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S-Nitrosothiol biology and therapeutic potential in metabolic disease. s -亚硝基硫醇生物学及其在代谢性疾病中的治疗潜力。
Current opinion in investigational drugs Pub Date : 2010-10-01
Christopher G Kevil, Rakesh P Patel
{"title":"S-Nitrosothiol biology and therapeutic potential in metabolic disease.","authors":"Christopher G Kevil,&nbsp;Rakesh P Patel","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>S-Nitrosothiols (RSNOs) have been used widely as experimental nitric oxide (NO) donors, but the clinical use of these agents remains limited. Recent data support a role for endogenous RSNOs as mediators of NO signaling via the post-translational modification of proteins. This review discusses the increased understanding of the role of RSNOs in NO signaling, as well as emerging insights into NO donor-dependent and -independent mechanisms of action of RSNOs, in the context of emerging and potential therapeutics that target endogenous RSNOs or use synthetic RSNOs to stimulate NO signaling. The focus of this review is the treatment of diabetes and metabolic disease, pathologies in which dysfunction in NO signaling is clearly implicated.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1127-34"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677214/pdf/nihms474369.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29304807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity. 黑素皮质素-3受体(MC3R)基因突变:对人类肥胖或肥胖的影响。
Current opinion in investigational drugs Pub Date : 2010-10-01
Ya-Xiong Tao
{"title":"Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity.","authors":"Ya-Xiong Tao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The melanocortin-3 receptor (MC3R), together with the related melanocortin-4 receptor (MC4R), are important regulators of energy homeostasis. Rodent studies have demonstrated that the two receptors have non-redundant roles in regulating energy balance. However, while mutations for the MC4R have been established as a cause of monogenic obesity, mutations in the MC3R gene remain controversially associated with human obesity pathogenesis. This editorial summarizes the current status of MC3R in rodent energy homeostasis and human obesity pathogenesis.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1092-6"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29313943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plant-derived therapeutics for the treatment of metabolic syndrome. 植物源性疗法治疗代谢综合征。
Current opinion in investigational drugs Pub Date : 2010-10-01
Brittany L Graf, Ilya Raskin, William T Cefalu, David M Ribnicky
{"title":"Plant-derived therapeutics for the treatment of metabolic syndrome.","authors":"Brittany L Graf,&nbsp;Ilya Raskin,&nbsp;William T Cefalu,&nbsp;David M Ribnicky","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Metabolic syndrome is defined as a set of coexisting metabolic disorders that increase an individual's likelihood of developing type 2 diabetes, cardiovascular disease and stroke. Medicinal plants, some of which have been used for thousands of years, serve as an excellent source of bioactive compounds for the treatment of metabolic syndrome because they contain a wide range of phytochemicals with diverse metabolic effects. In order for botanicals to be effectively used against metabolic syndrome, however, botanical preparations must be characterized and standardized through the identification of their active compounds and respective modes of action, followed by validation in controlled clinical trials with clearly defined endpoints. This review assesses examples of commonly known and partially characterized botanicals to describe specific considerations for the phytochemical, preclinical and clinical characterization of botanicals associated with metabolic syndrome.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1107-15"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755736/pdf/nihms309398.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29305455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
BI-10773, a sodium-glucose cotransporter 2 inhibitor for the potential oral treatment of type 2 diabetes mellitus. BI-10773，一种钠-葡萄糖共转运蛋白2抑制剂，用于2型糖尿病的潜在口服治疗。
Current opinion in investigational drugs Pub Date : 2010-10-01
Inês Aires, Joaquim Calado
{"title":"BI-10773, a sodium-glucose cotransporter 2 inhibitor for the potential oral treatment of type 2 diabetes mellitus.","authors":"Inês Aires,&nbsp;Joaquim Calado","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>BI-10773, being developed by Boehringer Ingelheim Corp, is a sodium-glucose cotransporter (SGLT)2 inhibitor for the oral treatment of type 2 diabetes mellitus (T2DM). Preclinical and clinical research has demonstrated that inhibition of SGLT2, the major pathway of renal glucose reabsorption, leads to increased urinary glucose excretion with concomitant reductions in fasting and postprandial plasma glucose levels, HbA1c levels and body mass. In phase I clinical trials in patients with T2DM, once-daily BI-10773 increased urinary glucose excretion resulting in dose-proportional reductions in fasting plasma glucose and mean daily glucose levels. BI-10773 was not associated with significant hypoglycemic episodes or other clinically important adverse events. Because of its mechanism of action, BI-10773 may be combined with other oral antidiabetic agents; indeed, the results of small trials suggested that coadministration of BI-10773 and metformin was safe and well tolerated. In animal studies, BI-10773 correlated with an increase in urinary volume and a reduction in body fat but not water content. This may represent an additional benefit of BI-10773 for the control of T2DM. At the time of publication, phase III clinical trials of BI-10773 were underway.