J Chromatogr. 1986 Nov 28;383(1):119-27.
Development of a rapid extraction and high-performance liquid chromatographic separation for amitriptyline and six biological metabolites.

Kiel JS, Abramson RK, Smith CS, Morgan SL.

The development of a rapid high-performance liquid chromatographic method for the determination of amitriptyline, amitriptyline-N-oxide, 10-hydroxy amitriptyline, 10-hydroxynortriptyline (E and Z isomers), nortriptyline and desmethylnortriptyline in plasma and liver tissue is described. A liquid--liquid extraction with hexane--butanol and back-extraction into phosphoric acid provides efficient extraction of amitriptyline-N-oxide along with amitriptyline and the other metabolites. A Supelcosil C8 reversed-phase column with 5-micron packing and a methanol--sodium phosphate buffer--amine modifier mobile phase was used. The combination of mobile phase pH and amine modifier concentration for the best separation within a reasonable analysis time for all seven solutes plus an internal standard was determined using a factorial design coupled with a multi-factor window diagram technique. Ultraviolet detection at 214 nm provided limits of detection of approximately 1 ng/ml.

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Arch Int Pharmacodyn Ther. 1983 Jun;263(2):197-207.
Acute cardiac effects of fluvoxamine and other antidepressants in conscious rabbits.

Wouters W, Deiman W.

The effects of continuous infusion of amitriptyline (0.35 mg/kg/min), mianserin (0.70 mg/kg/min) or fluvoxamine (0.70 mg/kg/min) were studied on electrocardiogram (ECG), heart contractility and temperature in conscious rabbits. Lethal doses for amitriptyline (median 13.6 mg/kg) were much lower than for mianserin (median 56.0 mg/kg) or fluvoxamine (median 59.5 mg/kg). Amitriptyline induced severe arrhythmias and ECG disturbances at relatively low doses. Mianserin induced arrhythmias and ECG disturbances at higher doses, while arrhythmias were infrequently seen with fluvoxamine. ECG disturbances were observed at fluvoxamine doses approaching lethality. Amitriptyline very much lowered contractility as assessed by LVdP/dt. With fluvoxamine a decrease in LVdP/dt was only observed at moderate doses while at nearly lethal doses neither fluvoxamine nor mianserin induced a decrease in LVdP/dt. Fluvoxamine raised body temperature significantly. Fluvoxamine seems, at least in this animal model, a drug which induces far fewer cardiac disturbances than amitriptyline and even fewer than mianserin. It is concluded that fluvoxamine is relatively free from cardiotoxicity.

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Nippon Yakurigaku Zasshi. 1980 Apr;76(3):213-25.
[Effects of mianserin on functions of ascending and descending monoaminergic systems, using experimental models (author's transl)]

[Article in Japanese]

Sakai Y, Deguchi T.

Studies were carried out to evaluate the antidepressant action of Mianserin as related to noradrenergic and serotonergic systems. The actions of known tricyclic anti-depressants were comparatively investigated together with Mianserin (Organon). Self-stimulation behavior induced by stimulation of the posterior hypothalamus and substantia nigra was unaffected by Mianserin and imipramine, was suppressed with chlorpromazine and markedly enhanced by methamphetamine. The enhancement due to methamphetamine was suppressed by both Mianserin and chlorpromazine, and was potentiated by imipramine. Mianserin, imipramine and amitriptyline enhanced the rolling movements induced by methamphetamine in rats in which the nigro-striatal dopaminergic system was destroyed by the injection of 6-hydroxydopamine. The excitation induced by ldopa administration, of isocarboxazid treated mouse was enhanced by Mianserin in doses over 25 mg/kg and by imipramine or amitriptyline. The excitation of MK-486 treated mouse, induced by L-5HTP was suppressed by Mianserin, nortriptyline augmented the excitation. The head twitches induced by 5HTP were reduced to 1/10 in onset frequency by Mianserin, 1 mg/kg, p.o. The suppressive potency of amitriptyline in this model was less than 1/5 of that of Mianserin. The potentiation of the flexor reflex of hind limbs of the spinal rat induced by the pretreatment with isocarboxazid and l-dopa, 20 hours after the reserpinization, was markedly suppressed by Mianserin and amitriptyline, but unaffected by imipramine nor chlorimipramine. The potentiation of the extensor reflex of hind limbs of the spinal rat, induced 20 hours after the reserpinization by pretreatment with isocarboxazid and 5-HTP was suppressed by Mianserin, even in a low dose of 0.5 mg/kg, and by amitriptyline in a dose of 10 mg/kg. As far as monoaminergic mechanisms are concerned, the mode of antidepresant action of Mianserin is probably different from that of tricyclic antidepressants.

