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Update on 18F-Fluciclovine PET for Prostate Cancer Imaging.
Parent, EE, Schuster, DM
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;(5):733-739
Abstract
PET is a functional imaging method that can exploit various aspects of tumor biology to enable greater detection of prostate cancer than can be provided by morphologic imaging alone. Anti-1-amino-3-18F-flurocyclobutane-1-carboxylic acid (18F-fluciclovine) is a nonnaturally occurring amino acid PET radiotracer that was recently approved by the U.S. Food and Drug Administration for detection of suspected recurrent prostate cancer. The tumor-imaging features of this radiotracer mirror the upregulation of transmembrane amino acid transport that occurs in prostate cancer because of increased amino acid metabolism for energy and protein synthesis. This continuing medical education article provides an overview on 18F-fluciclovine PET diagnostic capabilities for primary and metastatic disease, including reviews of published comparisons to conventional imaging and other molecular imaging agents. Additionally, the imaging procedure and image interpretation are detailed, including physiologic and pathologic uptake patterns and pitfalls.
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A review discussing fluciclovine (18F) PET/CT imaging in the detection of recurrent prostate cancer.
Zanoni, L, Bossert, I, Matti, A, Schiavina, R, Pultrone, C, Fanti, S, Nanni, C
Future oncology (London, England). 2018;(11):1101-1115
Abstract
A significant number of patients radically treated for prostate cancer (PCa) will develop prostate-specific antigen recurrence (27-53%). Localizing the anatomical site of relapse is critical, in order to achieve the optimal treatment management. To date the diagnostic accuracy of standard imaging is low. Several desirable features have been identified for the amino-acid-based PET agent, fluciclovine (18F) including: long 18F half-life which allows more practical use in centers without a cyclotron onsite; acting as a substrate for amino acid transporters upregulated in PCa or associated with malignant phenotype; lacking of incorporation into protein; and limited urinary excretion. Fluciclovine (18F) is currently approved both in USA and Europe with specific indication in adult men with suspected recurrent PCa based on elevated prostate-specific antigen following prior treatment.
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Cardiovascular risk-benefit profile of sibutramine.
Scheen, AJ
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2010;(5):321-34
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Abstract
Sibutramine is a combined norepinephrine and serotonin reuptake inhibitor used as an antiobesity agent to reduce appetite and promote weight loss in combination with diet and exercise. At a daily dose of 10-20 mg, it was initially considered to have a good safety profile, as it does not induce primary pulmonary hypertension or adverse effects on cardiac valves, in contrast to previous reports relating to some other antiobesity agents. However, it exerts disparate effects on cardiovascular risk factors. On the one hand, sibutramine may have antiatherogenic activities, as it improves insulin resistance, glucose metabolism, dyslipidemia, and inflammatory markers, with most of these effects resulting from weight loss rather than from an intrinsic effect of the drug. On the other hand, because of its specific mode of action, sibutramine exerts a peripheral sympathomimetic effect, which induces a moderate increase in heart rate and attenuates the reduction in BP attributable to weight loss or even slightly increases BP. It may also prolong the QT interval, an effect that could induce arrhythmias. Because of these complex effects, it is difficult to conclude what the final impact of sibutramine on cardiovascular outcomes might be. Sibutramine has been shown to exert favorable effects on some surrogate cardiovascular endpoints such as reduction of left ventricular hypertrophy and improvement of endothelial dysfunction. A good cardiovascular safety profile was demonstrated in numerous 1- to 2-year controlled trials, in both diabetic and nondiabetic well selected patients, as well as in several observational studies. However, since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, and myocardial infarction) have been reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. SCOUT (Sibutramine Cardiovascular and Diabetes Outcome Study) was designed to prospectively evaluate the efficacy/safety ratio of sibutramine in a high-risk population. The efficacy/safety results of the first 6-week lead-in open period of treatment with sibutramine 10 mg/day were reassuring in 10 742 overweight/obese high-risk subjects (97% had cardiovascular disease, 88% had hypertension, and 84% had type 2 diabetes mellitus). However, the final results of SCOUT showed that long-term (5 years') treatment with sibutramine (10-15 mg/day) exposed subjects with pre-existing cardiovascular disease to a significantly increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality. Because the benefit of sibutramine as a weight-loss aid seems not to outweigh the cardiovascular risks, the European Medicines Agency recommended the suspension of marketing authorizations for sibutramine across the EU. The US FDA stated that the drug should carry a 'black box' warning due to an increased risk of stroke and heart attack in patients with a history of cardiovascular disease. In conclusion, concern still persists about the safety profile of sibutramine regarding cardiovascular outcomes, and the drug should not be prescribed for overweight/obese patients with a high cardiovascular risk profile.
