Two different initial dosing regimens with clomipramine (CMI) were compared with particular attention to early response indicators. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading (P-L) group received 150 and 200 mg of CMI on two consecutive evenings, then placebo for 8 days; the traditional group began at 50 mg, followed by gradual increases every second day until 200 mg was reached. Both groups were then placed on an adjustable dosing schedule of CMI, initially set at 200 mg for an additional 2 weeks. After the completion of P-L, the improvement in scores on the Hamilton Rating Scale for Depression across protocol days 7 to 13 (the P-L placebo period) was equivalent for both dosage regimens and was significantly associated with therapeutic response at the end of the study (p = 0.0186). Desmethylclomipramine levels were significantly greater in P-L nonresponders (p = 0.0039), and a ratio of desmethylclomipramine/CMI of 2 or more after P-L was strongly associated with failure to respond to CMI (p = 0.02). Early, acute responses and assessments of metabolism observed with targeted doses of CMI may be predictive of later successful treatment.

1986-01-01·Pharmacology4区 · 医学

Physiologic Responses to Chronic Dietary Tyrosine Supplementation in DOCA-Salt-Treated Rats

4区 · 医学

Article

作者: Hathaway, Susan ; Wilson, Karen M. ; Henley, William N. ; Fregly, Melvin J.

The antihypertensive effect of chronic administration of L-tyrosine (Tyr) was investigated in a two-part study. In the first experiment, adult male Sprague-Dawley rats were assigned to 1 of 4 treatment groups: control diet plus unilateral nephrectomy (Nphx) and 0.15 M NaCl (Sal) as the sole drinking solution (C-CTRL); control diet plus deoxycorticosterone acetate (DOCA, 268 micrograms/rat/day), Nphx, and Sal (C-DOCA); control diet supplemented with 2.5% L-p-Tyr plus Nphx and Sal (Tyr-CTRL), and Tyr plus DOCA, Nphx, and Sal (Tyr-DOCA). Systolic blood pressure (SBP) increased within 2 weeks after initiation of treatment with DOCA-salt and remained elevated throughout the duration (8 weeks) of the study (p less than 0.001). Dietary administration of Tyr to DOCA-treated rats failed either to affect SBP in normotensive rats or the elevation of SBP in DOCA-treated rats. Dietary supplementation with Tyr induced a significant elevation in urinary excretion of free dopamine (week 1, 3, 5, and 7) and a decreased excretion of free norepinephrine (week 1) without regard to DOCA treatment. Metabolic responsiveness (change in colonic temperature) and cardiovascular responsiveness (change in heart rate) to subcutaneous administration of the beta-adrenergic agonist, isoproterenol, were significantly prolonged while alpha 2-adrenoceptor number (cerebral cortical membranes; 3H-yohimbine binding) was reduced in rats receiving Tyr. In the second experiment, similar rats were assigned to 1 of 3 treatment groups: control diet plus Nphx and Sal, control diet plus Nphx, DOCA and Sal, and Tyr plus DOCA, Nphx, and Sal; however, Tyr was not started until DOCA-salt-induced hypertension developed (4 weeks). Neither acute (2.5 h post-meal) nor chronic (4 weeks) effects of administration of Tyr on SBP were noted. Thus, the Tyr-induced changes observed in these studies include a chronic increase in free dopamine, and a transient decrease in norepinephrine, excretion. No significant effects of Tyr on blood pressure of DOCA-salt-treated rats were observed.

100 项与 L-MMC/P 相关的药物交易

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