Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles

Article

关键词: NERVOUS-SYSTEM ACTIVITY;    ORTHOSTATIC INTOLERANCE;    PLASMA NOREPINEPHRINE;    HEALTHY-SUBJECTS;    RAT-BRAIN;    SEROTONIN;    DULOXETINE;    DESIPRAMINE;    INHIBITION;   

DOI  :  10.1161/01.CIR.0000130847.18666.39

来源: SCIE

【 摘 要 】

Background-To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine ( NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. Methods and Results-Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P = 0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P < 0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. Conclusions-These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.

【 授权许可】

Free