Fundam Clin Pharmacol. 1994;8(6):525-31.
Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half-life repeated administration. Comparison with acute administration.

Coudore F, Fialip J, Eschalier A, Lavarenne J.

Laboratoire de Pharmacologie, Universite d'Auvergne (NPPUA), Faculte de Pharmacie, Clermont-Ferrand, France.

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z-10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

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Ann Emerg Med. 1995 Jul;26(1):58-64.
Does a sodium-free buffer affect QRS width in experimental amitriptyline overdose?

Stone CK, Kraemer CM, Carroll R, Low R.

Department of Emergency Medicine, East Carolina University School of Medicine, Greenville, North Carolina, USA.

STUDY OBJECTIVES: We carried out this study to determine the effects of pH alteration on QRS width with administration of tromethamine, a non-sodium-containing buffering agent, in experimental amitriptyline overdose. DESIGN: Prospective, nonblinded trial. PARTICIPANTS: Adult mongrel dogs. INTERVENTIONS: Pentobarbital-anesthetized dogs were overdosed with amitriptyline 5 mg/kg followed by infusion at 1.0 mg/kg/minute until the QRS width doubled, then decreased to .5 mg/kg/minute until the end of the experiment. At two defined points of toxicity, the dose of tromethamine required to raise the pH to 7.50 +/- 4 was given. pH and QRS width at a speed of 100 mm/second were measured over a 30-minute period after each tromethamine dose. Data were analyzed with non-linear-regression analysis. RESULTS: At toxicity 1 the mean pH was 7.32, with a QRS width of 11.6 mm. Two minutes after the tromethamine dose the pH rose to 7.51, with narrowing of the QRS width to 8.4 mm. At toxicity 2 the pH was 7.40, with QRS width of 10.6 mm. Two minutes after tromethamine, the pH rose to 7.49 and the QRS width decreased to 9.7 mm. Regression analysis showed a correlation between pH and QRS width; as pH increased, QRS width decreased (P = .0001). CONCLUSION: Cardiac toxicity of amitriptyline overdose, as manifested by QRS widening, is reversible by pH changes alone.

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J Pharmacol Exp Ther. 1995 Jan;272(1):177-83.
Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex.

Kihara T, Ikeda M.

Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.

The effects of duloxetine (LY248686), a new inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake on extracellular levels of NE, 5-HT and dopamine (DA), were studied in the rat frontal cortex and nucleus accumbens, using in vivo microdialysis. The oral administration of duloxetine (3.125-12.5 mg/kg) produced a dose-dependent increase in the output of both NE and 5-HT from the frontal cortex, this increase being maintained throughout the 4-hr observation period. Chronic administration of duloxetine (6.25 mg/kg, p.o.) for 14 days failed to alter basal NE and 5-HT levels in the frontal cortex, but augmented the duloxetine-induced increase in output of NE and 5-HT. Amitriptyline and maprotiline, administered p.o. at doses of 6.25 to 25 mg/kg, increased NE output, but the effect was weaker than that of duloxetine, and neither amitriptyline nor maprotiline changed 5-HT output from the frontal cortex. Duloxetine, amitriptyline, and maprotiline brought about increases in DA levels in the rat frontal cortex, the increase in DA levels induced by duloxetine being approximately two or three times more potent than that induced by amitriptyline and maprotiline. In the nucleus accumbens, duloxetine also produced a dose-dependent increase in DA output more potent than that produced by amitriptyline and maprotiline. These results show that duloxetine causes a potent and sustained increase in the output of both NE and 5-HT in the rat frontal cortex, related to its inhibition of NE and 5-HT uptake; these results also show that duloxetine increases DA output in the frontal cortex.

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BMJ. 1994 Dec 10;309(6968):1546-9.
Choice of antidepressants: questionnaire survey of psychiatrists and general practitioners in two areas of Sweden.

Isacsson G, Redfors I, Wasserman D, Bergman U.

Department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.

OBJECTIVE--To identify factors that affect physicians' choice of specific antidepressant drugs in order to evaluate the validity of epidemiological studies of the risks (particularly suicide) and benefits of different compounds. DESIGN--Questionnaire survey of 264 psychiatrists and general practitioners in an urban area and a rural area of Sweden with validation of data by independent prescription surveys. SETTING--Urban area of greater Stockholm and rural county of Jamtland, Sweden. SUBJECTS--228 physicians (86%) who answered the questionnaire. MAIN OUTCOME MEASURES--The drugs used as first line drugs of choice, as drugs of choice in particularly severe depression, and as drugs of choice for disorders other than depression. RESULTS--Amitriptyline was the most common first line drug of choice among both psychiatrists and general practitioners. The patterns of choice of antidepressants in the two areas accorded with prescribing patterns in two independent prescription surveys. Amitriptyline was chosen even more frequently for severe depression and depression with severe insomnia. Clomipramine was chosen comparatively more often for depression with severe anxiety. Low toxicity compounds (mainly lofepramine, mianserin, and moclobemide) were more often the drug of choice in depression associated with overt risk of suicide. Amitriptyline and clomipramine were used extensively for disorders other than depression (40% and 54% of prescriptions, compared with 13-19% for some other major antidepressants). CONCLUSION--Patient groups treated with different antidepressant compounds may not be comparable with respect to diagnoses and severity of disease. In particular, lofepramine, mianserin, and moclobemide, and possibly amitriptyline, seem to be chosen more often for patients prone to suicide.

