J Forensic Sci. 1991 Jan;36(1):153-65.
A comparison of three computer models for prediction of dose in acute amitriptyline overdose.

Wimbish G, Shores J, Spiehler V.

Institute of Forensic Medicine, Texas College of Osteopathic Medicine, Fort Worth.

The pharmacokinetics of amitriptyline in overdose have been reported not to fit conventional compartmental models. In this study, the dose-concentration-time relationships of amitriptyline in overdose were modeled with discriminant analysis, with an evolutionary heuristic search program, and with a decision-tree model based on the entropy of uncertainty of classification. The computer models all used the same data from dogs administered treatment (80 mg/kg), toxic (250 mg/kg), or fatal (500 mg/kg) doses directly into the surgically isolated duodenum. All the models achieved a high degree of success (77 to 93%) in assigning records to the high-, low-, or middle-dose groups. Two of the models gave a probability of the assignment. Results of this analysis suggest that blood amitriptyline and nortriptyline concentrations are most useful in estimating dose in acute amitriptyline overdose.

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Crit Care Med. 1991 Apr;19(4):544-9.
Efficacy of dopamine and norepinephrine for treatment of hemodynamic compromise in amitriptyline intoxication.

Vernon DD, Banner W Jr, Garrett JS, Dean JM.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84113.

BACKGROUND AND METHODS: Dopamine and norepinephrine were evaluated for treatment of hemodynamic compromise in amitriptyline intoxication. Fifteen anesthetized dogs underwent hemodynamic monitoring and amitriptyline intoxication, and received three infusion rates of dopamine (5, 15, and 30 micrograms/kg.min) and three infusion rates of norepinephrine (0.25, 0.5, and 1.0 micrograms/kg.min), sequentially, with hemodynamic measurements at each dose. Data were analyzed using repeated-measures analysis of variance; p less than .05 was considered significant. RESULTS: Amitriptyline intoxication lowered cardiac output, peak left ventricular dP/dt, and mean arterial pressure (MAP). All doses of norepinephrine and the two higher doses of dopamine increased cardiac output, MAP, and peak left ventricular dP/dt during the intoxicated state. Both agents restored all variables to preintoxication values. Values obtained at the highest doses of the two drugs were not different for any variable. CONCLUSION: Dopamine and norepinephrine each appeared effective in reversing amitriptyline-induced hemodynamic alterations.

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J Clin Psychiatry. 1990 Sep;51 Suppl:27-9.
A drug utilization review of prescribing patterns for trazodone versus amitriptyline.

Bryant SG, Hokanson JA, Brown CS.

Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston 77550.

The second-generation antidepressant trazodone has been thought by some clinicians to exert a less robust antidepressant effect than do tricyclic agents. This impression differs from the findings of numerous published clinical trials. In an effort to determine whether this discrepancy may be due to possible inappropriate dosing or use of trazodone for different patient subtypes, a retrospective chart review of 138 depressed inpatients treated with amitriptyline and of 42 depressed inpatients treated with trazodone was performed to compare their respective prescribing patterns. While these two groups did not differ with regard to most demographic variables, results revealed that patient prescribed trazodone were older (trazodone, mean +/- SD age = 54.5 +/- 8.8 years versus amitriptyline, 43.2 +/- 12.9 years; p less than .001), more often had a recurrent depressive disorder (trazodone = 57.1%, amitriptyline = 39.1%, p less than .06), and more frequently had a history of unresponsiveness to other antidepressants (trazodone = 47.6%, amitriptyline = 11.6%; p less than .001). In addition, initially prescribed daily doses of trazodone were below the recommended starting dose of 150 mg/day (mean +/- SD starting dose = 113.7 +/- 42.1 mg/day), while starting daily doses for amitriptyline (mean +/- SD = 69.8 +/- 20.1 mg/day) were judged to be more adequate relative to the recommended daily dose of 75 mg/day. Final trazodone dosage (mean +/- SD final dose = 217.9 +/- 87.5 mg/day) could be judged to have been far short of optimal levels of 250 to 350 mg/day and of up to 600 mg/day for inpatients and 400 mg/day for outpatient.(ABSTRACT TRUNCATED AT 250 WORDS)

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Farmakol Toksikol. 1990 Jul-Aug;53(4):19-21.
[The effect of antidepressants on the experimental anticonvulsant activity and acute toxicity of anticonvulsants]

[Article in Russian]

Tregubov AL, Kolla VE.

