapêutico , Benzazepinas/uso terapêutico , Ingestão de Alimentos/fisiologia , Obesidade/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Núcleo Solitário/metabolismo , Análise de Variância , Animais , Depressores do Apetite/metabolismo , Regulação do Apetite/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/citologia , Benzazepinas/metabolismo , Linhagem Celular Tumoral , Comportamento Alimentar/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Estatísticas não Paramétricas , Transfecção
15.
Obes Facts ; 11(4): 335-343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30089303

RESUMO

OBJECTIVE: The aim of the study was to assess the effectiveness and safety of long-term sibutramine therapy in routine clinical practice. METHODS: In total, 98,774 patients (82.3% women, 17.7% men) from 142 cities of the Russian Federation were enrolled in the PRIMAVERA program. The mean age of the patients was 39.39 ± 10.38 years, the mean body weight was 99.1 ± 14.28 kg, and the mean BMI was 35.7 ± 4.41 kg/m2. The duration of the sibutramine therapy was determined by physicians: 59.3% of patients took the drug for 6 months, the treatment course of 37.7% of patients was 12 months, and 3% of patients had treatment for 3 months. RESULTS: The BMI reduction correlated with the treatment duration: 3.4 ± 1.53 kg/m2 after 3 months of therapy, 5.4 ± 2.22 kg/m2 after 6 months, and 7.2 ± 3.07 kg/m2 after 12 months. The body weight reduction after 3, 6 and 12 months of treatment was 9.5%, 15.1%, and 19.7%, respectively. The body weight loss associated with sibutramine treatment was accompanied by a slight decrease in blood pressure and did not lead to any significant increases of the heart rate. CONCLUSIONS: The results of the PRIMAVERA study confirmed the lack of increased risk of using sibutramine in routine clinical practice in patients without underlying cardiovascular disease and low rate of adverse events.


Assuntos
Depressores do Apetite/uso terapêutico , Ciclobutanos/uso terapêutico , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Fármacos Antiobesidade/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Atenção Primária à Saúde , Federação Russa
16.
Diabetes Obes Metab ; 20(8): 1836-1851, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29938884

RESUMO

AIM: We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator. METHODS: The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake. RESULTS: The mouse-specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist-treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP-1R-/- mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey-specific dual agonist reduced total energy intake to 60%-70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed. CONCLUSIONS: In DIO mice and non-human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP-1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.


Assuntos
Depressores do Apetite/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Receptores de Glucagon/agonistas , Animais , Animais não Endogâmicos , Depressores do Apetite/administração & dosagem , Depressores do Apetite/efeitos adversos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Secreção de Insulina/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Distribuição Aleatória , Receptores de Glucagon/metabolismo
18.
Diabetes ; 67(8): 1538-1548, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29776968

RESUMO

Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.


Assuntos
Depressores do Apetite/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Hipotálamo/efeitos dos fármacos , Liraglutida/uso terapêutico , Neurônios/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Genes Reporter/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Camundongos Knockout , Camundongos Transgênicos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Distribuição Aleatória , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/química , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/química , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Perda de Peso/efeitos dos fármacos
19.
Diabetes Obes Metab ; 20(8): 1817-1828, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29687585

RESUMO

Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.


Assuntos
Osso e Ossos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Modelos Biológicos , Estado Pré-Diabético/tratamento farmacológico , Animais , Depressores do Apetite/metabolismo , Depressores do Apetite/farmacologia , Depressores do Apetite/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/prevenção & controle , Metabolismo Energético/efeitos dos fármacos , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Lipocalina-2/genética , Lipocalina-2/metabolismo , Lipocalina-2/farmacologia , Lipocalina-2/uso terapêutico , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/uso terapêutico , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteocalcina/genética , Osteocalcina/metabolismo , Osteocalcina/farmacologia , Osteocalcina/uso terapêutico , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Estado Pré-Diabético/prevenção & controle , Ligante RANK/genética , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Ligante RANK/uso terapêutico , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Secretagogos/metabolismo , Secretagogos/farmacologia , Secretagogos/uso terapêutico
20.
Int J Obes (Lond) ; 42(11): 1890-1899, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29535451

RESUMO

BACKGROUND: The control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight-loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC. METHODS: Thirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire. RESULTS: After NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039). CONCLUSIONS: NB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711.


Assuntos
Depressores do Apetite/uso terapêutico , Apetite/efeitos dos fármacos , Bupropiona/uso terapêutico , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Naltrexona/uso terapêutico , Lobo Parietal/diagnóstico por imagem , Adulto , Depressores do Apetite/farmacologia , Mapeamento Encefálico , Bupropiona/farmacologia , Sinais (Psicologia) , Combinação de Medicamentos , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Naltrexona/farmacologia , Vias Neurais/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/fisiologia , Resultado do Tratamento , Adulto Jovem
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