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1182-90"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29304812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The mechanism of action for oxyntomodulin in the regulation of obesity. 氧同调素在调节肥胖中的作用机制。
Current opinion in investigational drugs Pub Date : 2010-10-01
Katie Wynne, Benjamin Ct Field, Stephen R Bloom
{"title":"The mechanism of action for oxyntomodulin in the regulation of obesity.","authors":"Katie Wynne,&nbsp;Benjamin Ct Field,&nbsp;Stephen R Bloom","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Oxyntomodulin, a product of the proglucagon gene, is released from the enteroendocrine L-cells of the gastrointestinal tract after the digestion of food, and acts via glucagon-like peptide 1 receptors in the arcuate nucleus to induce satiety. The administration of oxyntomodulin to animals and humans causes weight loss by reducing food intake in combination with increasing energy expenditure. Thus, the development of potent and long-acting analogs of oxyntomodulin is an exciting new therapeutic avenue for addressing the global obesity epidemic. This review discusses the role of oxyntomodulin in the physiological control of appetite, and presents the currently available evidence suggesting its potential as an obesity treatment.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1151-7"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29304809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sirtuin-targeting drugs: Mechanisms of action and potential therapeutic applications. sirtwin靶向药物:作用机制和潜在的治疗应用。
Current opinion in investigational drugs Pub Date : 2010-10-01
Ahmad Aljada, Lynn Dong, Shaker A Mousa
{"title":"Sirtuin-targeting drugs: Mechanisms of action and potential therapeutic applications.","authors":"Ahmad Aljada,&nbsp;Lynn Dong,&nbsp;Shaker A Mousa","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The sirtuins are NAD+-dependent histone/protein deacetylases that are similar to Saccharomyces cerevisiae silent information regulator 2 (Sir2). Sirtuins regulate various normal and abnormal cellular and metabolic processes, including tumorigenesis, neurodegeneration, and processes associated with type 2 diabetes and obesity. Several age-related diseases, such as Alzheimer's disease, and longevity have also been linked to the functions of sirtuins. A thorough understanding of the mechanisms of action of the sirtuins may therefore yield novel therapeutic strategies targeting these processes; several small-molecule and naturally occurring inhibitors and activators of these enzymes have been identified. This review describes the mechanisms regulating sirtuin activity, as well as how these modes of regulation may be exploited to manipulate activity in the context of various pathological states (ie, metabolic diseases, cancer and neurodegenerative diseases). The possible metabolic outcomes of the pharmacological manipulation of sirtuins are also discussed.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1158-68"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29304810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases. 酒石酸Eliglustat是一种口服活性糖脑苷合成酶抑制剂，可用于治疗戈谢病和其他溶酶体积存病。
Current opinion in investigational drugs Pub Date : 2010-10-01
Timothy M Cox
{"title":"Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases.","authors":"Timothy M Cox","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Eliglustat tartrate (Genz-112638), currently under development by Genzyme Corp, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Gaucher disease is an inherited defect of lysosomal functions caused by mutations in the GBA1 gene leading to accumulation of glucocerebroside, primarily in macrophages. Gaucher disease is characterized by visceromegaly and skeletal complications, including osteoporosis and painful episodes of osteonecrosis. In vitro studies demonstrated that, following exposure to eliglustat tartrate, the abundance of GM1 and GM3 gangliosides in cultured human erythroleukemia cells and murine melanoma cells was decreased. In vivo, eliglustat tartrate administered to Asp409Val/null mice lowered the concentrations of glucocerebroside in the liver, lung and spleen and reduced the number of Gaucher cells in the liver. In a phase Ib clinical trial in healthy volunteers, plasma glucocerebroside concentrations were decreased after dosing with eliglustat tartrate, and in phase II clinical trials in patients with type 1 (non-neuronopathic) Gaucher disease, spleen and liver volumes were diminished. Patients also demonstrated improved bone mineral density, correction of abnormal bone marrow signal with MRI and normalization of glucocerebroside and ganglioside GM3 levels. Eliglustat tartrate is orally active and, with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1169-81"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29304811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Testosterone therapy in women with androgen deficiency: Its time has come. 雄激素缺乏症女性的睾酮治疗:时机已到。