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Myocardial infarction associated with sibutramine use: case report and discussion.
Fernandez, WG, Biswas, AK
Military medicine. 2010;(8):622-4
Abstract
We present the case of a young woman presenting to a military field hospital in Afghanistan with a non-ST-elevation myocardial infarction (NSTEMI) associated with the diet drug sibutramine. We also provide a brief literature review on the association between sibutramine and myocardial infarction.
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Long-term effects of weight-reducing drugs in hypertensive patients.
Siebenhofer, A, Horvath, K, Jeitler, K, Berghold, A, Stich, AK, Matyas, E, Pignitter, N, Siering, U
The Cochrane database of systematic reviews. 2009;(3):CD007654
Abstract
BACKGROUND All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option. PRIMARY OBJECTIVES To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events SECONDARY OBJECTIVES - changes in systolic and/or diastolic blood pressure - body weight reduction SEARCH STRATEGY Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews. SELECTION CRITERIA Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo. DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity. MAIN RESULTS Eight studies comparing orlistat or sibutramine to placebo fulfilled our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg. AUTHORS' CONCLUSIONS In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are needed.
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The first decade of sibutramine and orlistat: a reappraisal of their expanding roles in the treatment of obesity and associated conditions.
Coutinho, W
Arquivos brasileiros de endocrinologia e metabologia. 2009;(2):262-70
Abstract
Ancillary therapies for weight management, consisting mainly of diet and exercise programs that incorporate variable levels of lifestyle modification techniques, are frequently ineffective to achieve clinically meaningful weight loss and maintenance. Although pharmacological treatment of obesity is widely used in most countries, the number of available drugs is still very limited. The most widely used anti-obesity agents are sibutramine and orlistat, both available in clinical practice for about a decade. A large number of clinical trials have demonstrated that both agents are safe and well tolerated, with a level of efficacy in the moderate weight loss recommended by the most relevant clinical guidelines. Several studies have assessed the efficacy and safety of sibutramine and orlistat in adolescents and also for the treatment of some associated conditions in adults, including type 2 diabetes, polycystic ovary syndrome and binge eating disorder. The positive results of these studies suggest an expanding role for both agents, not only for the treatment of obesity, but also for associated conditions. After the efficacy of orlistat for the prevention of type 2 diabetes demonstrated in the XENDOS study, the results of SCOUT study are awaited for a better evaluation of sibutramine impact on cardiovascular outcomes.
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Weight loss medications--where do they fit in?
Dixon, JB
Australian family physician. 2006;(8):576-9
Abstract
BACKGROUND Obesity is a chronic disease requiring a similar long term approach to management as that of other chronic conditions. OBJECTIVE This article discusses the role of medications in the overall management of obesity. DISCUSSION Management needs to be multifaceted, aiming to alter the patient and family micro-environment to one favouring better weight control through sustainable behavioural changes to physical activity and diet. Weight loss medications may provide additional benefit. Currently we have only two medications suitable for long term therapy--orlistat and sibutramine. Sibutramine, which acts centrally to suppress appetite, has shown efficacy for up to 2 years. Orlistat, a lipase inhibitor, reduces fat absorption and has been shown to reduce and maintain weight for up to 4 years. The effect of these medications is modest, generally providing less than 5 kg weight loss when compared with placebo. Patients need to have realistic expectations and understand the benefits of sustained modest weight loss. It is important that weight loss medications are prescribed in combination with lifestyle modification.
