A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.
The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4-6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P<0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P<0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted. (+info)
Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist.
1. We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2. One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH2(22)]-beta-MSH11-22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3. HS028 antagonised a alpha-MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4. Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5. This is the first report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis. (+info)
Model for the regulation of energy balance and adiposity by the central nervous system.
In 1995, we described a new model for adiposity regulation. Since then, data regarding the biology of body weight regulation has accumulated at a remarkable rate and has both modified and strengthened our understanding of this homeostatic system. In this review we integrate new information into a revised model for further understanding this important regulatory process. Our model of energy homeostasis proposes that long-term adiposity-related signals such as insulin and leptin influence the neuronal activity of central effector pathways that serve as controllers of energy balance. (+info)
SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. II. In vivo pharmacological characterization.
SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans. (+info)
Neuropeptide Y restores appetite and alters concentrations of GH after central administration to endotoxic sheep.
The objective of this study was to determine whether neuropeptide Y (NPY) and recombinant human interleukin-1 receptor antagonist (IL-1ra) would: first, increase food intake; secondly, decrease concentrations of GH; thirdly, reduce GHRH-induced release of GH; and fourthly, reduce changes to concentrations of IGF-I in plasma during experimental endotoxemia in sheep. Six treatments were given to six castrated male sheep in a 6x6 Latin square treatment order. Osmotic mini-pumps were implanted at 0 h and a jugular vein was cannulated. Each sheep was continuously infused with saline (0.9%) or lipopolysaccharide (LPS) (20 micrograms/kg per 24 h, s.c.) at 10 microliters/h for 72 h via the osmotic mini-pumps. Blood samples (3 ml) were collected at 15-min intervals from 24 to 33 h. At 26 h, one of three treatments (artificial cerebrospinal fluid, NPY or IL-1ra) was injected i.c.v. within 30 s (0.3 microgram/kg), then infused i.c.v. from 26 to 33 h (600 microliters/h) at 0.3 microgram/kg per h. GHRH was injected i.v. (0.075 microgram/kg) at 32 h after which blood samples were collected at 5, 10, 15, 30, 45 and 60 min. Feed intake was reduced up to 50% for 48 h in LPS-treated compared with non-LPS-treated sheep. NPY restored feed intake in LPS-treated sheep and induced hyperphagia in non-LPS-treated sheep from 24 to 48 h. In contrast, IL-1ra did not affect appetite. Injection of NPY increased concentrations of GH from 26 to 27 h, while IL-1ra had no effect. Infusion of NPY suppressed GHRH-induced release of GH. However, no treatment altered pulse secretion parameters of GH. Concentrations of IGF-I were 20% higher at 72 h in LPS-treated sheep given NPY than in sheep treated with LPS alone, and this may reflect increased appetite from 24 to 48 h. We concluded that reduced appetite during endotoxemia is due to down-regulation of an NPY-mediated mechanism. Furthermore, NPY stimulates release of GH in healthy sheep, does not reduce pulse secretion parameters of GH, but does suppress GHRH-induced release of GH in endotoxic sheep. Therefore, NPY may be an important neurotransmitter linking appetite with regulation of GH during endotoxemic and healthy states in sheep. (+info)
Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice.
The present study examined effects of diazepam (DZP) alone or in combination with delta 9-tetrahydrocannabinol (THC) on feeding behavior as well as body weight in male ddY strain mice at 5 weeks of age. Because we saw no hyperphagic effect of DZP with or without THC in mice, we explored the hyperphagia elicitable by DZP. THC [2 (THC2) or 4 (THC4) mg/kg/day s.c.] was given daily for 7 days. For the last day the mice were starved and injected i.p. with DZP (2 mg/kg) 10 min prior to a food or maze test. Controls received vehicle injections. Feeding behavior was measured after giving food for 2 hr. THC4 significantly reduced body weight gain. DZP, with or without THC, induced hyperphagia. THC4 alone also induced hyperphagia that was not significantly affected by DZP. Time taken to find food was extended by DZP and further with THC. Both DZP and THC can therefore interact on food ingestion but synergize on food seeking in mice through different mechanisms. (+info)
Geriatric cachexia: the role of cytokines.
Weight loss in elderly patients is a common clinical problem. Wasting and cachexia are associated with severe physiologic, psychologic, and immunologic consequences, regardless of the underlying causes. Cachexia has been associated with infections, decubitus ulcers, and even death. Multivariate analyses of risk and prognostic factors in community-acquired pneumonia in the elderly have found that age by itself is not a significant factor related to prognosis. Among the significant risk factors, only nutritional status is amenable to medical intervention. Cachexia in the elderly may have profound consequences: medical, cognitive, and psychiatric disorders may diminish self-reliance in activities of daily living, thus reducing quality of life and increasing the frequency of secondary procedures, hospitalizations, and the need for skilled care. Cachexia is associated with higher-than-normal concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1, IL-6, serotonin, and interferon gamma. The role of these proinflammatory cytokines has been established in the cachexia seen in cancer and AIDS patients. Reduction in the concentrations of these cytokines is associated with weight gain. Drugs that promote appetite stimulation and weight gain, such as progestational agents, cyproheptadines, pentoxifylline, and thalidomide may work by down-regulating these proinflammatory cytokines. An understanding of the relation between cachexia and negative regulatory cytokines may point to effective treatment of geriatric cachexia as well. (+info)
Evaluation and treatment of weight loss in adults with HIV disease.
Weight loss late in the course of human immunodeficiency virus (HIV) disease is common and often multifactorial. Increased energy expenditure in response to opportunistic disease, as well as to HIV infection itself, can lead to protein-calorie malnutrition similar to that observed in starvation. Weight loss of as little as 5 percent in patients with HIV infection is associated with an increased risk of disease progression. Loss of body cell mass carries a particularly poor prognosis, and aggressive measures should be taken to stop such depletion. Patients exhibiting unexpected weight loss should be carefully examined to exclude decreased food intake, malabsorption, occult infection or neoplasm as the etiology of the weight loss. Early aggressive treatment of HIV disease and underlying opportunistic pathology, along with adequate pharmacologic, hormonal, nutritional and physical therapy, can often restore normal weight and body composition. (+info)