Arch Int Pharmacodyn Ther. 1986 Jan;279(1):103-20.
Protective actions of carbocromene against amitriptyline-induced cardiotoxicity in anesthetized rats.

Fiedler VB, Martorana PA, Nitz RE.

This study was designed to analyze the effects of carbocromene on circulatory and electrophysiologic failure in rats anesthetized with urethane. Amitriptyline was infused at 0.4 mg/kg/min (n = 12) until death of the animals at 30 +/- 6.7 min due to vascular collapse. Following initial heart rate increase and QRS prolongation, this was characterized by progressive hypotension, bradycardia, intraventricular conduction delay, S-T segment elevation and A-V block. In the initial 31 rats, carbocromene was administered i.v. with 4 mg/kg followed in two groups by 40 (n = 13) and 80 micrograms/kg/min (n = 18) i.v., respectively. The drug was effective in protecting the animals against the acute cardiovascular failure induced by amitriptyline. The preservation was associated with a diminution of the hypotension, negative chronotropic actions, S-T segment elevation and the incidence of A-V block produced by amitriptyline. Survival time of the rats increased to 46 +/- 5.3 min (p less than 0.05 vs. amitriptyline controls) and 63 +/- 6.5 min (p less than 0.01) with infusion of 40 and 80 micrograms/kg/min carbocromene, respectively. These results suggest that carbocromene is an effective treatment of amitriptyline-induced cardiotoxicity by massive overdose with beneficial effects largely due to hemodynamic and metabolic oxygen-sparing impact on the heart. Membrane stabilizing antiarrhythmic carbocromene effects may be contributory factors in its protective value in the treatment of acute amitriptyline poisoning.

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J Cardiovasc Pharmacol. 1985 Jul-Aug;7(4):666-72.
Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning.

Fiedler VB, Gobel H, Nitz RE.

We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.

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J Pharmacol Exp Ther. 1978 May;205(2):499-502.
A radioimmunoassay for the determination of combined amitriptyline and nortriptyline concentrations in microliter samples of plasma.

Robinson JD, Risby D, Riley G, Aherne GW.

A sensitive radioimmunoassay for amitriptyline and nortriptyline in blood has been developed. The antibodies used in the radioimmunoassay were raised in a sheep against a conjugate of nortriptyline and bovine serum albumin. Using tritiated amitriptyline as the label, the assay is capable of detecting concentrations as low as 2.0 ng/ml in a 50 microliter sample of plasma. Cross-reactivity studies have demonstrated the specificity of the radioimmunoassay for both amitriptyline and nortriptyline, and comparison with gas-liquid chromatography assay has indicated the applicability of the assay to a routine situation. The radioimmunoassay has been used to study the plasma drug levels after single oral administration of amitriptyline to four volunteers. A wide variation in maximum drug concentrations, ranging from 18 to 62 ng/ml, was seen, with the time taken to reach the maxima ranging between 1.5 and 3 hours. A second concentration peak was seen in three of the volunteers, at 4 to 5 hours after ingestion of the drug.

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Acta Pharmacol Toxicol (Copenh). 1975;36(5):395-408.
Tricyclic antidepressant agents. II. Effect of oral administration on the uptake of 3-H-noradrenaline and 14-C-5-hydroxytryptamine in slices of the midbrain-hypothalamus region of the rat.

Ross SB, Renyi AL.

The inhibition of the simultaneous uptake of 3-H-l-noradrenaline (NA) and 14-C-5-hydroxytryptamine (5-HT) in slices of the midbrain-hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5-HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5-HT uptake (ED50 = 35 mg/kg orally) as on the NA uptake (ED50 = 20mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED50 greater than 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED50 = 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED50 values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5-HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED50 = 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre-treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of 14-C-imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the5-HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED50 = 11 mg/kg intraperitoneally).

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Arch Int Pharmacodyn Ther. 1989 Nov-Dec;302:49-67.
Some effects of desmethylimipramine and amitriptyline on the schedule-controlled behavior of pigeons and rats.

Lamb RJ, McMillan DE.

Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.

