RESUMO
OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014). PATIENTS: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS: Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS: Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.
Assuntos
Leptina/análogos & derivados , Lipodistrofia/tratamento farmacológico , Obesidade/tratamento farmacológico , Adolescente , Adulto , Anticorpos/sangue , Formação de Anticorpos , Criança , Feminino , Humanos , Fenômenos Imunogenéticos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Leptina/efeitos adversos , Leptina/sangue , Leptina/imunologia , Leptina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
We have previously shown that combined amylin + leptin agonism elicits synergistic weight loss in diet-induced obese (DIO) rats. Here, we assessed the comparative efficacy of amylin, leptin, or amylin + leptin in the maintenance of amylin + leptin-mediated weight loss. DIO rats pretreated with the combination of rat amylin (50 microg/kg/day) and murine leptin (125 microg/kg/day) for 4 weeks were subsequently infused with either vehicle, amylin, leptin, or amylin + leptin for an additional 4 weeks. Food intake, body weight, body composition, plasma parameters, and the expression of key metabolic genes in liver and white adipose tissue (WAT) were assessed. Amylin + leptin treatment (weeks 0-4) reduced body weight to 87.5% of baseline. Rats subsequently maintained on vehicle or leptin regained all weight (to 104.2 and 101.2% of baseline, respectively), those maintained on amylin had partial weight regain (97.0%). By contrast, weight loss was largely maintained with continued amylin + leptin treatment (91.4%), associated with a 10% decrease in adiposity. Cumulative food intake (weeks 5-8) was reduced by amylin and amylin + leptin, but not by leptin alone. Amylin + leptin, but not amylin or leptin alone, reduced plasma triglycerides (by 55%), total cholesterol (by 19%), and insulin (by 57%) compared to vehicle. Amylin + leptin also reduced hepatic stearoyl-CoA desaturase-1 (Scd1) mRNA, and increased WAT mRNA levels of adiponectin, fatty acid synthase (Fasn), and lipoprotein lipase (Lpl). We conclude that, in DIO rats, maintenance of amylin + leptin-mediated weight loss requires continued treatment with both agonists, and is accompanied by sustained improvements in body composition, and indices of lipid metabolism and insulin sensitivity.
Assuntos
Amiloide/farmacologia , Peso Corporal/efeitos dos fármacos , Dieta , Leptina/farmacologia , Obesidade/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Adiponectina/sangue , Tecido Adiposo Branco/metabolismo , Amiloide/sangue , Análise de Variância , Animais , Depressores do Apetite/farmacologia , Composição Corporal/efeitos dos fármacos , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Perfilação da Expressão Gênica , Insulina/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/sangue , Fígado/metabolismo , Masculino , Obesidade/metabolismo , RNA Mensageiro/metabolismo , RatosRESUMO
The neurohormonal control of body weight involves a complex interplay between long-term adiposity signals (e.g., leptin), and short-term satiation signals (e.g., amylin). In diet-induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat-specific weight loss. To evaluate the weight-lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24-week, randomized, double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 +/- 8 years; BMI 32.0 +/- 2.1 kg/m(2); 93.3 +/- 13.2 kg; mean +/- s.d.). After a 4-week lead-in period with pramlintide (180 microg b.i.d. for 2 weeks, 360 microg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2-8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 microg b.i.d.), or pramlintide/metreleptin (360 microg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (-12.7 +/- 0.9%; least squares mean +/- s.e.) than treatment with pramlintide (-8.4 +/- 0.9%; P < 0.001) or metreleptin (-8.2 +/- 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.
Assuntos
Amiloide/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Leptina/análogos & derivados , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Adulto , Amiloide/efeitos adversos , Amiloide/farmacocinética , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacocinética , Índice de Massa Corporal , Terapia Combinada , Método Duplo-Cego , Combinação de Medicamentos , Ingestão de Energia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/efeitos adversos , Leptina/farmacocinética , Leptina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas , Receptores para Leptina/agonistas , Receptores para Leptina/metabolismo , Receptores de Peptídeos/agonistas , Receptores de Peptídeos/metabolismo , Saciação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
Previously, we reported that combination treatment with rat amylin (100 microg/kg.d) and murine leptin (500 microg/kg.d) elicited greater inhibition of food intake and greater body weight loss in diet-induced obese rats than predicted by the sum of the monotherapy conditions, a finding consistent with amylin-induced restoration of leptin responsiveness. In the present study, a 3 x 4 factorial design was used to formally test for a synergistic interaction, using lower dose ranges of amylin (0, 10, and 50 microg/kg.d) and leptin (0, 5, 25, and 125 microg/kg.d), on food intake and body weight after 4 wk continuous infusion. Response surface methodology analysis revealed significant synergistic anorexigenic (P < 0.05) and body weight-lowering (P < 0.05) effects of amylin/leptin combination treatment, with up to 15% weight loss at doses considerably lower than previously reported. Pair-feeding (PF) experiments demonstrated that reduction of food intake was the predominant mechanism for amylin/leptin-mediated weight loss. However, fat loss was 2-fold greater in amylin/leptin-treated rats than PF controls. Furthermore, amylin/leptin-mediated weight loss was not accompanied by the counterregulatory decrease in energy expenditure and chronic shift toward carbohydrate (rather than fat) utilization observed with PF. Hepatic gene expression analyses revealed that 28 d treatment with amylin/leptin (but not PF) was associated with reduced expression of genes involved in hepatic lipogenesis (Scd1 and Fasn mRNA) and increased expression of genes involved in lipid utilization (Pck1 mRNA). We conclude that amylin/leptin interact synergistically to reduce body weight and adiposity in diet-induced obese rodents through a number of anorexigenic and metabolic effects.
Assuntos
Amiloide/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Leptina/farmacologia , Obesidade/patologia , Transdução de Sinais/efeitos dos fármacos , Amiloide/administração & dosagem , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Restrição Calórica , Dieta/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/administração & dosagem , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.
Assuntos
Amiloide/agonistas , Amiloide/química , Leptina/metabolismo , Tecido Adiposo/metabolismo , Amiloide/metabolismo , Amiloide/farmacologia , Animais , Peso Corporal , Restrição Calórica , Modelos Animais de Doenças , Hormônios/metabolismo , Hipotálamo/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/análogos & derivados , Leptina/farmacologia , Modelos Biológicos , Obesidade/genética , Obesidade/terapia , Consumo de Oxigênio , RatosRESUMO
Four patients with inoperable hepatocellular carcinoma were treated with a magnetic targeted carrier bound to doxorubicin (MTC-DOX) by using a joint magnetic resonance (MR) imaging/conventional angiography system consisting of a 1.5-T short-bore magnet connected to a C-arm angiography unit by a sliding tabletop. Selective transcatheter delivery of the MTC-DOX to the hepatic artery was monitored by using intraprocedural MR imaging, and interim catheter manipulation was performed with fluoroscopic guidance to optimize agent delivery to the tumor and minimize delivery to normal tissue. The final fraction of treated tumor volume ranged from 0.64 to 0.91. The fraction of affected normal liver volume ranged from 0.07 to 0.30. The dual MR imaging/conventional angiography system shows promise for directing magnetically targeted tumor therapies.