The major goals of this project are: 1) To investigate the mechanisms underlying the anabolic effects of thalidomide, 2) To determine the dose of hGH which achieves the optimal anabolic effect, 3) To determine whether a combination and thalidomide act synergistically to improve the functional lean body mass (LBM). The applicant proposes that administration of a lower doses of hGH may avoid the metabolic and structural side effects of hGH and combination with thalidomide may be additive or synergistic. He proposes to study the effects of these two agents under metabolic ward conditions, using metabolic balance studies, whole body kinetic studies, direct determination of muscle protein synthesis, and body fluid compartments.
The specific aims are: 1) to find an optimal dose of hGH which will achieve the protein-anabolic effects without causing (or minimizing), the hypermetabolism and accumulation of non-functional extracellular tissue. 2) to determine whether thalidomide decreases the net protein degradation without increasing lipid oxidation and REE. 3) to test whether administration of thalidomide in combination with lower doses of hGH achieve a selective increase in the functional, as opposed to non-functional, lean tissue and causes a smaller increase in the REE. Total number of 42 HIV+ patients and HIV- control subjects will be included over a period of 5 years. All subjects will participate in a 2 week inpatient study, which will involve treatments with hGH or thalidomide or both. Then the HIV+ patients will continue their treatments for another 10 weeks. At the end of these period HIV+ patients will be readmitted for a 5 day period for the repeat studies. The investigations will include 1) the measurements of body weight and composition (by DEXA, bioelectrical impedance, D20 and Na bromide dilution, and midarm circumference measurement techniques), 2) metabolic balance studies of nitrogen, K, Na, SO4, 3) determination of resting energy expenditure and substrate oxidation rates by indirect calorimetry, 4) protein and lipid metabolism studies using stable isotopes of leucine and glycerol, 5) determination of muscle protein synthesis by measuring the incorporation of leucine to muscle protein and abundance of myosin heavy chain mRNA, 6) measurements of hormones, metabolites, TNFalpha and other cytokines, immunologic and virologic parameters. This study will address the mechanisms of HIV-induced wasting and investigate the role of two potential medical treatments.
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