Arch Toxicol. 1987 Aug;60(6):467-9.
The effect of a lipid suspension on amitriptyline disposition.

Minton NA, Goode AG, Henry JA.

Poisons Unit, Guy's Hospital, London, UK.

A 5-h infusion of a lipid suspension or saline was given on separate occasions to four healthy volunteers taking amitriptyline. Mean plasma levels of amitriptyline plus nortriptyline were 14% higher at the end of the lipid infusion but the difference was not statistically significant. Infusion of a lipid suspension is unlikely to materially affect the severity of amitriptyline intoxication.

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J Anal Toxicol. 1988 Jul-Aug;12(4):216-24.
Application of expert systems analysis to interpretation of fatal cases involving amitriptyline.

Spiehler V, Spiehler E, Osselton MD.

Central Research Establishment, Home Office Forensic Science Service, Aldermaston, Reading, Berkshire, United Kingdom.

Part I. Expert 4: The object of this study was to investigate the applicability of commercially available expert system shells to interpretation in forensic toxicology. Amitriptyline toxicology was selected as a pilot trial. Blood and tissue concentrations of amitriptyline and nortriptyline in fatal and nonfatal amitriptyline cases from the literature and from the Registry of Human Toxicology databank were entered into the expert system shell Expert 4 (Rivers, Elsevier). The statistical evaluation routines of the shell were used to search for patterns in the data. Successive changes in the data base were made to test for the influence of the data base on the conclusions. Finally the data base was refined, based on the evaluations, to strengthen the probabilities of the conclusions. The refined database was coupled with the Expert 4 inference engine to infer unknown parameters in the cases. The results of the expert system analysis were compared to known values and published expert opinions. The ratio of amitriptyline/nortriptyline and tissue levels of nortriptyline were found to be the most significant measures for interpretation of effect and time since ingestion. Part II. Computer Induction of Rules: Blood and tissue concentrations of amitriptyline and nortriptyline in fatal and nonfatal amitriptyline cases from the literature and from the Registry of Human Toxicology databank were entered into the expert system shell BEAGLE, (Forsyth, Machine Learning Research, Ltd.). The automatic rule induction routines of the shell were used to search for patterns in the data. The program expressed these patterns as numerical predictions or Boolean logic rules. The results were compared to those obtained with the Expert 4 (Rivers, Elsevier) using the same case knowledge base.(ABSTRACT TRUNCATED AT 250 WORDS)

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J Pharmacol Exp Ther. 1984 Nov;231(2):430-5.
Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs.

Nattel S, Mittleman M.

This study was designed to analyze the effects of lidocaine and sodium bicarbonate on ventricular arrhythmias resulting from amitriptyline infusion in dogs. Amitriptyline was infused i.v. at 0.5 mg/kg/min for 30 min, followed by 1 mg/kg/min to dogs anesthetized with morphine and alpha-chloralose. When arrhythmia occurred, the infusion rate was reduced by one-third and the effect of various interventions studied. In the initial 18 dogs, lidocaine, sodium bicarbonate or isotonic saline was administered i.v. to six dogs each in a randomized, blinded fashion. The prevalence of ventricular ectopic complexes was not changed after isotonic saline, but was reduced by lidocaine at concentrations greater than or equal to 5 mg/l and by sodium bicarbonate. The effects of lidocaine were transient and associated with significant blood pressure reduction. Sodium bicarbonate produced more dramatic and sustained arrhythmia reversal along with a reduction in amitriptyline-induced conduction slowing. Administration of hypertonic sodium chloride in equimolar quantities to sodium bicarbonate failed to affect amitriptyline-induced ventricular arrhythmias significantly, but hyperventilation to a pH similar to that produced by sodium bicarbonate (7.48) significantly reduced the frequency of amitriptyline-induced ventricular ectopy. When amitriptyline was infused into dogs ventilated with various respiratory rates, ventricular arrhythmia resulted in 18 of 18 (100%) dogs with pH less than 7.42, 2 of 4 (50%) dogs with pH between 7.48 and 7.51 and 0 of 8 (0%) dogs with a pH between 7.59 and 7.65 (P less than or equal to .001). These results suggest that sodium bicarbonate is effective treatment for amitriptyline-induced cardiac arrhythmias with beneficial effects largely due to alkalinization.(ABSTRACT TRUNCATED AT 250 WORDS)

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Environ Mol Mutagen. 1988;12(4):421-30.
Genotoxicity evaluation of the tricyclic antidepressants amitriptyline and imipramine using human lymphocyte cultures.

