Zerbe R L, Rowe H, Enas G G, Wong D, Farid N, Lemberger L
J Pharmacol Exp Ther. 1985 Jan;232(1):139-43.
Tomoxetine (LY139603) selectively inhibits norepinephrine uptake in animals and has activity in animal models of depression. Tomoxetine was administered in single oral doses up to 90 mg to healthy normal volunteers. In addition, normal human subjects received either 20 or 40 mg of tomoxetine b.i.d. for 1 week to evaluate the safety and pharmacologic activity of the compound in humans. At these doses, no serious drug-related adverse effects were encountered. Activity of the compound at the lower dose (20 mg b.i.d.) was evaluated by examining changes in the pressor responses to infused norepinephrine and tyramine and by determining [3H]serotonin uptake in platelets harvested from subjects receiving the compound. Pressor sensitivity to norepinephrine was increased by 261 +/- 69% of control, and pressor sensitivity to tyramine was decreased by 51 +/- 6% of control during treatment. Changes in the pressor sensitivity to norepinephrine in individual subjects were positively correlated with drug levels. There were no statistically significant changes in platelet [3H]serotonin uptake. These results indicate that tomoxetine selectively inhibits norepinephrine uptake in humans at doses which are clinically well tolerated and suggest that tomoxetine has potential clinical use as an antidepressant.
托莫西汀（LY139603）可选择性抑制动物体内去甲肾上腺素的摄取，并在抑郁症动物模型中具有活性。已对健康正常志愿者给予高达90毫克的单次口服剂量托莫西汀。此外，正常人类受试者接受20毫克或40毫克托莫西汀每日两次，持续1周，以评估该化合物在人体中的安全性和药理活性。在这些剂量下，未出现严重的药物相关不良反应。通过检查对输注去甲肾上腺素和酪胺的升压反应变化以及测定接受该化合物受试者采集的血小板中[3H]5-羟色胺摄取情况，评估了较低剂量（20毫克每日两次）时该化合物的活性。治疗期间，对去甲肾上腺素的升压敏感性较对照增加了261±69%，对酪胺的升压敏感性较对照降低了51±6%。个体受试者对去甲肾上腺素升压敏感性的变化与药物水平呈正相关。血小板[3H]5-羟色胺摄取未见统计学显著变化。这些结果表明，托莫西汀在临床耐受性良好的剂量下可选择性抑制人体去甲肾上腺素摄取，并提示托莫西汀有作为抗抑郁药的潜在临床用途。
