Emerging drugs for obesity therapy

Published on Mar 1, 2009in Arquivos Brasileiros De Endocrinologia E Metabologia
· DOI :10.1590/S0004-27302009000200019
Maria Teresa Zanella20
Estimated H-index: 20
(Federal University of São Paulo),
Fernando Flexa Ribeiro Filho8
Estimated H-index: 8
(Federal University of São Paulo)
Abstract
Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contribute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon and disappointing. Drug therapy is considered for individuals with a body mass index greater than 30 kg/m2 or ranging from 25 to 30 kg/m2 if they have comorbid conditions. Antiobesity agents can be helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceutical tools are of limited effectiveness considering the magnitude of the problem. At the present, only two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss. Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis.
  • References (47)
  • Citations (17)
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References47
Published on Oct 1, 2006in Cell Metabolism 20.57
Ngozi Erondu12
Estimated H-index: 12
(Merck & Co.),
Ira Gantz13
Estimated H-index: 13
(Merck & Co.)
+ 20 AuthorsHarold Bays4
Estimated H-index: 4
Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study,...
141 Citations Source Cite
Manfred Hallschmid41
Estimated H-index: 41
(University of Lübeck),
Rüdiger Smolnik8
Estimated H-index: 8
(University of Lübeck)
+ 2 AuthorsHorst L. Fehm43
Estimated H-index: 43
(University of Lübeck)
Context: By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH4–10 core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations. Objective: The present study aim...
28 Citations Source Cite
Published on Jun 1, 2006in Cns & Neurological Disorders-drug Targets 2.08
Tim C. Kirkham30
Estimated H-index: 30
,
Sonia Tucci27
Estimated H-index: 27
Research into the endocannabinoid 'system' has grown exponentially in recent years, with the discovery of cannabinoid receptors and their endogenous ligands, such as anandamide and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of endocannabinoid transduction mechanisms, their metabolic pathways, and of the biological processes in which they are implicated. A decade of endocannabinoid studies has promoted new insights into neural regulation and mammalian ph...
50 Citations Source Cite
Published on Nov 1, 1997in Clinical Therapeutics 3.19
William E. Rosenfeld1
Estimated H-index: 1
Abstract The antiepileptic drug (AED) topiramate is a monosaccharide derivative with a sulfamate functionality. It modulates voltage-dependent sodium conductance, potentiates gamma-aminobutyric acid—evoked currents, and blocks the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of the glutamate receptor. Topiramate is rapidly absorbed and has linear, proportional, steady-state pharmacokinetics. It has no known clinically significant effect on plasma levels of carbamaz...
153 Citations Source Cite
Rachel L. Batterham38
Estimated H-index: 38
(Imperial College London),
C. W. le Roux51
Estimated H-index: 51
(Imperial College London)
+ 6 AuthorsS.R. Bloom143
Estimated H-index: 143
(Imperial College London)
Pancreatic polypeptide (PP) is a gut hormone released from the pancreas in response to ingestion of food. Plasma PP has been shown to be reduced in conditions associated with increased food intake and elevated in anorexia nervosa. In addition peripheral administration of PP has been shown to decrease food intake in rodents. These findings suggest that PP may act as a circulating factor that regulates food intake. Therefore we investigated the effect of intravenous infusion of PP (10 pmol/kg/min)...
377 Citations Source Cite
Horst L. Fehm43
Estimated H-index: 43
,
Rüdiger Smolnik8
Estimated H-index: 8
+ 3 AuthorsJan Born92
Estimated H-index: 92
(University of Lübeck)
The control of body fat is a prominent factor in human health. Animal studies have indicated a homeostatic central nervous system regulation of body fat with particular involvement of the melanocortin receptor pathway. This study provides evidence for a similar role for melanocortins in the long-term control of fat stores in humans. Thirty-six normal weight humans were assigned to one of three experimental groups. After a 4-week baseline, one group was treated with MSH/ACTH4–10 (MSH/ACTH4–10) re...