Saxena R, Ahuja YR.

Department of Genetics, Osmania University, Hyderabad, India.

Two tricyclic antidepressants, amitriptyline and imipramine, were evaluated for their in vitro cytogenetic effects in human lymphocyte cultures. Peripheral blood cultures from three normal healthy donors were set up for 72 hr for each of the drugs. The drugs were added at the start (72-hr exposure), 24 hr (48-hr exposure), and 48 hr (24-hr exposure) after initiation of the cultures. The concentrations evaluated at each exposure time were 50, 250, 1,000, and 10,000 ng/ml for amitriptyline and 25, 500, and 5,000 ng/ml for imipramine. The first two concentrations correspond to the plasma levels of the respective drugs after therapeutic doses. All treatments for a donor were given at the same time. Untreated cultures served as controls for the baseline frequency of the parameters assayed. The parameters assayed were chromosome aberrations, mitotic index, and sister chromatid exchanges (SCEs). Amitriptyline was found to be nongenotoxic at plasma levels by all the parameters assayed. However, frequencies of chromosome aberrations and SCEs were significantly increased at concentrations 4 and 40 times the plasma level (1,000 and 10,000 ng/ml) although the actual increases was small. The mitotic index was not affected at any concentration. Through imipramine showed a significant increase in chromosome damage at the upper plasma level and at concentrations higher than that, SCE frequency was significantly increased only at concentration higher than the plasma level (5,000 ng/ml), the actual increase being small for both these parameters. The mitotic index was not affected at any concentration. These results suggest that amitriptyline may be a slightly safer drug than imipramine from a genetic point of view.

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Psychiatry Res. 1985 Jun;15(2):145-51.
Effect of amitriptyline on the thyrotropin response to thyrotropin-releasing hormone in endogenous depression.

Krog-Meyer I, Kirkegaard C, Kijne B, Lumholtz B, Smith E, Lykke-Olesen L, Bjorum N.

Patients with endogenous depression whose depressive episodes were clinically resolved after electroconvulsive therapy were divided into two groups: one in which patients remained well (n = 16) and another in which patients relapsed within 6 months (n = 11). Treatment with amitriptyline for 3 weeks did not affect the median thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) in recovered patients, whereas that in relapsed patients was significantly enhanced. The data suggest that amitriptyline affects the TSH response to TRH differently in stably recovered and relapsed patients. If this effect is maintained beyond the 3-week period studied, treatment with amitriptyline will invalidate the predictive value of the TRH test.

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J Pharmacol Exp Ther. 1982 Feb;220(2):299-304.
Quantitative assessment of the pre- and postsynaptic alpha adrenoceptor antagonist potency of amitriptyline.

Leighton HJ.

The pre- and postsynaptic alpha adrenoceptor blocking affinity of amitriptyline was determined in isolated tissues by Schild regression analysis. In the absence of uptake-1 blockade with cocaine, amitriptyline treatment (3 X 10(-8)-3 X 10(-6) M) affected only marginally norepinephrine concentration-response curves in the rat anococcygeus muscle; a result suggesting opposing pharmacological effects (uptake-1 blockade and alpha blockade). After cocaine (3 X 10(-5) M) treatment, amitriptyline (3 X 10(-8)-3 X 10(-6) M) antagonized competitively concentration-response curves to norepinephrine, yielding a postsynaptic pKb of 7.51. A similar pKb was obtained when methoxamine was the agonist. Presynaptic alpha blocking affinity was determined by using the field-stimulated rat vas deferens. Stimulus conditions were chosen which minimized the inhibition of twitch height by high concentrations of cocaine. Using these conditions (10 Hz, 200 msec duration at 100-sec intervals), amitriptyline antagonized competitively clonidine inhibition of field-stimulated twitch contractions, yielding at pKb of 5.23. The presynaptic pKb was not changed in the presence of theophylline (10(-4) M). Amitriptyline was also observed to increase the release of [3H]norepinephrine from the field-stimulated rat anococcygeus muscle pretreated with cocaine. Although this effect primarily reflects alpha blockade, other biochemical and presynaptic mechanisms may be involved. Comparing the pre- and postsynaptic alpha blocking affinities indicates that amitriptyline has 191 X greater affinity for post- than presynaptic alpha adrenoceptors (i.e., alpha-1 much greater than alpha-2). The relevance of these observations to the mechanism of action and side effects of amitriptyline are discussed.

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Lancet. 1982 Jul 24;2(8291):183-6.
Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?

Pare CM, Kline N, Hallstrom C, Cooper TB.

Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.

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