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Query: UMLS:C0028754 (obesity)
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Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, modulation of appetite may involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with lifestyle changes and dietary intervention may be useful in dealing with the rising world epidemic of obesity.
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PMID:Pharmacology of appetite suppression. 1085 85

A 66 year-old obese woman with arthrosis, self-medicated with oral nimesulide, 200 mg daily. After 6 weeks she developed nausea, jaundice and dark urine. Two weeks later she had recurrent hematemesis and was hospitalized. Besides obesity and anemia her physical examination was unremarkable. An upper GI endoscopy revealed 3 acute gastric ulcers and a 4th one in the pyloric channel. Abdominal ultrasonogram showed a slightly enlarged liver with diffuse reduction in ecogenicity; the gallbladder and biliary tract were normal. Blood tests demonstrated a conjugated hyperbilirubinemia (maximal total value: 18.4 mg/dl), ALAT 960 U/l, ASAT 850 U/l, GGT 420 U/l, alkaline phosphatases mildly elevated, pro-time 49% and albumin 2.7 mg/dl. Serum markers for hepatitis A, B and C viruses were negative. ANA, AMA, anti-SmA, were negative. Ceruloplasmin was normal. A liver biopsy showed bridging necrosis and other signs of acute toxic liver damage. Gastric ulcers healed after conventional treatment and hepatitis subsided after 2 months leaving no signs of chronic liver damage. The diagnosis of toxic hepatitis due to nimesulide was supported by the time-course of drug usage, sex, age, absence of other causes of liver disease, a compatible liver biopsy and the improvement after drug withdrawal. Peptic ulcers or toxic hepatitis have been previously described as independent adverse reactions in patients taking nimesulide or other NSAIDs but their simultaneous occurrence in a single patient is a unique event that deserves to be reported.
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PMID:[Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide in a case]. 1122 44

Hepatitis B and its sequelae are a major public health problem. Vaccines have been available for almost 20 years; however the disease still remains a global problem. Many factors contribute to the failure to control hepatitis B, including the limited nature of the vaccination programs implemented initially. Only relatively recently has mass childhood vaccination begun to be implemented and vaccination of high-risk groups, other than healthcare workers, is still not general policy. Additional factors contributing to continued persistence of hepatitis B in the developed world are that the present vaccines are not fully used by those recommended to be vaccinated and even when vaccination is carried out appropriately, there remain some who fail to achieve adequate protection. Clearly, the protection of at-risk groups who have inadequate response to current vaccines, and those who are unwilling or unable to comply with protracted multi-dose vaccine regimens, could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Adults who had never been vaccinated against hepatitis B were randomised to receive a vaccination course of either a present single antigen (S) vaccine (Recombivax-HB) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare Medeva Pharma plc). Doses were given at baseline and 1 month and 6 months later. Hepatitis B surface antibody (anti-HBs) levels were measured at 2, 4, 6, and 7 months after beginning vaccination. The primary efficacy parameter was the degree of protection, measured as the percentage of subjects with anti-HBs titres > or = 10 IU/L, 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 303 adult subjects entered the study and were vaccinated. Of these, 11 failed to complete the study (4 on Hepacare and 7 on Recombivax-HB); however all but 2 (1 to receive the triple antigen vaccine and 1 to receive Recombivax-HB) were included in the intent-to-treat population for efficacy evaluation. Treatment randomisation was stratified at entry based on age (above and below 40 years old) and gender. The standard three-dose/6-month vaccination regimen of the single antigen vaccine protected 83% of subjects by 7 months after starting vaccination whereas the triple antigen vaccine as a two-dose/1-month regimen protected 88% within 6 months and as a three-dose/6-month regimen protected 97% by 7 months after starting vaccination. Thus the protection rate provided by the shortened (0, 1) regimen of the novel vaccine was "essentially equivalent" (i.e., not statistically inferior) to that provided by the full (0, 1, and 6) regimen of today's vaccine (88% vs. 81%, P < 0.001), and the protection rate provided by a three-dose/6-month (0, 1, and 6) regimen of the new vaccine was significantly superior to that provided by present vaccines (97% vs. 83% P < 0.001). The percentage of subjects protected increases with time after beginning vaccination and at all time points up to and including 6 months was significantly greater with the two-dose regimen of the triple antigen vaccine than with the single antigen vaccine regimen. In adults at risk for a reduced response to hepatitis B vaccination [i.e., older adults (>/=40), the obese, males, and smokers], the triple antigen vaccine produced a significantly greater percentage of protected subjects (P < 0.001) and higher geometric mean titre (P < 0.001). Indeed as a three-dose/6 month regimen, the triple antigen vaccine raised the level of protection in these vulnerable subgroups to that seen when a single antigen vaccine is used in the optimal younger adult group. Both vaccines were well tolerated and had similar safety profiles. The most frequently (> or = 10%) reported adverse events with the use of either vaccine were pain at the site of injection (38% vs. 41% vs. 20% for the two-dose Hepacare regimen, the three-dose Hepacare regimen, and the three-dose Recombivax-HB regimen, respectively), infections at the site of injection (1% vs. 14% vs. 9%), headache (9% vs. 13% vs. 11%), and nausea (7% vs. 11% vs. 3%). It is concluded that in healthy normal adults, a triple antigen hepatitis B vaccine that contained S and pre-S antigens produced an enhanced immunological response. This was exemplified by the novel vaccine's ability to overcome factors such as advancing age (> or = 40 years), obesity, and smoking, each of which is known to reduce the potential for protection with present recombinant S only vaccines. A two-dose/1-month (0 and 1) regimen of this triple antigen vaccine was as effective as the standard three-dose/6 month (0, 1, and 6) regimen of present single antigen vaccines. (c) 2001 Wiley-Liss, Inc.
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PMID:Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination. 1142 17

