AQUARETIC EFFECT OF THE STABLE DYNORPHIN-A ANALOG E2078 IN THE HUMAN

Dynorphin-A is an endogenously released hormone that is now recognized as a kappa-opioid receptor agonist. Because kappa-agonists have been reported to induce water diuresis through negative modulation of antid iuretic hormone release and/or action, in the present study we investi gated the aquaretic effects and safety of E2078, a metabolically stabl e dynorphin-A analog, in 21 healthy subjects after single (1.0, 2.0, 3 .0, 5.0, 7.5 and 10.0 mg, i.m.) and repeated (5.0 mg t.i.d. for 4 and 1/3 days) administration. E2078 dose-dependently increased the 0 to 4- hr urine volume, which plateaued between 1032.4 +/- 130.1 and 1286.2 /- 113.0 ml/4 hr (mean +/- S.E.M.) at doses of between 5.0 and 10.0 mg . The drug decreased urine osmolality (U-osm) markedly, by 17 to 27%, and the free-water clearance (C-H2O) became positive, changing from -1 .8 +/- 0.2 (placebo) to 0.8 +/- 0.3-2.8 +/- 0.4 ml/min after a single E2078 administration (P < .01). In the repeated-dose study, the first dose of E2078 increased the 0 to 5-hr urine output (1256 +/- 164.9 ml/ 5 h), lowered U-osm (151.8 +/- 13.3 mOsm/kg) and brought about a posit ive C-H2O (1.9 +/- 0.2 ml/min). These values were similar to those see n after the single dose, but after the subsequent doses these aquareti c effects were attenuated, although the ranges of these same parameter s were still significantly greater (P < .01-0.05) (441.4 +/- 102.4-585 .3 +/- 131.9 ml/5 hr, 322.8 +/- 21.9-378.2 +/- 47.7 mOsm/kg and -0.2 /- 0.2-0.6 +/- 0.2 ml/min, respectively) than the day-1 base line (164 .1 +/- 41.3 ml/5 hr, 992.0 +/- 80.6 mOsm/kg and -1.2 +/- 0.2 ml/min, r espectively). Urinary excretion of electrolytes (Na, K and Cl) was not altered during either study period. A single E2078 administration red uced plasma antidiuretic hormone dose-dependently. On repeated dosing, the plasma concentration had rebounded to approximately 3 pg/ml by th e time of the first dose on days 3 and 5, which lowered it again. The present results suggest that E2078 is a safe and effective aquaretic a nd could be a useful therapeutic tool for patients with water-retainin g diseases.