The effects of desmethylimipramine and amitriptyline on schedule-controlled behavior of pigeons and rats were examined. Pigeons responded under either a multiple (mult) fixed-interval (FI) 600-sec, fixed-ratio (FR) 30-response schedule of food presentation or a mult FI 200-sec, FI 200-sec schedule, in which responding during one component was punished with electric shock. Rats responded under a mult FI 300-sec, FR 30-response schedule of food presentation. Under the mult FI, FR schedules, desmethylimipramine and amitriptyline decreased overall rates of FI and FR responding in both species. Overall rates of responding were decreased to similar extents under both the FI and FR components of the schedule. In the pigeon, but not in the rat, the effects of desmethylimipramine and amitriptyline on responding under the FI component of the mult FI, FR schedule depended on the control-rate of responding, i.e. desmethylimipramine and amitriptyline increased more or decreased less the low rates of FI responding at the beginning of the FI compared to the higher rates of FI responding at the end of the FI. In contrast, in the rat desmethylimipramine and amitriptyline did not differentially affect the low rates of responding at the beginning of the FI compared to the higher rates of responding at the end of the FI. Correspondingly, in the pigeon, but not in the rat, desmethylimipramine and amitriptyline decreased the fixed-interval quarter-life at relatively low doses. In the pigeon neither desmethylimipramine nor amitriptyline differentially affected the overall rate of punished as compared to unpunished responding.

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J Auton Pharmacol. 1983 Dec;3(4):287-95.
Effects of amitriptyline, desipramine and mianserin on noradrenergic transmission in the rat isolated right ventricle.

Bradley L, Doggrell SA.

The effects of amitriptyline, desipramine and mianserin on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and field stimulation-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition the effect of these agents on contractions produced by isoprenaline or by field stimulation are reported. Amitriptyline, desipramine (both at greater than or equal to 10(-8) M) and mianserin at greater than or equal to 10(-7) M inhibited the accumulation of radioactivity from [3H]-noradrenaline. The decline in the spontaneous outflow of radioactivity, following loading of the tissue with [3H]-noradrenaline, was not altered by amitriptyline, desipramine or mianserin. Rauwolscine, amitriptyline, desipramine and mianserin (all at 10(-6) M) reduced or reversed the decline in outflow of radioactivity evoked by field stimulation at 5 Hz. Desipramine had no additional effects in the presence of cocaine (10(-5) M) and amitriptyline and mianserin had no further effect in the presence of cocaine and rauwolscine. The effect of desipramine probably represents inhibition of neuronal uptake and that of amitriptyline and mianserin blockade of neuronal uptake and prejunctional alpha 2-adrenoreceptors. The rate of beating in the presence of isoprenaline (10(-6) M) was reduced by amitriptyline (10(-7) M), desipramine (10(-6) M) and mianserin (10(-7)--10(-6) M). Higher concentrations of the antidepressants greatly reduced or abolished the rate and force of beating in the presence of isoprenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

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Arzneimittelforschung. 1979;29(1):158-61.
Gas chromatographic determination of amitriptyline, nortriptyline and perphenazine in plasma of schizophrenic patients after administration of the combination of amitriptyline with perphenazine.

Cooper S, Albert JM, Dugal R, Bertrand M, Elie R.

A specific and sensitive gas-chromatographic technique using a common extraction procedure for the quantitative determination of amitriptyline, endogenous nortriptyline and perphenazine in plasma of schizophrenic patients receiving therapeutic doses of a combination of amitriptyline and perphenazine (Etrafon) has been developed. The lower limits of detection are 20 ng/ml for amitriptyline, 1 ng/ml for nortriptyline and 5 ng/ml for perphenazine. Amitriptyline is estimated with a flame ionization detector. Nortriptyline is quantitated using an electron capture detector after converting it to its heptafluorobutyryl derivative by reaction with the appropriate anhydride. Perphenazine is also determined using an electron capture detector after forming its stable, trimethylsilyl derivative by reaction with N,O-bis-(trimethylsilyl)-acetamide. In individual patients, the steady-state plasma levels ranged from 44 to 215 ng/ml for amitriptyline, from 49 to 270 ng/ml for nortriptyline and from less than 5 to 20 ng/ml for perphenazine. Steady-state plasma levels data on amitriptyline, nortriptyline and perphenazine in 23 patients treated with Etrafon are presented.

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