Chitosan (CAS 9012-76-4) is derived by alkaline deacetylation from chitin, an abundant polymeric product of natural biosynthesis especially in crustaceans. It is available in a primary, unorganised structure, but also in a microcrystalline form. As a dietary supplement, chitosan has been claimed to control obesity and to lower serum cholesterol. A variety of chitosan products have been freely available worldwide in health stores and pharmacies. This review summarises the current knowledge about cholesterol-lowering and safety properties of chitosan and focuses its possible application for the treatment of hypercholesterolaemia. Chitosan behaves as a polycationic(+) cellulose-like fibrillar biopolymer that forms films with negatively charged surfaces. It is not specifically hydrolysed by digestive enzymes in man, but limited digestion of chitosan due to bacterial flora and to the unspecific enzymes might occur. Negatively charged molecules in stomach attach strongly to the positive charged tertiary amino group (-NH3+) of chitosan. Therefore, chitosan reduces fat absorption from gastrointestinal tract by binding with anionic carboxyl groups of fatty and bile acids, and it interferes with emulsification of neutral lipids (i.e., cholesterol, other sterols) by binding them with hydrophobic bonds. In short-term animal studies the safety of chitosan has been good. There are only few studies with chitosan in humans. In man, dietary chitosan has been reported to reduce serum total cholesterol levels by 5.8-42.6% and low-density lipoprotein levels by 15.1-35.1%. In short-term trials up to 12 weeks, no clinically significant symptoms have been observed with chitosan compared to placebo. Mild and transitory nausea and constipation have been reported in 2.6-5.4% of subjects. Although chitosan has been clinically well tolerated, it cannot be recommended to people allergic to crustaceans.
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PMID:Cholesterol-lowering properties and safety of chitosan. 1183 68

