Clin Ther. 1981;3(5):374-81.
Relative speed of onset of the antidepressant effect of maprotiline.

Silverstone T.

In a double-blind clinical trial conducted in general practice, maprotiline was compared with amitriptyline. Thirty-three of 40 patients completed the trial, 19 on maprotiline and 14 on amitriptyline. The Hamilton Depression Rating Scale was administered on days, 0, 7, 14, and 21, and a global rating scale of improvement was administered on day 21. Although there were significant reductions in the Hamilton scores by day 21 in both groups, with no significant difference between the compounds, maprotiline produced significantly greater improvement by day 7 than did amitriptyline. A review of published double-blind clinical amitriptyline or imipramine for treatment of depression supports our finding that maprotiline has a faster onset of action than the standard tricyclic antidepressants.

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J Pharmacol Exp Ther. 1984 Nov;231(2):387-94.
Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate.

Sasyniuk BI, Jhamandas V.

Alkalinization with NaHCO3 can effectively reverse ventricular arrhythmias caused by amitriptyline intoxication, but the mechanism is unclear. To test whether alkalinization per se is important or whether increases in extracellular Na concentration also contribute, we exposed Purkinje fibers to 500 ng/ml (1.8 microM) of amitriptyline and then superfused them with three different test solutions, viz. 1) high Na-Tyrode's, 2) high NaHCO3-Tyrode's and 3) high pH-low pCO2-Tyrode's. Amitriptyline significantly depressed action potential amplitude and Vmax without altering resting membrane potential and abbreviated action potential duration at all phases of repolarization. Effects on phase 0 were accompanied by a depression of conduction velocity. All three test solutions produced significant hyperpolarization and improvement in action potential amplitude and Vmax. However, the magnitude of improvement of phase 0 characteristics was significantly greater after high NaHCO3 and resulted in significant improvement of conduction velocity in fibers depressed by amitriptyline. The effects of amitriptyline on phase 0 were rate-dependent. Reversal of this effect by NaHCO3 was equally effective at all rates. Improvement of Vmax was partly related to a shift of the Vmax-membrane potential relationship in the depolarizing direction. NaHCO3 had minimal and variable effects on action potential duration. The results suggest that the beneficial effects of NaHCO3 are related to a reversal of drug effects on phase 0 characteristics and that this effect is due both to alkalinization and to increases in extracellular Na concentration.

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Acta Pharmacol Toxicol (Copenh). 1985 Jan;56(1):75-80.
Anticholinergic activity in the serum of patients receiving maintenance amitriptyline or doxepin therapy.

Aaltonen L, Syvalahti E, Iisalo E, Peltomaki T.

The anticholinergic activity in serum of depressive patients receiving amitriptyline (50-300 mg/day) or doxepin (50-225 mg/day) was measured using a radioreceptor assay. In this method the membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist, quinuclidinyl benzilate. Using atropine as a standard, the antimuscarinic activity of several compounds can be measured in the serum of patients receiving drugs with anticholinergic effects or side-effects. The steady state serum levels of amitriptyline and doxepin and their desmethylated metabolites, nortriptyline and desmethyldoxepin were measured by radioimmunoassay in the same serum samples. The antimuscarinic activity in serum measured as atropine equivalents was 2.7 +/- 0.4 (S.E.M.) ng/ml in amitriptyline patients and 1.1 +/- 0.2 ng/ml in doxepin patients. There was a highly significant correlation (P less than 0.001) between amitriptyline (r = 0.92) and nortriptyline (r = 0.79) concentrations and serum antimuscarinic activity. The correlation was less clear, although statistically significant for doxepin (r = 0.42, P less than 0.05) and desmethyldoxepin (r = 0.58, P less than 0.01). The better correlation between serum drug levels and antimuscarinic activity in amitriptyline than in doxepin patients is probably due to the higher affinity of amitriptyline and its desmethylated metabolite to muscarinic receptors with the doses used in the present study. The method may have clinical applications e.g. in evaluation of excessive anticholinergic activity in patients.

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Psychopharmacology (Berl). 1984;83(4):378-9.
The effect of amitriptyline treatment on the growth hormone response to apomorphine.

Cowen PJ, Braddock LE, Gosden B.

