Objective: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SE 209670, a non peptide endothelin-A/endothelin-B receptor antagonist.Methods: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SE 209670 infused at doses that ranged from 0.2 to 1.5 mu g.kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SE 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study.Results: SE 209670 appeared to display Linear kinetics over the dose range from 0.2 to 1.5 mu g.kg(-1).min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-l increased in an apparent dose-dependent manner, Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007), Renal sodium excretion was similar during SE 209670 and placebo infusion.Conclusion: The pharmacokinetics of intravenous SE 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-l, The lack of an ti-natriuretic effect and the renal vasodilator response observed in this study indicate that SE 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

Local skin reactions at the application site are the most common adverse events associated with the testosterone transdermal delivery (TTD) systems used to treat post-pubertal hypogonadism in males. This open-label, controlled pilot study was conducted to determine whether topical pretreatment with triamcinolone acetonide 0.1% cream might be useful in reducing the incidence and/or severity of chronic skin irritation when used in healthy volunteers receiving TTD systems. Adult male volunteers wore three topical systems, which were applied to the upper back daily (Monday through Friday) for 6 weeks: (1) TTD with no pretreatment of application site; (2) TTD with pretreatment of application site using triamcinolone acetonide 0.1% cream; and (3) an inactive occlusive dressing (control). On Monday through Thursday, systems were removed 24 hours after application. Patches applied on Friday were worn continuously for 72 hours until their removal on Monday. Skin reactions were graded on a scale from 0 to 4 (0 = none, 4 = severe) and were assessed daily by research personnel, beginning at the time of system removal (assessment 1) and on the two subsequent clinic visits (assessments 2 and 3). All skin irritation scores of all subjects were totaled for each treatment regimen to obtain a cumulative score per treatment regimen. The cumulative scores were also analyzed by assessment time and study week (weeks 1–6). Eighty-two subjects were enrolled in the study, and 65 completed the 6-week treatment course. Mean age of subjects was 24 years (range, 18–69 years), and mean weight was 79.0 kg (range, 58.9–127.3 kg). All subjects were white males. At assessment 1, pretreatment with triamcinolone acetonide 0.1% cream (compared with no pretreatment) was associated more often with scores of 0 (no erythema), with comparable occurrences of mild skin irritation, and with fewer occurrences of moderate erythema. At all three assessments, more subjects had lower cumulative scores with pretreatment than without pretreatment. At every assessment and in each week of the study, total weekly cumulative skin irritation scores were also lower with pretreatment than without pretreatment. No adverse experiences other than skin irritation were reported. Results of this study suggest that in patients using TTD systems, the incidence and severity of skin irritation at application sites may be reduced through pretreatment with triamcinolone acetonide 0.1% cream.