No abstract

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 ؎ 858 mL to 4,568 ؎ 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. I n normal individuals, the administration of a water load (20 mL/kg body weight of 5% glucose intravenously or water orally over 45 min) is followed by an increase in the excretion of a hypotonic (Ͻ100 mOsm/ kg) urine flow responsible for an increase in free water clearance (FWC) reaching 6 to 12 mL/min. Cirrhotic patients without ascites have normal water handling. 1 Up to 75% of cirrhotic patients with ascites, however, have moderate reduction (1-6 mL/min) of FWC after a water load. In approximately 30% of cases, the impairment is severe (Ͻ1 mL/min after water load) leading to spontaneous hyponatremia because those patients are unable to excrete regular water intake. 2 Hyponatremia can also be triggered or aggravated by the use of diuretics in about 25% of cases. Pathophysiologic mechanisms leading to water overload are not fully understood, but several factors may be involved, among them: (1) reduced delivery of filtrate to the ascending limb of the loop of Henle, secondary to enhancement of proximal sodium reabsorption and decrease of glomerular filtration rate; (2) reduced renal synthesis of prostaglandins; and (3) increased secretion of antidiuretic hormone. 3 There is some evidence to indicate that increased plasma arginine vasopressin (AVP) concentration plays a major role: a correlation between plasma AVP levels and the magnitude of FWC impairment 4 ; the temporal relationship between impairment of water excretion and vasopressin hypersecretion in rats with experimental cirrhosis; 5 the aquaretic effect of -opioid agonists, which act through inhibition of AVP release

No abstract

Clinical Pharmacology & Therapeutics (2003) 73, P47–P47; doi:

Bazedoxifene is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This phase 1, double-blind, randomized, placebo-controlled study (N = 107) of healthy postmenopausal women examined the pharmacokinetics and safety/tolerability profile of multiple doses of bazedoxifene (1, 2.5, 5, 10, 20, 40, and 80 mg) administered orally once daily for 30 days. Bazedoxifene demonstrated a half-life of 25 to 30 hours, reached steady state within 7 days, and exhibited linear pharmacokinetics over a dose range of 5-80 mg. Fibrinogen levels decreased with bazedoxifene doses of 5 mg and greater; these changes were significant for bazedoxifene 20, 40, and 80 mg (P ≤ .05 vs placebo), but were not dose dependent. Bazedoxifene was associated with increased levels of sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin (CBG); only increases in the levels of CBG appeared to be dose related. Bazedoxifene was safe and well tolerated within the tested dose range. Bazedoxifene showed no differences from placebo in adverse event reports, vital sign measurements, or electrocardiogram findings.