115 Citations Source Cite
Published on Jan 1, 1997in Neuroendocrinology 5.02
Christian Broberger30
Estimated H-index: 30
(Karolinska Institutet),
Marc Landry11
Estimated H-index: 11
(Karolinska Institutet)
+ 2 AuthorsTomas Hökfelt155
Estimated H-index: 155
(Karolinska Institutet)
The arcuate nucleus of the hypothalamus houses a number of neurochemically different cell populations. Among these, a dense cluster of small neuropeptide-Y (NPY)-expressing neurons is located in its v
247 Citations Source Cite
Published on Nov 29, 2007in BMJ 23.56
Diana Rucker6
Estimated H-index: 6
(University of Alberta),
Raj Padwal42
Estimated H-index: 42
(University of Alberta)
+ 2 AuthorsDavid C.W. Lau27
Estimated H-index: 27
(University of Calgary)
Objective To summarise the long term efficacy of anti-obesity drugs in reducing weight and improving health status. Design Updated meta-analysis of randomised trials. Data sources Medline, Embase, the Cochrane controlled trials register, the Current Science meta-register of controlled trials, and reference lists of identified articles. All data sources were searched from December 2002 (end date of last search) to December 2006. Studies reviewed Double blind randomised placebo controlled trials o...
592 Citations Source Cite
Published on Aug 1, 2001in Metabolism-clinical and Experimental 5.96
Carol N. Boozer15
Estimated H-index: 15
,
Rudolph L. Leibel76
Estimated H-index: 76
+ 2 AuthorsLouis J. Aronne33
Estimated H-index: 33
Abstract Tachyphylaxis to the effects of anorexigenic agents, such as sibutramine (S), may be due, in part, to counterregulatory decreases in energy expenditure (EE) and increases in hunger that result from reduced circulating leptin (L) due to loss of body fat and lowered L production/adipocyte. The present study was conducted to test the hypothesis that L administered at low doses sufficient to restore ambient L to preweight loss concentrations would enhance the intercurrent efficacy of S by r...
45 Citations Source Cite
Alfredto Halpern4
Estimated H-index: 4
(University of São Paulo),
Marcio C. Mancini22
Estimated H-index: 22
(University of São Paulo)
+ 2 AuthorsAna Paula Arruda Costa3
Estimated H-index: 3
(University of São Paulo)
O objetivo do estudo foi avaliar os efeitos do GH sobre peso, composicao corporal, metabolismo de repouso e fatores de risco cardiovascular na obesidade visceral. O estudo foi prospectivo randomizado duplo-cego em 40 homens nao diabeticos de 20 a 50 anos com RAQ (relacao abdomen-quadril) > 1 tratados com GH (0,050 U/kg/dia) ou placebo por tres meses. Foram avaliados peso, composicao corporal por bioimpedância e DEXA, metabolismo de repouso atraves da calorimetria indireta e exames de fatores de ...
10 Citations Source Cite
  • References (47)
  • Citations (17)
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Cited By17
Published on Jan 1, 2013in American Journal of Therapeutics 1.00
Joselyn Rojas11
Estimated H-index: 11
,
Miguel Ángel Aguirre Echanove15
Estimated H-index: 15
+ 1 AuthorsBermúdez1
Estimated H-index: 1
5 Citations Source Cite
Published on Mar 22, 2011in Current Neuropharmacology 4.07
João R. Araújo15
Estimated H-index: 15
,
Fátima Martel27
Estimated H-index: 27
During the last 50 years the global pandemic of obesity and associated life-threatening co-morbidities strongly promoted the development of anti-obesity pharmacotherapy. Sibutramine is an anti-obesity drug that in conjunction with lifestyle modifications reduces food intake and body weight. This may result from several effects: inhibition of presynaptic reuptake of monoaminergic neurotransmitters in the central nervous system, thereby suppressing appetite, induction of an increase in anorexigeni...
19 Citations Source Cite
Published on Mar 1, 2011in Expert Opinion on Therapeutic Targets 4.60
Anna Maria Malfitano20
Estimated H-index: 20
(University of Salerno),
Ciaglia Elena12
Estimated H-index: 12
(University of Salerno)
+ 3 AuthorsMaurizio Bifulco20
Estimated H-index: 20
(University of Salerno)
Introduction: Recent studies have shown that the endocannabinoid system (ECS) could offer an attractive antitumor target. Numerous findings suggest the involvement of this system (constituted mainly by cannabinoid receptors, endogenous compounds and the enzymes for their synthesis and degradation) in cancer cell growth in vitro and in vivo. Areas covered: This review covers literature from the past decade which highlights the potential of targeting the ECS for cancer treatment. In particular, th...