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Pharmacotherapy to reduce visceral fat.
Blackburn, GL, Waltman, BA
Clinical cornerstone. 2005;(2-3):52-60
Abstract
Cardiovascular disease (CVD) is the leading cause of death of men and women in the United States. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing CVD and metabolic disease. Because visceral adipose tissue uniquely contributes to the pathophysiology of CVD and insulin resistance, waist circumference is now being considered as a more useful marker of potential health risks associated with overweight and obesity than body mass index. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, thereby reducing the risk of developing chronic disease and CVD.
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The efficacy and safety of sibutramine for weight loss: a systematic review.
Arterburn, DE, Crane, PK, Veenstra, DL
Archives of internal medicine. 2004;(9):994-1003
Abstract
BACKGROUND The primary goal of weight loss is to prevent or reduce obesity-associated morbidity and mortality by improving cardiovascular and metabolic risk factors. We conducted a systematic review to assess the efficacy and safety of sibutramine hydrochloride for weight loss. METHODS In April 2002, we searched MEDLINE, EMBASE, the Cochrane Library, and 7 other computerized bibliographic search tools using the keywords "sibutramine," "Meridia," and "Reductil" (in all languages and all available years). The authors and the manufacturer were contacted. We reviewed randomized placebo-controlled trials of sibutramine, 10 to 20 mg/d, in obese adults. Methodological quality was assessed. RESULTS A total of 29 trials had sufficient data for analysis after including unpublished data from 10 authors. The summary mean differences in weight loss, sibutramine minus placebo, for the 3-month and 1-year trials were -2.78 kg (95% confidence interval, -2.26 to -3.29 kg) and -4.45 kg (95% confidence interval, -3.62 to -5.29 kg), respectively. The 6-month trials were statistically heterogeneous, and evidence of publication bias was found. One trial found that sibutramine maintains weight loss better than placebo at 2 years. Weight loss with sibutramine was associated with modest increases in heart rate and blood pressure, small improvements in high-density lipoprotein cholesterol and triglycerides levels, and, among diabetic patients, small improvements in glycemic control. There was no direct evidence that sibutramine reduces obesity-associated morbidity or mortality. CONCLUSIONS Sibutramine is effective in promoting weight loss. Weight loss with sibutramine is associated with both positive and negative changes in cardiovascular and metabolic risk factors. There is insufficient evidence to accurately determine the long-term risk-benefit profile for sibutramine.
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10.
New antiobesity agents in type 2 diabetes: overview of clinical trials with sibutramine and orlistat.
Scheen, AJ, Ernest, P
Diabetes & metabolism. 2002;(6 Pt 1):437-45
Abstract
Besides genetic predisposition, obesity is the most important risk factor for the development of type 2 diabetes mellitus. Even modest weight reduction can improve blood glucose control in overweight subjects. After failure of lifestyle modifications, antiobesity drugs such as orlistat, a potent and selective inhibitor of gastric and pancreatic lipases that reduces lipid intestinal absorption, or sibutramine, a noradrenaline and 5-hydroxytryptamine reuptake inhibitor that regulates food intake, may be considered to favour weight loss and/or weight maintenance. Several placebo-controlled studies have recently demonstrated that both drugs are able to promote weight loss in obese type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. The greater weight reduction as compared to placebo was associated with a significant reduction of glycated haemoglobin levels and/or of the doses of classical antihyperglycaemic agents, especially in good responders who lost at least 10% of initial body weight. In addition, vascular risk factors associated to insulin resistance were also reduced after weight loss. These antiobesity agents may also contribute to delay or prevent the progression from impaired glucose tolerance to overt type 2 diabetes in at risk obese individuals ("Xenical in the prevention of diabetes in obese subjects" trial). Large long-term prospective studies, such as the "Sibutramine cardiovascular and diabetes outcome study" should better determine the place of pharmacological anti-obesity strategy in the overall management of obese patients with impaired glucose tolerance or type 2 diabetes.