J Toxicol Clin Toxicol. 1990;28(2):235-48.
Evaluation of the Abbott ADx total serum tricyclic immunoassay.

Poklis A, Soghoian D, Crooks CR, Saady JJ.

Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond.

The ADx total serum tricyclic antidepressant (TCA) fluorescence polarization immunoassay (Abbott Diagnostics) for the semi-quantitation of imipramine or amitriptyline and their respective N-demethylated metabolites in cases of TCA overdose was evaluated. The assay is linear from 75-1000 ng/mL total TCA in serum, and flaggs as "HI" all results exceeding 300 ng/mL. The within and between run precision of the assay for patient serum containing imipramine or amitriptyline and their metabolites gave CV's of less than 5.5% and 8.9%, respectively. A good correlation between the results of patient serum containing imipramine and desipramine simultaneously analyzed by ADx and gas liquid chromatography (GC) was observed, r2 = 0.964, n = 32. Results of patient serum containing amitriptyline and nortriptyline or doxepin and desmethyldoxepin analyzed by ADx and GC or GC-mass spectrometry were not well correlated; r2 = 0.738, n = 44 and r2 = 0.695, n = 21, respectively. The assay consistently flagged as "HI" serum with total imipramine and desipramine concentrations above 300 ng/mL by GC, and serum with greater than 360 ng/mL of amitriptyline and nortriptyline by GC/MS. No significant cross-reactivity was observed for drugs other than the TCA.

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Am J Emerg Med. 1986 Mar;4(2):121-5.
Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose.

Levitt MA, Sullivan JB Jr, Owens SM, Burnham L, Finley PR.

Reversing ventricular ectopy with plasma alkalinization following acute tricyclic antidepressant overdose is a recognized mode of therapy. The mechanism responsible for this effect is unclear. Changes in plasma protein binding of free drug, effects of the sodium ion on the myocardium, and alterations of plasma concentrations of alpha-1-acid glycoprotein may all interact to alter toxicity of tricyclics in overdose. An in vitro investigation using equilibrium dialysis was designed to examine the effect of altering plasma pH on percentage of free amitriptyline at clinical overdose plasma concentrations. A 1973 report on this effect lacked adequate controls and was faulty in experimental protocol. The current investigation used plasma concentrations typically present in amitriptyline overdose, a sensitive gas liquid chromatographic assay to detect total and free drug, and adequate control of plasma pH. The results of two separate experiments demonstrated a significant decrease in percentage of free amitriptyline of 20% over a pH range of 7.0-7.4 (P less than 0.05) and 42% over a pH range of 7.4-7.8 (P less than 0.05). The rate of change in slope in both experiments was not significantly different (P less than 0.01) indicating similar effects of pH change on plasma protein binding of amitriptyline within the two groups.

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Neuropharmacology. 1985 Mar;24(3):223-9.
Effects of acute and chronic treatment with amitryptyline on the sleep-wake activity of rats.

Obal F Jr, Benedek G, Lelkes Z, Obal F.

Amitriptyline (1, 5 or 15 mg/kg intraperitoneally, twice a day) was administered to rats and the sleep-wake activity was recorded for either 24 hr (1 mg/kg) or 12 hr (5 or 15 mg/kg) on the day before treatment with amitriptyline, on days 1 and 5 of the treatment and on day 6, when the drug was withdrawn. In the first 3 hr amitriptyline increased non-REM sleep (NREMS), and decreased REM sleep (REMS) and wakefulness; the effects were dose-dependent. The changes in non-REM sleep and wakefulness (W) were followed by a compensatory reaction 6-12 hr after the treatment. The effects of chronic injection of amitriptyline on non-REM sleep revealed a definite decrease only in the case of the 15 mg/kg dose. Rebound of REM sleep appeared after withdrawal of the 5 and 15 mg/kg doses. Amitriptyline at 1 mg/kg had no effect on the sleep-wake activity during the dark period. The results show that the increase in non-REM sleep is as characteristic of amitriptyline as the reduction of REM sleep, and that these effects are resistant to chronic treatment when the dose is small.

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Encephale. 1985 Mar-Apr;11(2):45-51.
[Measurement of basal plasma levels of 3 anterior pituitary hormones during acute or chronic treatment with tricyclic antidepressants]

[Article in French]

Goyot C, Debray Q, Hug R, Grenier J.