38 Citations Source Cite
Published on May 1, 2010in International Immunopharmacology 3.12
William E. Greineisen3
Estimated H-index: 3
(Chaminade University of Honolulu),
Helen Turner3
Estimated H-index: 3
(Chaminade University of Honolulu)
The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that c...
32 Citations Source Cite
André M. Faria7
Estimated H-index: 7
(University of São Paulo),
Marcio C. Mancini22
Estimated H-index: 22
(University of São Paulo)
+ 2 AuthorsAlfredo Halpern34
Estimated H-index: 34
(University of São Paulo)
Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and me...
5 Citations Source Cite
Published on Mar 1, 2011in Diabetes, Obesity and Metabolism 5.98
M. Amigó-Correig1
Estimated H-index: 1
(University of Barcelona),
S. Barceló-Batllori1
Estimated H-index: 1
+ 6 AuthorsRamon Gomis44
Estimated H-index: 44
(University of Barcelona)
Aims: Sodium tungstate is an anti-obesity drug targeting peripheral tissues. In vivo, sodium tungstate reduces body weight gain and food intake through increasing energy expenditure and lipid oxidation, but it also modulates hypothalamic gene expression when orally administered, raising the possibility of a direct effect of sodium tungstate on the central nervous system. Methods: Sodium tungstate was administered intraperitoneally (ip) to Wistar rats, and its levels were measured in cerebrospina...
10 Citations Source Cite
Swati Jain2
Estimated H-index: 2
(Defence Institute of Physiology and Allied Sciences),
Saroj K. Verma2
Estimated H-index: 2
(Defence Institute of Physiology and Allied Sciences)
+ 1 AuthorsSom Nath Singh15
Estimated H-index: 15
(Defence Institute of Physiology and Allied Sciences)
Abstract: The appetite suppressing property of Sibutramine is well reported. The present study was undertaken to investigate the appetite regulatory mechanism and associated metabolic changes induced in male Sprague Dawley rats by its short term supplementation. The effect of the drug on the regulatory hormones and biochemical variables was studied at an oral dose of 10 mg/kg body weight. There was a decrease in food intake of rats by 35.5% in comparison to their basal food intake as well as unt...
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Published on Jun 1, 2011in Journal of Natural Remedies
Shiv Kumar3
Estimated H-index: 3
,
K. R. Alagawadi3
Estimated H-index: 3
The present study was aimed to screen the possible antiobesity effects of ethanol extract of Alpinia galanga rhizomes in cafeteria diet fed obese rats. Obesity was induced in albino rats by feeding cafeteria diet daily for 6 weeks in addition to normal diet. The ethanol extract of rhizomes was administered at a daily dose of 500 mg/kg orally for 6 weeks. Body weight and food intake was measured initially and then every week thereafter. On day 42, serum glucose, lipids and leptin levels were esti...
3 Citations Source Cite
Published on Sep 1, 2014in Social Science & Medicine 3.01
Objetivos: Estimar a prevali?½ncia de obesidade geral, obesidade central e fatores associados em adultos de uma cidade na regii?½o Sul do Brasil.Mi?½todos: Estudo transversal de base populacional com adultos residentes em Tubari?½o, Santa Catarina, de novembro de 2011 a junho de 2012. Os participantes foram entrevistados e submetidos i?½ antropometria. A entrevista avaliou dados sociodemogri?½ficos, atividade fi?½sica, consumo de i?½lcool, tabagismo, hi?½bitos alimentares (passos da alimentai?½i...
Published on Jan 1, 2017in The Journal of Clinical Pharmacology 2.88
Nele Plock2
Estimated H-index: 2
(Takeda Pharmaceutical Company),
Leon Bax1
Estimated H-index: 1
+ 3 AuthorsMarc Pfister2
Estimated H-index: 2
(University of Basel)
The presented analysis was performed to characterize the relationship between treatment-related early (week 4) and longer term (3-6 months) weight loss to understand the potential utility of 4-week proof-of-mechanism studies in the early decision-making process during clinical development of new antiobesity compounds. A regression-based meta-analysis was performed leveraging publically available clinical outcomes data to (1) characterize the within-trial relationship between treatment-related ea...
2 Citations Source Cite
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