Approximately of the etamicastat dose
Approximately 50% of the etamicastat dose was recovered in urine, 30% in the form of etamicastat and 20% in the form of BIA 5-961. These data agree with those from a study with [14C]-labeled etamicastat in healthy subjects, which showed that approximately 95% of the administered radioactivity had been excreted for up to 11 days after single-dose administration, two thirds in urine and one third in SR 1555 hydrochloride (data on file, BIAL–Portela & Cª, S.A. [BIA-5453-103, 2009]). Besides N-acetylation, biotransformation of etamicastat involves glucuronidation, oxidation, oxidative deamination, and desulfation. Clearance values of etamicastat with the 100- and 200-mg doses were 9.9 and 11.4 L/h, respectively, which are in line with the results of a previous study (11.3–14.8 L/h) and are above the glomerular filtration rate (7.6 L/h).
In the present study, etamicastat showed very promising BP-lowering effects, with no clinically or statistically relevant changes in HR. Despite the relatively small sample size (5 or 6 patients in each dose group) and the short treatment period (10 days), a dose-dependent decrease in both SBP and DBP was apparent after 10 days of treatment. The observed decrease attained statistical significance versus placebo in nighttime SBP for all etamicastat doses: –11.66 mm Hg (95% CI, –21.57 to –1.76; P < 0.05) for 50 mg, –14.92 mm Hg (95% CI, –24.98 to –4.87; P < 0.01) for 100 mg, and –13.62 mm Hg (95% CI, –22.29 to –3.95; P < 0.01) for 200 mg. The decreases in nighttime DBP versus placebo did not attain statistical significance following any dose of etamicastat, which might be due to the small sample size, the large interindividual variability, or the relatively short duration of treatment. Surprisingly, etamicastat 200 mg provided decreases in both nighttime SBP and DBP that were numerically similar to those of the 100-mg dose. Results of a detailed meta-analysis of 147 randomized trials of BP reduction showed that, regardless of BP before treatment, lowering SBP by 10 mm Hg or DBP by 5 mm Hg significantly reduced coronary events and stroke without an increase in nonvascular mortality. On the other hand, it should be underlined that nighttime BP is a better predictor than daytime BP and that nocturnal BP may be a target for reducing cardiovascular morbidity and mortality in hypertensive patients.
Although in the present study an evaluation of DβH activity, a biological end point of efficacy for compounds such as etamicastat, was not performed, in previous studies the dose levels tested here caused a dose-dependent decrease in DβH activity and decreases in sympathetic drive, as evidenced by decreases in urinary catecholamines.24, 26
Conflicts of Interest
Introduction Eysenck’s Extraversion (E) and Neuroticism (N) dimensions of personality are widely accepted in trait models of personality. However, his third dimension of Psychoticism (P) has been more controversial (Bishop, 1977; Block, 1977). Originally, this dimension was hypothesized to discriminate between people with psychotic disorders at one extreme and normalcy at the other. While it is true that people with psychotic disorders score highly, so do many other non-psychotic groups, including criminals and creative artists. Such findings have led to a questioning of the appropriateness of the label of “Psychoticism” given to this trait. Zuckerman (1989) has proposed that this dimension really measures “impulsive unsocialized sensation seeking”. He described the dimension as encompassing traits of “sensation seeking, impulsivity, non-conformity and a lack of restraint, responsibility, need to think in a structured way, and an unwillingness to live by the rules and norms of society” (p. 397). Within the framework of the rival five-factor model of personality, P is seen as a blend of (low) agreeableness and conscientiousness (Eysenck, 1992).