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Arch Int Pharmacodyn Ther. 1994 Jul-Aug;328(1):39-53.
Effects of imipramine and amitriptyline on intraventricular conduction, effective refractory period, incidence of ventricular arrhythmias induced by programmed stimulation, and on electrocardiogram after myocardial infarction in dog.

Nishimoto M, Hashimoto H, Ozaki T, Taguchi T, Ohara K, Nakashima M.

Department of Pharmacology, Hamamatsu University School of Medicine, Japan.

The effects of imipramine and amitriptyline on intraventricular conduction, effective refractory period, incidence of ventricular arrhythmias induced by programmed stimulation and on electrocardiogram changes were studied after myocardial infarction in the dog. Amitriptyline, at doses of 1-3 mg/kg, significantly slowed the ventricular conduction of the infarcted zones in a dose- and frequency-dependent manner. Amitriptyline, at doses of 2 and 3 mg/kg, slowed the ventricular conduction slightly in the normal zone. The effective refractory period was prolonged by amitriptyline at a dose of 1 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. Amitriptyline, at doses of 1-3 mg/kg, increased heart rate and prolonged the PQ, QRS and QT interval. Imipramine, at a dose of 3 mg/kg, slowed the conduction in infarcted zones to a lesser extent than amitriptyline. Imipramine, at doses of 1 and 2 mg/kg, did not significantly increase the incidence of ventricular arrhythmias. Imipramine, at a dose of 3 mg/kg, prolonged the QRS interval. From the present results it appears that imipramine has a lower cardiac toxicity than amitriptyline.

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Crit Care Med. 1994 Nov;22(11):1851-5.
Effects of epinephrine, norepinephrine, magnesium sulfate, and milrinone on survival and the occurrence of arrhythmias in amitriptyline poisoning in the rat.

Knudsen K, Abrahamsson J.

Department of Anesthesia and Intensive Care, University of Goteborg, Sweden.

OBJECTIVES: Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to compare the effects of several inotropic drugs on survival and the occurrence of arrhythmias in the treatment of amitriptyline poisoning. DESIGN: Nonrandomized, controlled intervention trial. SETTING: University laboratory. SUBJECTS: Eighty-six male Wistar rats anesthetized with pentobarbital and mechanically ventilated. INTERVENTIONS: Rats subjected to a 60-min continuous infusion of amitriptyline (1.25 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, milrinone, magnesium, epinephrine + magnesium, or norepinephrine + magnesium. MEASUREMENTS AND MAIN RESULTS: Without treatment, all animals exhibited arrhythmias on the electrocardiogram within 20 mins. All treatment drugs delayed the onset of arrhythmias, but significant differences were only observed after administration of epinephrine, epinephrine + magnesium sulfate, and norepinephrine + magnesium sulfate. All the inotropic drugs markedly increased survival. Sodium concentrations were unaffected by all treatments. In control animals, potassium concentrations increased during amitriptyline infusion. Norepinephrine treatment had no effect on potassium concentrations, whereas all other treatments resulted in decreased potassium concentrations. CONCLUSIONS: All inotropic drugs used in the study increased survival in tricyclic antidepressant poisoning in rats without increasing the risk of arrhythmias. Furthermore, epinephrine and norepinephrine + magnesium sulfate were effective in preventing arrhythmias, possibly due to improved hemodynamic performance or potassium homeostasis.

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Ther Drug Monit. 1994 Jun;16(3):298-311.
Immunoassay reagents for psychoactive drugs. Part 4. Quantitative determination of amitriptyline and nortriptyline by fluorescence polarization immunoassay.

Adamczyk M, Fishpaugh JR, Harrington CA, Hartter DE, Vanderbilt AS, Orsulak P, Akers L.

Abbott Laboratories, Abbott Park, Illinois 60064.

Methods for the quantitative determination of amitriptyline and nortriptyline by fluorescence polarization immunoassay (FPIA) is described. One immunoassay allows for the accurate quantification of amitriptyline in the presence of nortriptyline while the second immunoassay allows for the accurate quantification of nortriptyline in the presence of amitriptyline.

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