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Abstract: We measured plasma concentration of α-melanoctye-stimulating hormone (α-MSH), a proopiomelanocortin derivative that modulates pyrogenic and proinflammatory effects of cytokines, in infectious and inflammatory disorders in humans to learn if changes in this peptide take place in naturally occurring disease. α-MSH was elevated in HIV-infected patients of the CDC groups III and IV. Although the peptide increased in the circulation of normal subjects injected with endotoxin, it was reduced in patients with septic syndrome. α-MSH was found in the synovial fluid of arthritis patients, and its concentration was greater in the forms of arthritis marked by greater inflammation. We found that α-MSH is increased in the circulation of patients with acute myocardial infarction receiving thrombolitic therapy. Plasma concentrations of α-MSH is increased in the circulation of patients with acute myocardial infarction receiving thrombolitic therapy. Plasma concentrations of α-MSH were lower in healthy elderly subjects than in young controls. Because an excess of proinflammatory cytokines can have detrimental effects, we investigated the influences of α-MSH on the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in HIV-infected patients and in patients with septic syndrome. Production of these cytokines in whole-blood samples stimulated with endotoxin was significantly reduced by treatment of blood with α-MSH. α-MSH has been injected into at least 106 human subjects to study its effects on pituitary function, menstrual bleeding, and tanning. The peptide was always well tolerated. α-MSH administration could open new perspectives in treatment of inflammatory diseases in humans.