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Purpose: RC-1291 is a novel, oral ghrelin mimetic and growth hormone (GH) secretagogue being developed to increase appetite and lean muscle mass in patients with cancer-associated anorexia/cachexia. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation phase I study in healthy volunteers evaluated RC-1291 once daily (qd) and twice daily (bid) for effect on body weight and safety., Methods: The study was conducted with three sequential groups of volunteers. Panel A subjects (n = 8) received placebo or RC-1291, 25 mg qd, for 5 days. Panel B subjects received RC-1291, 25 mg bid or 50 mg qd, for 6 days then crossed over to the other dosage for 5 days (n = 12); three subjects received placebo for all 11 doses to maintain double-blinding. Panel C subjects (n = 9) received placebo or RC-1291, 75 mg qd, for 6 days., Results: Subjects who received RC-1291, 50 or 75 mg, had significant dose-related weight gain after 6 days versus placebo, with the greatest increases seen with daily dosing. The mean increase in weight from baseline after 50 mg qd was 1.25 +/- 0.725 kg (p = .0022 versus placebo), and after 75 mg qd it was 1.16 +/- 0.651 kg (p = .0022 versus placebo). One subject in the 50 mg qd group had moderate transient elevation in aspartate aminotransferase and alanine aminotransferase levels. No other laboratory or clinical adverse events of consequence were reported., Conclusions: Results indicate that RC-1291 produces dose-related increases in body weight with no dose-limiting adverse effects, and may be an effective treatment for anorexia/cachexia.

Background: A recent development in critical care medicine makes it urgent that research into the effect of hormones on immunity be pursued aggressively. Studies have demonstrated a large reduction in mortality as a result of infusion with glucose, insulin and potassium. Our work in the oncology setting has led us to propose that the principal reason for such an effect is that GIK stimulates lymphocytes to proliferate and attack pathogens, sparing the patient the stress of infection. That suggestion is based on a new model of immunity that describes the effect of hormones on lymphocytes. We hypothesized that the application of glucose, insulin, thyroid and potassium would awaken inert tumor infiltrating lymphocytes to destroy the tumor., Methods: The antitumor effect of a thyroxine, glucose, insulin, and potassium (TGIK) combination was studied in a series of controlled experiments in murine models of tumor progression to assess the biologic activity of the formulation, the effect of route of administration, the effect on tumor type, and the requirement for insulin in the TGIK formulation., Results: Melanoma and colon tumors inoculated with TGIK were significantly reduced in size or retarded in growth compared to controls injected with saline. I.P. and I.M. injections showed that the formulation had no effect systemically at the doses administered., Conclusion: We conclude that TGIK has anti-tumor activity when administered intratumorally, probably by stimulating lymphocytes to attack tumors. This is similar to the effect of GIK on reducing sepsis in critical care patients. We suggest that when GIK is administered exogenously, it restores immune competence to the critically ill or cancer patient and causes destruction of pathogens or tumors, while endogenous resources are devoted to repair. This implies that hormonal therapy may be useful in treating various other pathologies involving immune suppression, as well as malignancies. We also propose research that could bring resolution of the controversy over mechanism and point the way to new therapeutic strategies for numerous diseases including chronic infections and auto-immune diseases.

Aims: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers., Methods: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion., Results: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness., Conclusions: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.