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PubMed1977

Mechanisms of amitriptyline induced hypothermia in the rat.

Effects of amitriptyline on rectal temperature of male rats were studied at the ambient temperature of 25 degrees C. Drugs were administered intraperitoneally. Amitryptyline elicited a dose related hypothermia. The hypothermia was attenuated by phenoxybenzamine 10 mg/kg, haloperidol 2 mg/kg, diphenhydramine 5 mg/kg, atropine 20 mg/kg, and cyproheptadine 5 mg/kg. Propranolol, at a dose of 5 mg/kg, had no effect on the hypothermia. Theophylline 50 mg/kg and dibutyryl cyclic AMP 20 mg/kg inhibited the hypothermia produced by anitriptyline. Pretreatment with parachloroamphetamine (PCA), 2 or 5 mg/kg daily for 3 days, strongly antagonized the hypothermia. In addition, pretreatment with parachlorophenylalanine (PCPA), 100 mg/kg daily for three days, reduced the brain 5-hydroxytryptamine (5-HT) concentration to 20% of the control level and completely blocked the hypothermia response. When brain 5-HT concentration recovered to 50% of the control level in PCPA treated rats following the administration of 10 mg/kg 5-hydroxytryptophan (5-HTP) the hypothermia induced by amitriptyline was restored. However, the administration of 5-HT, 5 mg/kg, to PCPA treated rats did not increase brain 5-HT concentration or restore the amitriptyline induced hypothermia (AIH). Results suggest that amitriptyline interacts with several transmitter substances to produce hypothermia. Since the ability of amitriptyline to produce hypothermia was correlated with brain 5-HT content, 5-HT might play an important role in the mediation of AIH.

Amitriptyline↗
PubMed1991

Chronic treatment with amitriptyline alters the GABA-mediated uptake of 36Cl- in the rat brain.

Amitriptyline inhibits the GABA-mediated uptake of 36Cl- in membrane vesicles prepared from the cerebral cortices of drug-naive and saline-treated rats. In contrast, chronic in vivo treatment with amitriptyline affects an increase in the GABA-stimulated uptake of chloride ions in its presence. The benzodiazepine receptor antagonist ZK 93426 blocks the capacity of amitriptyline to augment the uptake of 36Cl- by 30 microM GABA. There is a possibility that there are two distinct effects of amitriptyline's action in the rat forebrain. The first is evident in vesicles from drug-naive animals and the second only after chronic treatment with this antidepressant. The authors discuss the pertinence of this finding to the mechanism of action of amitriptyline.

Amitriptyline↗
PubMed1983

Tryptophan and tyrosine ratios to neutral amino acids in endogenous depression. Relation to antidepressant response to amitriptyline and lithium + L-tryptophan.

The plasma ratios of tryptophan and tyrosine to those amino acids that compete with them during transport across the blood-brain barrier have been determined in depressed patients before and after treatment for four weeks with amitriptyline or lithium + L-tryptophan. There was no relation between the absolute plasma concentrations of free or total tryptophan or tyrosine and the clinical response to amitriptyline. There was also no relation between pre-treatment ratio of plasma tyrosine to competing amino acids and response to amitriptyline, but depressives with subnormal tryptophan ratio improved significantly more than patients with supernormal tryptophan ratio with comparable serum drug levels. The therapeutic response to lithium + L-tryptophan was predicted neither by the absolute plasma concentrations of free or total tryptophan or tyrosine nor by the tyrosine ratio, but there was also a trend towards greater improvement in patients with subnormal compared with supernormal tryptophan ratio. The results suggest that the pre-treatment plasma ratio of tryptophan to competing amino acids is a useful predictor of clinical response to amitriptyline. The possible mode of action of amitriptyline and lithium + L-tryptophan is briefly discussed.

Amino Acids↗
PubMed1990

Alprazolam and amitriptyline in the treatment of major depressive disorder: a double-blind clinical and sleep EEG study.

This study was designed to compare the antidepressant effects of alprazolam and amitriptyline in a group of 30 inpatients suffering from a severe major endogenous depression, diagnosed by Research Diagnostic Criteria and the Newcastle Rating scale, and to examine the effects of alprazolam and amitriptyline on two biological markers of depression, the dexamethasone suppression test and sleep EEG parameters. The 6-week study was double-blind with a random allocation of treatment. Patients were treated with flexible doses of 4-9 mg of alprazolam and 100-225 mg of amitriptyline. After 4 weeks of treatment the antidepressant effects of amitriptyline significantly exceeded those of alprazolam, as measured on the Hamilton Rating Scale for Depression. There was a high drop-out rate in the alprazolam group because of ineffectiveness of treatment. Alprazolam showed similar effects on sleep parameters as amitriptyline: lengthening of the REM latency and a tendency to shorten stages 3 and 4 and stage REM. These negative clinical results should be interpreted with caution, because of the severity of our selection criteria, and should not be extended to all depressive disorders.