Current opinion in investigational drugs Pub Date : 2010-10-01
André Guay, Abdulmaged Traish
{"title":"Testosterone therapy in women with androgen deficiency: Its time has come.","authors":"André Guay,&nbsp;Abdulmaged Traish","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The concept that women may have a testosterone deficiency is controversial, as is the possibility of testosterone replacement therapy for women. It has been stated that androgen deficiency is a new concept; however, women have been treated off-label for more than 50 years. A number of objections to such therapy in women have been reviewed and discussed, including the lack of a normal age-related concentration range for androgens, the lack of randomized, placebo-controlled clinical trials, and the possibility of chronic adverse effects, particularly the risk of cardiovascular disease and breast cancer. However, recent data have adequately addressed these concerns. Moreover, the 4-year safety data that are available for women is more than that available for testosterone replacement in men. Although more precise diagnostic techniques to measure total testosterone and free testosterone in women would be welcome, it is believed that physicians are able to identify women at risk of testosterone deficiency and safely replace these hormones in carefully selected patients.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1116-26"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29305456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Appetite- and volume-regulating neuropeptides: Role in treating alcohol dependence. 调节食欲和体积的神经肽:在治疗酒精依赖中的作用。
Current opinion in investigational drugs Pub Date : 2010-10-01
Thomas Hillemacher, Kai G Kahl, Annemarie Heberlein, Marc An Muschler, Christian Eberlein, Helge Frieling, Stefan Bleich
{"title":"Appetite- and volume-regulating neuropeptides: Role in treating alcohol dependence.","authors":"Thomas Hillemacher,&nbsp;Kai G Kahl,&nbsp;Annemarie Heberlein,&nbsp;Marc An Muschler,&nbsp;Christian Eberlein,&nbsp;Helge Frieling,&nbsp;Stefan Bleich","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recent studies have demonstrated a role for appetite- and volume-regulating neuropeptides in alcohol dependence, particularly in association with alcohol craving. The peptides leptin, ghrelin, adiponectin, vasopressin and the atrial natriuretic peptide (ANP) have been of particular interest because of their central effects on various brain circuits, including the hypothalamic-pituitary-adrenocortical (HPA) axis. In addition, pro-opiomelanocortin (POMC) plays an important role in linking appetite regulation with the HPA axis. Recent research has also demonstrated that the expression of these peptides in alcohol dependence is, at least partially, regulated by genetic and epigenetic mechanisms. These peptides and their associated circuits provide an intriguing new field for future pharmacological approaches for treating depression, anxiety and, potentially, addictive disorders such as alcohol dependence.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 10","pages":"1097-106"},"PeriodicalIF":0.0,"publicationDate":"2010-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29305454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Apolipoprotein A-I and its mimetics for the treatment of atherosclerosis. 载脂蛋白A-I及其模拟物治疗动脉粥样硬化。
Current opinion in investigational drugs Pub Date : 2010-09-01
Jonathan D Smith
{"title":"Apolipoprotein A-I and its mimetics for the treatment of atherosclerosis.","authors":"Jonathan D Smith","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Although statin treatment leads consistently to a reduction in major adverse coronary events and death in clinical trials, approximately 60 to 70% residual risk of these outcomes still remains. One frontier of investigational drug research is treatment to increase HDL, the 'good cholesterol' that is associated with a reduced risk of coronary artery disease. HDL and its major protein apolipoprotein A-I (apoAI) are protective against atherosclerosis through several mechanisms, including the ability to mediate reverse cholesterol transport. This review focuses on the preclinical and clinical findings for two types of therapies for the treatment of atherosclerosis: apoAI-containing compounds and apoAI mimetic peptides. Both of these therapies have excellent potential to be useful clinically to promote atherosclerosis regression and stabilize existing plaques, but significant hurdles must be overcome in order to develop these approaches into safe and effective therapies.</p>","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 9","pages":"989-96"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074469/pdf/nihms-275271.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29207141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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