Obesity is a multifactorial, chronic disorder that has reached epidemic proportions in most industrialised countries and is threatening to become a global epidemic. Clinical management of obese patients is complex and serious doubts have arisen with regard to safety and efficacy of drug therapy. Following the withdrawal of fenfluramine and dexfenfluramine in 1997, interest has focused on novel anti-obesity drugs. Pharmacological approaches to the management of obesity can, in broad terms, use different distinct strategies: firstly, to reduce energy intake; secondly, to increase energy expenditure; and thirdly, to alter the partitioning of nutrients between fat and lean tissue. Sibutramine is a serotonin-noradrenaline (norepinephrine) reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely due to a combination of reduced appetite, feelings of satiety and possibly the induction of thermogenesis. The efficacy of sibutramine for inducing initial weight loss and the subsequent maintenance of weight loss is well proven in short- and long-term clinical trials of up to 2 years' duration. Most individual placebo-controlled trials and pooled estimates found that the drug produced statistically significant greater weight loss than placebo at all observed endpoints (weighted mean difference for weight change at 8 weeks: -3.4 kg; mean difference range for weight change at 6 months: -4.0 to -9.1 kg; and at 1 year: -4.1 to -4.8 kg). The most frequent dosage regimen in these trials was 10-20 mg daily. Findings suggested a dose-effect relationship in terms of weight loss. Sibutramine was also associated with better weight maintenance relative to placebo (statistically significant difference). Results from mainly small trials showed that sibutramine produced more favourable outcomes in terms of loss of fat mass, reduction in body mass index and loss of > or = 5-10% of initial bodyweight. The most commonly reported adverse effects of sibutramine are headache, constipation and nausea. Certain adverse events associated with the nervous system, including dizziness, dry mouth and insomnia, are reported by > 5% of patients receiving sibutramine. Increases in blood pressure and heart rate were possible adverse effects that require regular monitoring especially in obese hypertensive patients. Neither left-sided cardiac valve disease nor primary pulmonary hypertension was associated with the use of sibutramine. The assessment of the benefit-risk profile of sibutramine remained positive, although the product must be kept under regular review.
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PMID:A benefit-risk assessment of sibutramine in the management of obesity. 1458 64

An unresolved problem in the management of type 2 diabetes is that improvement of glycemic control with insulin, insulin secretagogues, and insulin sensitizers is often accompanied by undesired weight gain. This problem is of particular concern in ethnic groups with a high propensity for diabetes and obesity, such as African Americans and Hispanics. Two 1-year, randomized, double-blind, placebo-controlled clinical trials in insulin-treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide, an analog of the human beta-cell hormone amylin, reduces A(1C) with concomitant weight loss, rather than weight gain. To assess the effect of pramlintide in various ethnic groups with type 2 diabetes using insulin, we conducted a pooled post hoc analysis of the 2 trials, which included all Caucasian (n = 315), African American (n = 47), and Hispanic (n = 48) patients (age 57 years, A(1C) 9.1%, body mass index [BMI] 33 kg/m(2), mean values) who completed 52 weeks of treatment with either pramlintide (120 microg twice daily or 150 microg 3 times a day) or placebo. Primary endpoints included changes from baseline to week 52 in A(1C) and body weight. Collectively, pramlintide-treated patients achieved significant reductions from baseline in both A(1C) and body weight (placebo-corrected treatment effects at week 52: -0.5% and -2.6 kg, respectively, both P <.0001). The simultaneous reduction in A(1C) and body weight at week 52 was evident across all 3 ethnic groups and appeared to be most pronounced in African Americans (-0.7%, -4.1 kg), followed by Caucasians (-0.5%, -2.4 kg) and Hispanics (-0.3%, -2.3 kg). The glycemic improvement with pramlintide was not associated with an increased incidence of hypoglycemia over the entire study period (43% pramlintide v 40% placebo). Nausea, the most common adverse event associated with pramlintide treatment, was mostly mild and confined to the first 4 weeks of therapy (25% pramlintide v 16% placebo) with comparable patterns in the 3 ethnic groups. Thus, pending further experience, the combined improvement in glycemic and weight control with pramlintide treatment appears to be generalizable to a broad population of mixed ethnicity.
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PMID:Effect of pramlintide on A1C and body weight in insulin-treated African Americans and Hispanics with type 2 diabetes: a pooled post hoc analysis. 1466 70

