If you don't know where you are going, you can't tell if you have arrived: defining goals for drug safety announcements.

One of the responses available to drug regulators facing a potential drug safety issue is to release a "Dear Doctor" letter describing the problem. Although numerous such safety alerts are issued every year, we know almost nothing about their effectiveness in improving patient outcomes. The article by Reber et al. in this issue is important because it is one of the few studies to examine the effect of such safety alerts on physician behavior.

The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.

Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade.

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.

Differences in clearance and sensitivity to Triazolam in American blacks as compared with whites

BACKGROUND: Inter-ethnic differences exist in both pharmocodynamics and pharmocokinetics. CYP3A is the most abundant cytochrome P450 enzyme in human liver and is responsible for the metabolism of a large number of drugs and xenobiotics. AIM OF STUDY: The purpose of the present study was to determine whether there are differences in the metabolism and drug responsiveness to triazolam, a substrate of CYP3A, in American blacks and whites. METHODS: Eight American blacks and eight age - and body weight- matched whites receved orally a triazolam 0.375 mg tablet in a double-blind placebo-controlled randomized study. Plasma concentrations and effects of triazolam were measured at multiple time points over 24 hours. The pharmacodynamics of triazolam were examined by measurement of postural sway, digital symbol substitution testing (DSST), and a visual analog scale (VAS) of drowiness. Sensitivity, or the drug effect at a given concentration, was determined. RESULTS: Following oral administration of triazolam, the AUC was significantly lower in blacks (625 +- 160 ng/ml/min) (P<0.05). The systemic clearance of triazolam was three and a half fold higher in blacks (6.6 +- 2.0 vs 1.8 +- 0.2 ml/min/kg in whites, P<0.05) resulting in a shorter elimination t 1/2 (98 +- 24 vs 199 +- 29 min, P<0.05). Triazolam significantly increased postural sway and drowsiness and impaired DSST in both groups. However, there was no significant differences between the two groups in drug effects such that a similar effect of triazolam was observed in blacks with lower plasma concentration. When compared to whites, the sensitivity to triazolam was significantly higher in blacks (P<0.05). CONCLUSIONS: This study demonstrates increased clearance and increased sensitivity to triazlam in American blacks. These findings may have major therapeutic implications in a racially diverse population. (AU)