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 [(ϩ)-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%) (Pϭ0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD 30 ) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (PϽ0.001). 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, PϽ0.001). 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 (PϽ0.001), 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.

Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, threeperiod crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD 30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p ¼ 0.07; 60 mg b.i.d.: p ¼ 0.02; combined regimens: p ¼ 0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (po0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD 30 increased significantly with desipramine dosing (po0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD 30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.

1 In a double-blind crossover trial, the effect of 4 week daily ingestion of eight cups of regular coffee (corresponding to 504 mg caffeine) vs eight cups of decaffeinated coffee was studied. Blood pressure, heart rate and urinary catecholamines were measured in eight healthy, young volunteers. 2 In both groups, regular coffee immediately led to a significant increase in mean blood pressure (+ 3 and + 5 mm Hg respectively). The difference between both groups, however, existed only in the first 3 to 5 days of ingestion of regular coffee. On day 5 after ingestion of regular coffee, and thereafter in weekly intervals, no significant increase in catecholamine excretion was observed. 3 The data suggest that long-term consumption of large amounts of coffee leads to only a small and transient rise in mean blood pressure. This may be due to an adaptation phenomenon. 4 Therefore, continuous heavy coffee ingestion (eight cups/day for 4 weeks) by young persons does not appear to involve a risk of the development of hypertension.

The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty-five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase-B (MAO-B) when administered in doses of 20 mg/day and higher.