We present a unique case of a prolactin (PRL)-producing pituitary adenoma showing incomplete neuronal differentiation without ganglion cells. A 27-year-old man presented with nausea, headaches, and instability over the last 2 months. Clinical examination revealed obesity with no other endocrinological signs. His serum PRL levels were slightly elevated (38 ng/ml), whereas concentrations of the other adenohypophysial hormones were within normal range. Histology revealed an unusual pituitary adenoma containing many hypocellular areas with fibrillar appearance. The sizable tumor cells were polyhedral or elongated harboring an ovoid, vesicular nucleus with prominent nucleolus, lacking, however, the typical features of ganglion cells. By immunohistochemistry, many adenoma cells were positive for PRL. Immunostain for neurofilament protein revealed variable amounts of fibrils dispersed throughout the stroma, mostly in the hypocellular areas. In addition, neurofilament protein and chromogranin were strongly reactive in approximately 15% of the tumor cell population, whereas reactivity for synaptophysin was uniform throughout the tumor. These findings led to the conclusion that part of the tumor-cell population expressed a hybrid immunoprofile of adenoma-neuronal cell. Our case is the first PRL-producing pituitary adenoma showing incomplete neuronal differentiation lacking mature ganglion cells.
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PMID:Prolactin-producing pituitary adenoma with incomplete neuronal transformation: an intermediate adenoma-neuronal tumor. 1517 51

The pathophysiology of nausea and the physiological mechanisms underlying perceptions of stomach emptiness and fullness are not clearly understood, but several potentially important factors have been identified. Gastric dysrhythmias are believed to contribute to the subjective experience of nausea and may also be involved with perceptions of stomach emptiness, hunger, and even dyspepsia symptoms like bloating and early satiety. Normal gastric neuromuscular function is more evident in the absence of nausea and is also thought to be related to feelings of satiety or comfortable stomach fullness. Autonomic and endocrine influences may also play a critical role in the pathophysiology of nausea and abnormal perceptions of stomach emptiness or fullness. Achieving a better understanding of the gastric neuromuscular and neurohormonal influences on perceptions arising from the viscera may prove invaluable in the development of novel treatments for such conditions as unexplained nausea, functional dyspepsia, and obesity.
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PMID:Sickness and satiety: physiological mechanisms underlying perceptions of nausea and stomach fullness. 1604 11

Rimonabant is the first selective blocker of the cannabinoid CB1 receptors being developed for the treatment of obesity, tobacco smoking and cardiometabolic risk factors. Following 1 year of treatment, rimonabant 20 mg/day leads to greater weight loss compared with placebo. Therapy with rimonabant is also associated with favourable changes in serum lipids and an improvement in glycaemic control in Type 2 diabetics. At the same dose, rimonabant significantly increases the cigarette smoking quit rates compared with placebo. Rimonabant appears to be generally well tolerated, with primary side effects of mild nausea, diarrhoea, anxiety and depression. As an agent with a novel mechanism of action, rimonabant has the potential to be a useful adjunct to lifestyle modification in the treatment of obesity, metabolic syndrome and cigarette smoking.
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PMID:Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. 1650 66

(1) Intragastric balloons are a temporary non-surgical obesity treatment that induces short-term weight loss by partially filling the stomach to achieve satiety and reduce food intake. (2) Moderate weight loss may be achieved if patients adhere to a weight-reduction program. Weight gain often recurs when the balloon is removed after six months. (3) Abdominal pain, nausea, and vomiting are common, particularly in the first week after balloon implantation. (4) More data on benefits, harm, and cost effectiveness are required before the intragastric balloon can be compared with other short-term weight loss interventions, including low-calorie diets.
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PMID:Intragastric balloons: a temporary treatment for obesity. 1654 43


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