Prolactin, growth hormone and thyrotropin plasma levels have been evaluated in depressive in-patients, either during the first day of clomipramine or amitriptyline treatment, or after their chronic administration. Prolactin levels temporary rise during the first day of clomipramine or amitriptyline treatment in 6 patients out of 11, with a lag in relation to the drug plasma peak. A significant increase is observed after a 28 days treatment with clomipramine and a non significant decrease, after a 28 days treatment with amitriptyline. As for human growth hormone, a rise is found in 5 out of 8 clomipramine treated subjects but neither any variation with amitriptyline nor any significant variation with chronic administration of both drugs occur. Finally, thyrotropin plasma levels display no variation after acute or prolonged treatment with clomipramine or amitriptyline. These results are compared with those of literature, then discussed in the light of present theories on pituitary hormones secretion aminergic control and of tricyclic antidepressants effect on these hormones.

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Br J Clin Pharmacol. 1979 Apr;7(4):343-8.
Specific radioimmunoassay of amitriptyline and nortriptyline.

Brunswick DJ, Needelman B, Mendels J.

1 Antisera to nortriptyline were prepared by immunizing rabbits with N-succinylnortriptyline--bovine serum albumin conjugate. 2 A sensitive radioimmunoassay has been developed for the tricyclic antidepressants amitriptyline and nortriptyline. 3 amitriptyline and nortriptyline are separated from each other and from interfering metabolites before assay. 4 Using [3H]-imipramine and [3H]-succinylnortriptyline as tracers the radioimmunoassay can measure amitriptyline and nortriptyline levels down to 2--3 ng/ml using 0.05 ml plasma sample. 5 Agreement between the radioimmunoassay and a gas-chromatographic assay was excellent for both amitriptyline and nortriptyline.

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J Pharmacol Exp Ther. 1980 Jun;213(3):616-22.
Interaction of the tricyclic antidepressant amitriptyline with prejunctional alpha and muscarinic receptors in the dog saphenous vein.

Collis MG, Shepherd JT.

Amitriptyline can cause tachycardia and arrhythmia associated with an excessive release of cardiac catecholamines. We have investigated its effects on norepinephrine release from adrenergic nerves by using the dog saphenous vein as a model of the sympathetic neuroeffector junction. Isolated strips of vein were mounted for isometric tension recording or incubated with [3H]norepinephrine and mounted for superfusion, tension recording and the superfusate. Amitriptyline (10(-6); 5 x 10(-6) M) increased the overflow of [3H]norepinephrine but decreased that of [3,4-3H]dihydroxyphenylglycol from electrically stimulated strips. The selective decreased in the overflow of this metabolite indicates that amitriptyline inhibits neuronal uptake. However, the increased overflow of [3H]norepinephrine caused by amitriptyline also occurred when neuronal uptake was blocked by cocaine (3 x 10(-5) M) but was abolished when prejunctional alpha receptors were blockade by phentolamine (10(-5) M). Amitriptyline attenuated the prejunctional inhibitory action of exogenous norepinephrine, this indicates that the drug interacts with prejunctional alpha receptors. Amitriptyline also antagonized the prejunctional inhibitory action of acetylcholine, both in the absence and presence of cocaine and phentolamine. These effects were not due to a nonspecific action of the drug as it did not reduce the prejunctional inhibitory effect of histamine. Thus, amitriptyline can increase the concentration of norepinephrine at the neuroeffector junction by blockade of neuronal uptake and by interacting with prejunctional alpha and muscarinic receptors. Since the cardiac adrenergic nerves also possess these receptors, the results could help to explain the cardiotoxic effects of the drug.

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Acta Psychiatr Scand Suppl. 1981;290:425-32.
Cardiovascular, sedative and anticholinergic effects of amitriptyline and zimelidine in young and elderly volunteers.

Swift CG, Haythorne JM, Clarke P, Stevenson IH.

Single doses of amitriptyline (50 mg) and zimelidine (100 mg) were administered orally to 4 young and 4 elderly healthy volunteers (aged 21--26 and 68--75 respectively) in a comparative study of the two drugs. Systolic time intervals, supine and standing blood pressure, salivary flow and indices of sedation were measured at regular intervals up to 6 hours post dose. No conclusive changes in the QS2 interval, left ventricular ejection time (LVETc) LVET index, pre-ejection period (PEPc), resting heart rate, or blood pressures were observed with either drug. Salivary flow was reduced by about 40% at 3.5 hours and 50% at 5.5 hours after ingestion of amitriptyline. No change in salivary flow was observed after zimelidine (significant difference between treatments; P less than 0.01 at 3.5 and 5.5 hours). Subjective drowsiness as measured by visual analogue ratings was significantly greater for amitriptyline at 3.5 hours (P less than 0.01). Postural sway was also increased by amitriptyline but not zimelidine (difference between treatments significant at 3.5 and 5.5 hours; P less than 0.01 and 0.05 respectively). Auditory reaction time increased with amitriptyline, the difference between treatments achieving significance at 5.5 hours. No differences in response to either drug between young and elderly volunteers were demonstrable in these small groups, although variability was greater in the older group. Possible implications of these findings for the treatment of depression in the elderly are discussed.

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