The growth hormone response to subcutaneous administration of the dopamine agonist apomorphine (0.005 mg/kg) was assessed in six normal male subjects before and at the end of a course of amitriptyline. Amitriptyline treatment significantly reduced the growth hormone response to apomorphine, confirming the findings of an earlier study in depressed patients. The way in which amitriptyline attenuates the effect of apomorphine is not clear. Direct blockade of dopamine receptors in the hypothalamus is a possibility, but long-term amitriptyline treatment could result in adaptive changes in the monoamine pathways which control GH release.

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J Anal Toxicol. 1980 Sep-Oct;4(5):232-6.
Interpretation of blood and tissue concentrations in fatal self-ingested overdose involving amitriptyline: an update (1978-1979).

Bailey DN, Shaw RF.

Thirty-two cases of fatal self-ingested overdose involving amitriptyline were studied over the two-year period 1978 to 1979. The average decedent was a 44-year-old woman who ingested amitriptyline and at least one other drug (usually ethanol, diazepam, propoxyphene, or codeine). The mean concentrations of amitriptyline and nortriptyline were significantly higher in liver than in myocardium, and they were significantly higher in myocardium than in blood. In addition, concentrations in these tissues showed significant correlation with each other. The mean tissue concentrations of amitriptyline and nortriptyline in this series of overdoses were significantly greater than those in fourteen other decedents whose deaths were not due to drug overdose but involved amitriptyline as an incidental finding. The mean ratio of amitriptyline to nortriptyline in each tissue was also significantly higher in overdose than those in the corresponding tissues of the non-overdose group, suggesting that the former ingestions were more acute. The estimated survival times showed no significant correlation with tissue concentrations of either amitriptyline or nortriptyline.

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J Neurobiol. 1986 Nov;17(6):681-95.
Inhibition of fast axonal transport in bullfrog nerves by dibenzazepine and dibenzocycloheptadiene calmodulin inhibitors.

Lavoie PA, Tiberi M.

The effects of the calmodulin inhibitors amitriptyline, desipramine, imipramine, and clomipramine on fast axonal transport, oxidative metabolism, and density of axonal microtubules were measured in bullfrog spinal nerves in vitro. The four drugs tested inhibited the fast orthograde transport of [3H]leucine-labelled proteins and the fast retrograde transport of acetylcholinesterase at a concentration of 0.2 mM. Amitriptyline, desipramine, and imipramine were equipotent inhibitors of transport, and clomipramine was a more potent inhibitor than imipramine. The adenosine triphosphate content of the nerves was reduced by at most 19% by the compounds under study; such a reduction cannot account for the inhibition of fast axonal transport. Desipramine and imipramine had no significant effect on the density of microtubules in unmyelinated axons, whereas amitriptyline only reduced it by 18%; the inhibition of axonal transport by these three drugs can therefore not be explained by microtubule disruption. Clomipramine reduced microtubular density by 40%, and this effect may have contributed to the inhibition of fast axonal transport. The inhibition of fast axonal transport by desipramine, imipramine, and amitriptyline may be related to the inhibition of calmodulin function by these drugs. The similar potency of these three drugs as inhibitors of fast axonal transport goes in parallel with their known similar potency as calmodulin antagonists.

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Brain Res. 1980 Aug 4;194(2):443-53.
Amitriptyline: long-term treatment elevates alpha-adrenergic and muscarinic receptor binding in mouse brain.

Rehavi M, Ramot O, Yavetz B, Sokolovsky M.

The effects of long-term treatment of the tricyclic antidepressant drug, amitriptyline, on alpha-adrenergic, muscarinic and dopaminergic receptor binding were studied in mouse brain. No changes could be observed after 7 or 14 days of amitriptyline administration, but after 21 days a two-fold increase in alpha-adrenergic binding was detected in the medulla pons and in the hippocampus using [3H]WB-4101 as the binding ligand. In the same two regions, a moderate increase in muscarinic receptor binding (25%) as measured by [3H]4NMPB was seen, while no change was detected in dopaminergic receptor binding measured by [3H]spiperone. Scatchard analysis reveals that the increases in receptor densities are not a result of changes in the dissociation constants of the tritiated drugs for their receptors. It is suggested that the increase in alpha-adrenergic as well as in muscarinic binding is a consequence of a chronic blockade of these two types of receptors by amitriptyline in vivo.

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