J Neural Transm. 1983;57(4):281-95.
Some effects of chronic antidepressant treatments on rat brain monoaminergic systems.

Sugrue MF.

A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha 2-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days. Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO4 were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied. Central alpha 2-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25 mg/kg i.p.) to decrease rat brain MHPG-SO4 content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective. The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex 3H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. CHronic, but not acute, pargyline decreased 3H-clonidine binding and this was due to a diminished number of binding sites. The induction of subsensitive presynaptic alpha 2-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical 3H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha 2-adrenoceptors.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6197507&dopt=Abstract Elavil amitriptyline




Clin Biochem. 1982 Feb;15(1):56-61.
Monitoring of tricyclic antidepressant therapy.

Dawling S.

During the three-year period 1978-1980, 2141 plasma samples from 1055 patients receiving therapy with amitriptyline (77%) or nortriptyline (23%) were analysed using GLC with nitrogen selective detection. Compared to the recommended therapeutic ranges, wild inter-individual differences were observed in plasma drug concentration, even when corrections for dosage were made. Concentrations ranged from below the limit of sensitivity of the assay (5 microgram.1(-1)) to greater than 1 mg.1(-1). The reporting of toxic symptoms subjective side-effects) was found not to reliably predict high drug concentrations. Serious complications, however, were associated with high plasma drug concentrations. Neither nortriptyline nor amitriptyline displayed dose-dependent pharmacokinetics over the concentration ranges studied. Treatment with either drug produced age-related increases in drug concentration, which were more pronounced in female patients. With amitriptyline therapy, there was an age-related decrease in the plasma nortriptyline:amitriptyline ratio, suggesting that demethylation may be more influenced by increasing age than hydroxylation. Plasma drug monitoring of tricyclic antidepressant therapy is the only reliable means of ensuring that all patients receive a fair opportunity to benefit from these drugs.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7067078&dopt=Abstract Elavil amitriptyline




J Pharmacol Exp Ther. 1988 May;245(2):455-9.
Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro.

Kachur JF, Allbee WE, Gaginella TS.

NOVA Pharmacentical Corp., Baltimore, Maryland.

Amitriptyline, a tricyclic antidepressant, was tested for antimuscarinic and antihistamine effects against bethanechol and histamine-stimulated contractility and secretion in the guinea pig ileum in vitro. Comparisons were made with muscarinic-receptor antagonists, as well as with H1 and H2 histamine-receptor antagonists. Amitriptyline (0.01-5.0 microM) produced a parallel rightward shift in the concentration-response curves to histamine in muscle (Ki 0.4 nM) and mucosa (Ki 450 nM). The H1-receptor antagonists pyrilamine and diphenhydramine were less potent against histamine in the muscle and more potent against histamine in the mucosa than was amitriptyline. The H2-receptor antagonist cimetidine was ineffective in the muscle and mucosa. Amitriptyline (0.1-2 microM) also produced a parallel rightward shift in the concentration-response curve to bethanechol in muscle (Ki 133 nM) and mucosa (Ki 143 nM). Against bethanechol, in both tissues, atropine and 4-diphenylacetoxy-N-methyl piperidine methiodide were more potent competitive antagonists than was amitriptyline. Pirenzepine produced a competitive blockade of bethanechol in the muscle and a noncompetitive blockade in the mucosa. The data indicate that amitriptyline exerts more potent antihistaminic effects on guinea pig ileal muscle than the mucosa but that the tricyclic drug is equipotent as an antimuscarinic in both tissues.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2896792&dopt=Abstract Elavil amitriptyline




Farmakol Toksikol. 1989 May-Jun;52(3):22-5.
[Effect of amitriptyline on analgesia induced by acupuncture and inescapable painful electrodermal stimulation in the rat]

[Article in Russian]

Bragin EO, Batueva NN, Vasilenko GF, Ponomarenko TP, Zol'nikov SM.

The effect of amitriptyline (1.5 and 3 mg/kg intraperitoneally once a day for 1, 3, 5 days) on the latencies (L) of hot plate (HP) and tail flick (TF) at rest, after acupuncture (A) of bilateral Ho-ku and after inescapable foot-shock (IFS--1.0 mA, 50 Hz, 5 min) was studied in experiments on rats. It was shown that amitriptyline in the above doses, used in different periods of time, failed to effect L of HP and TF at rest. However, after A an increase of the analgesic effect was observed in the rats treated with 3 mg/kg of amitriptyline for 3 days. In the experiment with IFS an increase of the effect was pronounced in TF test 24 hours following administration of 1.5 and 3.0 mg/kg of amitriptyline.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2792349&dopt=Abstract Elavil amitriptyline




J Clin Psychopharmacol. 1987 Apr;7(2):78-82.
Long-term versus short-term amitriptyline side effects as measured by a postmarketing surveillance system.