Adult↗
PubMed1984

Double blind study comparing the efficacy of zimelidine and amitriptyline in endogenous depression.

Thirty-nine (39) patients entered a double blind study conducted to compare the therapeutic efficacy and safety of Zimelidine and amitriptyline in endogenous depression. Following a 3-5 day washout period, patients were randomly allocated to Zimelidine or amitriptyline for 6 weeks period and were assessed regularly. 63% of Zimelidine and 65% of amitriptyline patients showed significant clinical improvement. Side effects recorded with amitriptyline were predominantly anticholinergic and headaches with Zimelidine. It is concluded that while Zimelidine and amitriptyline show equally efficacous antidepressant properties, zimelidine may offer a slight therapeutic advantage due to lack of anticholinergic side-effects.

Adult↗
PubMed1992

Column switching and high-performance liquid chromatography in the analysis of amitriptyline, nortriptyline and hydroxylated metabolites in human plasma or serum.

A column-switching system for the direct injection of plasma or serum samples, followed by isocratic high-performance liquid chromatography and ultraviolet detection, is described for the simultaneous quantitation of the tricyclic antidepressant amitriptyline, its demethylated metabolite nortriptyline and the E- and Z-isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline. The method included adsorption of amitriptyline and metabolites on a reversed-phase C8 clean-up column (10 microns; 20 mm x 4.6 mm I.D.), washing of unwanted material to waste and, after on-line column-switching, separation on a cyanopropyl analytical column (5 microns; 250 mm x 4.6 mm I.D.). The compounds of interest were separated and eluted using acetonitrile-methanol-0.01 M phosphate buffer (pH 6.8) (578:188:235, v/v) within less than 20 min. Various drugs frequently co-administered with amitriptyline or other antidepressants did not interfere with the determinations. In plasma samples spiked with 25-300 ng/ml, the recoveries were between 84 and 112% and the inter-assay coefficients of variation were 3-11%. After a minor modification, as little as 5 ng/ml could be quantitated. There were linear correlations (r greater than 0.99) between drug concentrations of 5-500 ng/ml and the detector signal. The method allows routine measurements of amitriptyline, nortriptyline and hydroxylated metabolites in blood plasma or serum of patients treated with amitriptyline or nortriptyline, and enables the results to be reported within 1 h.

Amitriptyline↗
PubMed1995

Intravenous amitriptyline in pediatrics.

Oral amitriptyline has been used as an analgesic in a wide range of pain settings. Despite long-term availability of a parenteral form, the few reports about this formulation have been limited to pharmacokinetic studies in normal volunteers, trials in depressed patients, and analyses of electroencephalogram (EEG) activation. We retrospectively reviewed our experience using intravenous (IV) amitriptyline at Children's Hospital, Boston and at Children's Hospital at Stanford. Eight children (aged 5-16.6 years), who were unable to tolerate medications by the oral route, received IV amitriptyline for a variety of indications, including neuropathic pain, depression, sleep disturbance, and as an adjuvant agent for opioid analgesia. One patient experienced an extrapyramidal reaction temporally related to the administration of IV amitriptyline, which was successfully managed with diphenhydramine. Further prospective, controlled studies are needed to further assess the safety, efficacy and tolerability of this novel use of amitriptyline.

Adolescent↗
PubMed1992

Effects of chronic anethole trithione and amitriptyline treatment on rat parotid gland signalling.

The present study examines the mechanism(s) of action of anethole trithione (Sulfarlem S25) compared to the sialogogue pilocarpine. The chronic effects (7 days of treatment) of anethole trithione, pilocarpine and/or amitriptyline on autonomic receptor binding (homogenates) were measured together with parallel tests of stimulation-induced rises in delta [Ca2+]i in collagenase-isolated rat parotid acini. The results revealed that chronic treatment with amitriptyline resulted in significantly increased rises in delta [Ca2+]i after stimulation with 20 microM of carbachol or adrenaline, and a significant increase in muscarinic acetylcholine receptor density. In addition, anethole trithione also increased cholinergic and adrenergic responsiveness. The double treatment of amitriptyline and anethole trithione or amitriptyline and pilocarpine did, however, prevent the rise in delta [Ca2+]i observed under conditions when these drugs were administered alone. Furthermore, anethole trithione, but not pilocarpine, was able to prevent the amitriptyline-induced upregulation in muscarinic acetylcholine receptor density. In conclusion, the experimental data presented in this study are compatible with the hypothesis that anethole trithione might stimulate some post-receptor effect in the coupling to the secretory response. In addition, this study supports the beneficial effects of anethole trithione in treating drug-induced xerostomia.