In the experiments on white mice there was studied the anticonvulsant activity by the test of the maximal electric shock and acute toxicity of anticonvulsants and antidepressants at separate and combined administration. The combined use of anticonvulsants and antidepressants showed the increase of the anticonvulsant activity of phenobarbital with amitriptyline, levomepromazine and lithium oxybutyrate; diphenine and carbamazepine with amitriptyline as well as hexamidine with all antidepressants. The combination of phenobarbital with amitriptyline, levomepromazine and lithium oxybutyrate, diphenine with amitriptyline, hexamidine with amitriptyline and imizine proved to be the safest.

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Xenobiotica. 1990 Jul;20(7):727-38.
Quaternary N-glucuronides of 10-hydroxylated amitriptyline metabolites in human urine.

Breyer-Pfaff U, Becher B, Nusser E, Nill K, Baier-Weber B, Zaunbrecher D, Wachsmuth H, Prox A.

Department of Toxicology, University of Tubingen, FRG.

1. Conjugated metabolites were isolated from the urine of patients receiving amitriptyline treatment using a combination of solid-phase extraction, h.p.l.c. and t.l.c. 2. By n.m.r. and mass spectrometry, N-glucuronides of E- and Z-10-hydroxy amitriptyline and of trans-10,11-dihydroxy amitriptyline were identified in addition to the previously described O-glucuronides of E- and Z-10-hydroxy amitriptyline and -nortriptyline and amitriptyline-N-glucuronide. 3. The quaternary ammonium glucuronides proved to be resistant to acid hydrolysis, but could be cleaved enzymatically. 4. In urine samples from three patients, 35-60% of conjugated 10-hydroxy amitriptyline was found in the form of N-glucuronides. 5. A volunteer given an i.v. infusion of amitriptyline-N-glucuronide excreted E- and Z-10-hydroxy amitriptyline-N-glucuronide; following ingestion of E-10-hydroxy amitriptyline its N-glucuronide could be measured in urine.

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Arch Int Pharmacodyn Ther. 1990 Mar-Apr;304:181-95.
Comparison of the cardiac electrophysiologic effects of amitriptyline and clomipramine in the dog after myocardial infarction.

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

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

The effects of the tricyclic antidepressants amitriptyline and clomipramine on intraventricular conduction, effective refractory period and incidence of ventricular arrhythmias induced by programmed stimulation, were studied in the dog heart after myocardial infarction. Amitriptyline, at doses of 1 to 3 mg/kg, significantly slowed ventricular conduction of the infarcted zones in a frequency-dependent and a dose-dependent manner. Amitriptyline, at doses of 2 and 3 mg/kg, slightly slowed conduction in normal zones. The effective refractory period was prolonged by amitriptyline at a dose of 2 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. On the other hand, the depressant effect of clomipramine, at doses of 1 to 3 mg/kg, on the conduction of infarcted zones was lower than that of amitriptyline, whereas the severely depressed conduction in the infarcted zone was obviously slowed by clomipramine. The incidence of ventricular arrhythmias did not significantly increase with clomipramine. From the present results, clomipramine seems to have a lower cardiac toxicity than amitriptyline, although clomipramine produces a slight depression of conduction in infarcted zones.

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J Anal Toxicol. 1990 Sep-Oct;14(5):325-6.
The production of amitriptyline from nortriptyline in formaldehyde-containing solutions.

Dettling RJ, Briglia EJ, Dal Cortivo LA, Bidanset JH.

Division of Forensic Sciences, Suffolk County, Hauppauge, New York.

The stability of nortriptyline in aqueous solutions containing various concentrations of formaldehyde was investigated. Amitriptyline, as a reaction product, was determined by gas chromatography/mass spectrometry (GC/MS) in these experiments. Factors that may contribute to this phenomenon, including pH, formaldehyde concentration, and incubation time were evaluated. At 40% (v/v) formaldehyde concentration and pH 4, there was a 68% decrease in nortriptyline concentration along with a concomitant formation of amitriptyline after 24 h. The N-methylated product was responsible for 48% of the total tricyclic drug present. The data also clearly indicate that the formation of amitriptyline is favored at elevated pH.

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