title: Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.
abstract: The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.
authors.affiliation: Department of Clinical Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
authors.forename: P A
authors.initials: PA
authors.lastname: Reece
authors.forename: A J
authors.initials: AJ
authors.lastname: Sedman
authors.forename: S
authors.initials: S
authors.lastname: Rose
authors.forename: D S
authors.initials: DS
authors.lastname: Wright
authors.forename: R
authors.initials: R
authors.lastname: Dawkins
authors.forename: R
authors.initials: R
authors.lastname: Rajagopalan
mesh_terms: D000328:Adult; D001572:Benzofurans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004232:Diuretics / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D001572:Benzofurans; D004232:Diuretics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C067110:enadoline