Treatment of cachexia with ghrelin in patients with COPD

Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Chest (Impact Factor: 7.48). 10/2005; 128(3):1187-93. DOI: 10.1378/chest.128.3.1187
Source: PubMed


Ghrelin is a novel growth hormone (GH)-releasing peptide that also induces a positive energy balance by decreasing fat utility and stimulating feeding through GH-independent mechanisms. We investigated whether ghrelin improves cachexia and functional capacity in patients with COPD.
This is an open-label pilot study. Human ghrelin (2 microg/kg bid) was IV administered to seven cachectic patients with COPD for 3 weeks. Food intake, body composition, muscle strength, exercise capacity, pulmonary function, and sympathetic nerve activity were examined before and after ghrelin therapy.
A single administration of ghrelin markedly increased serum GH (21-fold). Three-week treatment with ghrelin resulted in a significant increase in mean (+/- SEM) body weight (49.3 +/- 3.6 to 50.3 +/- 3.8 kg; p < 0.05). Food intake was significantly increased during ghrelin therapy. Ghrelin increased lean body mass and peripheral and respiratory muscle strength. Ghrelin significantly increased Karnofsky performance status score and the distance walked in 6 min (370 +/- 30 to 432 +/- 35 m; p < 0.05), although it did not significantly alter pulmonary function. Ghrelin attenuated the exaggerated sympathetic nerve activity, as indicated by a marked decrease in plasma norepinephrine level (889 +/- 123 to 597 +/- 116 pg/mL; p < 0.05).
These preliminary results suggest that repeated administration of ghrelin improves body composition, muscle wasting, functional capacity, and sympathetic augmentation in cachectic patients with COPD.

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    • "Meanwhile, as a GH-independent mechanism, ghrelin induces a positive energy balance by decreasing fat utilization [11], stimulating food intake and adiposity [12], increasing cardiac output in healthy humans [13], and inhibiting sympathetic nerve activity [13,14]. In an open-label pilot study, we previously demonstrated that ghrelin may improve walking distance and inhibit sympathetic nerve activity in underweight COPD patients [15]. More recently, a multicenter, randomized, double-blind, placebo-controlled trial was conducted to investigate the efficacy and safety of adding ghrelin to PR in underweight COPD patients, and it showed that ghrelin administration improved symptoms and respiratory muscle strength. "
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    ABSTRACT: BACKGROUND: The aim of this substudy of the ghrelin treatment, multicenter, randomized, double-blind, placebo-controlled trial was to investigate the effects of ghrelin administration on exercise capacity and the underlying mechanisms in underweight patients with chronic obstructive pulmonary disease (COPD) using cardiopulmonary exercise testing. METHODS: Twenty underweight COPD patients were randomized to pulmonary rehabilitation with intravenous ghrelin (2 mug/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in a double-blind fashion. The primary outcome was changes in peak oxygen uptake V[bullet]o2 Secondary outcomes included changes in exertional cardio-respiratory functions: O2-pulse, physiologic dead space/tidal volume-ratio (VD/VT), ventilatory equivalent for oxygen V[bullet]E/V[bullet]o2, and ventilatory equivalent for carbon dioxide V[bullet]E/V[bullet]co2. RESULTS: With incremental exercise, at peak exercise, there was a significant difference in the mean difference (ghrelin minus placebo), i.e., treatment effect in: i) peak V[bullet]o2 (1.2 mL/kg/min, 95% CI: 0.2-2.3 mL/kg/min, between-group p = 0.025); ii) V[bullet]E/V[bullet]o2 (-4.2, 95% CI: -7.9 to -0.5, between-group p = 0.030); iii) V[bullet]E/V[bullet]co2 (-4.1, 95% CI: -8.2 to -0.1, between-group p = 0.045); iv) VD/VT (-0.04, 95% CI: -0.08 to -0.00, between-group p = 0.041); and v) O2-pulse (0.7 mL/beat, 95% CI: 0.3 to 1.2 mL/beat, between-group p = 0.003). Additionally, repeated-measures analysis of variance (ANOVA) indicated a significant time-course effect of ghrelin versus placebo in the peak V[bullet]o2 (p = 0.025). CONCLUSION: Ghrelin administration was associated with improved exertional capacity and improvements in ventilatory-cardiac parameters.Trial registration: UMIN (University Hospital Medical Information Network in Japan: C000000061.
    BMC Pulmonary Medicine 06/2013; 13(1):37. DOI:10.1186/1471-2466-13-37 · 2.40 Impact Factor
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    • "Recombinant growth hormone (GH) improves FFM compared with placebo but does not improve muscle strength or exercise capacity.86 Ghrelin is a novel GH-releasing peptide that induces a positive energy balance by decreasing fat utility and stimulating feeding through GH-independent mechanisms. In a small open-label study, ghrelin increased FFM, muscle strength, and 6-minute walk distance in cachectic COPD patients.160 Systemic side effects with hormonal drugs are a concern, hence there is current interest in the development of anabolic drugs without the unwanted side effects. "
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    ABSTRACT: The skeletal muscles play an essential role in life, providing the mechanical basis for respiration and movement. Skeletal muscle dysfunction is prevalent in all stages of chronic obstructive pulmonary disease (COPD), and significantly influences symptoms, functional capacity, health related quality of life, health resource usage and even mortality. Furthermore, in contrast to the lungs, the skeletal muscles are potentially remedial with existing therapy, namely exercise-training. This review summarizes clinical and laboratory observations of the respiratory and peripheral skeletal muscles (in particular the diaphragm and quadriceps), and current understanding of the underlying etiological processes. As further progress is made in the elucidation of the molecular mechanisms of skeletal muscle dysfunction, new pharmacological therapies are likely to emerge to treat this important extra-pulmonary manifestation of COPD.
    International Journal of COPD 08/2012; 7:523-35. DOI:10.2147/COPD.S28247 · 3.14 Impact Factor
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    • "It stimulates appetite and body weight by chronic administration of ghrelin. It can also increase body weight in many species by food intake, energy expenditure, and fuel utilization [2] [20] [21] [22] [37] [41] [42]. "
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    ABSTRACT: Background. Stressful events in early life predispose to the development of eating disorders in adulthood. This study investigates how neonatal maternal separation (NMS) affects satiety and ghrelin secretion in adulthood. Methods. Sprague-Dawley rats underwent NMS and controls were without NMS. Experiments were conducted on day 60: (1) water avoidance stress (WAS); (2) feeding after overnight fasting; (3) feeding after overnight fasting and WAS. Blood samples, gastric and hypothalamic tissues expression were collected for ghrelin analysis. Results. (1) MS rats had a higher basal ghrelin. After WAS, MS rats had enhanced ghrelin. (2) A higher initial calorie intake and lower postprandial gastric ghrelin protein in MS are observed without difference in overall calorie intake. (3) MS had symptoms of binge eating and early satiation. Overall reduction of calorie intake was observed until 48 hours in MS. Conclusion. Stressful events in early life led to aberrant ghrelin profile and early satiation in response to stressful experience in adulthood.
    08/2012; 1(1):1-8. DOI:10.4303/ne/235603
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