Bryant SG, Fisher S, Kluge RM.

As part of a large-scale postmarketing surveillance study, the adverse clinical events (ACEs) reported by 85 outpatients taking amitriptyline were investigated. Two discrete groups of patients were identified based on their duration of amitriptyline treatment: 45 had started the drug within 2 weeks of their interview (mean = 10.1 days, SD = 1.6 days), while 40 were much longer term tricyclic antidepressant patients (mean = 227.2 days, SD = 135 days). Our analysis of amitriptyline side effects reported by each of these two discrete groups challenges the common clinical impression that tricyclic side effects, in general, abate with continued treatment. Shorter term patients were much better able to correctly attribute their adverse clinical events to their drug therapy. Anticholinergic side effects were reported as new symptoms by the long-term patients just as frequently with similar ratings of subjective severity. These reports of adverse drug reactions of recent onset by long-term amitriptyline users may reflect the fact that such symptoms fluctuate in their occurrence and may not be recognized as potentially drug-induced until some threshold for patient tolerance is exceeded.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3584525&dopt=Abstract Elavil amitriptyline




Pharmacol Biochem Behav. 1985 Jan;22(1):119-25.
Effects of chronic lithium, amitriptyline and mianserin on glucoregulation, corticosterone and energy balance in the rat.

Storlien LH, Higson FM, Gleeson RM, Smythe GA, Atrens DM.

Major negative side-effects reported for mood-stabilizing and antidepressant drugs in humans are excess weight gain and carbohydrate craving. The aim of the present study was to establish whether the rat could usefully be employed in investigation of these phenomena. Three experiments investigated the effects of chronic lithium (40 mg/kg LiCl), amitriptyline (2.5 mg/kg), mianserin (2.5 mg/kg) and saline administration (15-20 days, one subcutaneous injection/day) on body weight, food intake and fluid intake. Water and food cubes were provided in all experiments. Additionally available, as separate fluid sources, in Experiment 2 were 24% sucrose and 0.6% saccharin and in Experiment 3, 0.6% saccharin. Blood was collected for plasma glucose and insulin determinations 20-24 hours after the final injections. Lithium administration resulted in a marked increase in weight gain but only if both sucrose and saccharin were available (Experiment 2). Saccharin intake was increased with lithium treatment as was total caloric intake with sucrose available. Amitriptyline induced a sweetness craving; however, weight gain was somewhat depressed with just cubes available (Experiment 1) and only normalised by the additional availability of sucrose and saccharin (Experiment 2). With amitriptyline, total caloric intake was never different from controls. Weight gain was slightly suppressed and caloric intake slightly elevated by mianserin but importantly the two effects combined for a decrease in metabolic efficiency which was particularly exaggerated under the condition of carbohydrate availability (Experiment 2). Lithium and amitriptyline both produced hyperinsulinemia with normoglycemia whether or not the rate of weight gain was changed and whether or not intake was increased. Corticosterone levels were elevated by all drug treatments in Experiment 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3883369&dopt=Abstract Elavil amitriptyline




J Toxicol Environ Health. 1984;14(2-3):137-43.
Cardiotoxicity of tricyclic antidepressants in primary cultures of rat myocardial cells.

Acosta D, Ramos K.

Primary cultures of myocardial cells were used to evaluate the cardiotoxic potential of various tricyclic antidepressants (TCAs). Lactate dehydrogenase (LDH) leakage, cellular viability, and beating rates were measured to compare the cardiotoxicity of amitriptyline, desipramine, imipramine, and nortriptyline. Tricyclic antidepressants were added to the cultures to give final concentrations of 1 X 10(-5), 1 X 10(-4), and 1 X 10(-3) M. Treatments lasted 1 and 4 h. All TCAs tested caused significant release of LDH and decreased cellular viability when added at 1 X 10(-3) M for 1 and 4 h. Amitriptyline was the only compound that caused significant LDH release 4 h after exposure to lower doses. Decreased viability was observed 4 h after exposure to all TCAs at a concentration of 1 X 10(-4) and 1 X 10(-3) M. Arrhythmias were observed 1 h after exposure to 1 X 10(-5) and 1 X 10(-4) M amitriptyline. All doses of amitriptyline inhibited beating 4 h after exposure. Imipramine, desipramine, and nortriptyline at a concentration of 1 X 10(-5) M decreased the beating rates of cultured myocytes 1 and 4 h after exposure. Arrhythmias and/or total inhibition of beating were observed when the cultures were exposed to higher concentrations of these compounds. Based on these data, the rank order of cardiotoxicity was amitriptyline greater than imipramine = desipramine greater than nortriptyline.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6502730&dopt=Abstract Elavil amitriptyline