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Drug Metab Dispos. 1981 Nov-Dec;9(6):565-8.
Demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxy amitriptyline in human liver microsomes.

Mellstrom B, von Bahr C.

The rates of demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxy amitriptyline by microsomes from adult human livers were determined by use of mass-fragmentographic or liquid-chromatographic quantitation of the formed metabolites. The demethylation rates of amitriptyline and 10-hydroxy amitriptyline were higher than the hydroxylation rates of amitriptyline and nortriptyline, especially at high substrate concentration. The amitriptyline demethylation rates were 96-570 and 1750-9230 pmol per mg of protein per 10 min at substrate concentrations of 5 and 100 micro M, respectively. The corresponding rates for the hydroxylations were 43-146 and 305-871, respectively. At high substrate concentration (250 micro M) the curve of concentration vs. rate for 10-hydroxylation of amitriptyline seemed to approach a plateau, whereas those for demethylation did not. Interaction between amitriptyline and nortriptyline at the microsomal level was studied by use of deuterium-labeled amitriptyline, and these two compounds were found to inhibit the hydroxylation of each other. In contrast to hydroxylation, the demethylation of labeled amitriptyline increased upon addition of nortriptyline. These results suggest that the well-established variation in steady-state plasma levels of tricyclic antidepressants is due to interindividual differences in liver enzyme activity.

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J Protozool. 1990 Jan-Feb;37(1):54-8.
Antimalarial properties of imipramine and amitriptyline.

Dutta P, Pinto J, Rivlin R.

Memorial Sloan-Kettering Cancer Center, New York, New York.

Dietary riboflavin deficiency is known to diminish malarial parasitemia. In this study, we determined whether imipramine and amitriptyline, drugs which inhibit riboflavin metabolism, have antimalarial efficacy. In addition, we evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of Plasmodium falciparum (FCR3) in the absence and presence of these drugs (10 to 75 microM) was measured by determining (3H)hypoxanthine uptake by intra-erythrocytic parasites for 48 h in RPMI 1640 medium. The uptake of (3H)hypoxanthine was significantly reduced in a dose-dependent manner by both imipramine and amitriptyline. The IC50 values of imipramine and amitriptyline at 48 h were 56 and 45 microM, respectively. Both drugs enhanced hemolysis induced by FP (10 or 20 microM). No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, imipramine and amitriptyline, possess substantial antimalarial properties.

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Postgrad Med J. 1980;56 Suppl 1:127-9.
Plasma levels and clinical improvement--a comparative study of clomipramine and amitriptyline in depression.

Moyes IC, Ray RL, Moyes RB.

To see if the clinical efficacy of amitriptyline and clomipramine is related to plasma level of the active drug or its main metabolite, or to the balance between them, plasma levels and clinical progress have been studied in 48 patients taking standard dosage. Dose for dose, plasma levels of clomipramine and desmethylclomipramine are usually higher than those of amitriptyline and its main metabolite nortriptyline, but no significant relationship between plasma levels and clinical improvement was found following clomipramine administration. By contrast, optimum responses to amitriptyline therapy were obtained at plasma levels of 50--100 micrograms/l for amitryiptyline itself and 25--75 micrograms/l for nortriptyline, but when their ratio exceeded 0--7 improvement declined. Steady states were reached after two to three weeks but a crude measure could be obtained from the plasma level after four days' treatment. Clomipramine and amitriptyline appeared to be equally effective, with clomipramine taking slightly longer to relieve depression.

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Eur J Clin Pharmacol. 1978 Jun 19;13(4):259-62.
Effect of intravenous infusion of amitriptyline on total blood serotonin content.

Banki CM, Vojnik M.

18 female patients with primary depression received a slow intravenous infusion of amitriptyline and a good therapeutic response was observed in 15 patients as early as after 6 days. A highly significant correlation was found between improvement scores following the first and last infusions, which suggests that intravenous infusion of amitriptyline may serve as a prognostic test for prediction of drug efficacy. Total blood serotonin content prior to treatment was significantly lower than in normal controls. Amitriptyline infusion caused variable changes in blood serotonin and the changes were inversely correlated with pretreatment levels. A series of six infusions caused a gradual increase in baseline levels, together with a rapid decrease in the magnitude of the amitriptyline-induced changes in serotonin content.

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