Amitriptyline↗
PubMed2004

Loss of amitriptyline analgesia in alpha 2A-adrenoceptor deficient mice.

Tricyclic antidepressants have analgesic and sedative effects in addition to their antidepressive properties. We tested the acute analgesic and locomotor inhibitory effects of the tricyclic antidepressant amitriptyline and the alpha(2)-adrenoceptor agonist clonidine in wild-type control and in alpha(2A)-adrenoceptor knockout mice in hot-plate and tail-flick tests. Amitriptyline-induced analgesia was lost in alpha(2A)-adrenoceptor knockout mice. The locomotor inhibitory effect of amitriptyline was reduced, but not fully abolished in alpha(2A)-adrenoceptor knockout mice. Similar results were obtained with clonidine. We conclude that alpha(2A)-adrenoceptors appear to have a significant role in amitriptyline-induced acute analgesia in mice, and that alpha(2A)-adrenoceptors also participate in the sedative effects of amitriptyline.

Amitriptyline↗
PubMed2000

Amitriptyline modulation of Na(+) channels in rat dorsal root ganglion neurons.

The effects of amitriptyline, a tricyclic antidepressant, on tetrodotoxin-sensitive and tetrodotoxin-resistant Na(+) currents in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp method. Amitriptyline blocked both types of Na(+)currents in a dose-and holding potential-dependent manner. At the holding potential of -80 mV, the apparent dissociation constants (K(d)) for amitriptyline to block tetrodotoxin-sensitive and tetrodotoxin-resistant Na(+) channels were 4.7 and 105 microM, respectively. These values increased to 181 and 193 microM, respectively, when the membrane was held at a potential negative enough to remove the steady-state inactivation. Amitriptyline dose-dependently shifted the steady-state inactivation curves in the hyperpolarizing direction and increased the values of the slope factors for both types of Na(+) channels. The voltage dependence of the activation of both types of Na(+) channels was shifted in the depolarizing direction. It was concluded that amitriptyline blocked the two types of Na(+) channels in rat sensory neurons by modulating the activation and the inactivation kinetics.

Amitriptyline↗
PubMedDate not supplied

Regulation of glucocorticoid receptor-mRNA in human blood cells by amitriptyline and dexamethasone.

Recent research suggests that antidepressants exert their clinical action in depression via the restoration of glucocorticoid receptor (GR) function with a subsequent normalization of the altered feed-back regulation of the hypothalamic-pituitary adrenocortical (HPA) system. We, therefore, studied the effects of amitriptyline, a standard antidepressant, and of the glucocorticoid dexamethasone, which has recently been reported to possess antidepressive properties, on glucocorticoid receptor mRNA (GR-mRNA) derived from blood cells of healthy male volunteers. Whole blood samples were exposed in vitro for 24 h to amitriptyline and dexamethasone, the mRNA was extracted, transcripts of the 'house-keeping gene' glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the GR-gene were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) and semiquantitatively determined by subsequent densitometry. In a concentration of 10 nM, amitriptyline induced a significant increase in GR-mRNA (GR/GAPDH ratio) to 186 +/- 31% of the control condition, while a concentration of 10 microM of amitriptyline resulted in an increase of GR-mRNA (GR/GAPDH ratio) to 165 +/- 36%. Dexamethasone also up-regulated blood cell GR-mRNA (GR/GAPDH ratio) levels at a concentration of 10 nM to 184 +/- 29%, whereas an incubation with 10 microM apparently resulted in toxic effects on blood cells with a decreased amount of total mRNA samples recovered. In conclusion, we here show an increase of GR-mRNA in human blood cells after treatment with amitriptyline and dexamethasone, pointing to a direct action of these substances on GR-gene expression in a human system.

Adult↗
PubMed2001

Involvement of potassium channels in amitriptyline and clomipramine analgesia.

The effect of the administration of modulators of different subtypes of K(+) channels on antinociception induced by the tricyclic antidepressants amitriptyline and clomipramine was evaluated in the mouse hot plate test. The administration of the voltage-gated K(+) channel blocker tetraethylammonium (0.01-0.5 microg per mouse i.c.v. ) prevented antinociception induced by both amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.). The K(ATP) channel blocker gliquidone (0.1-1.0 microg per mouse i.c.v.) prevented antinociception produced by amitriptyline and clomipramine whereas the K(ATP) channel openers minoxidil (10 microg per mouse i. c.v.) and pinacidil (25 microg per mouse i.c.v.) potentiated tricyclic antidepressant-induced analgesia. The administration of the Ca(2+)-gated K(+) channel blocker apamin (0.1-1.0 ng per mouse i. c.v.) completely prevented amitriptyline and clomipramine analgesia. At the highest effective doses, none of the drugs used induced behavioural side effects or impaired motor coordination, as revealed by the rota-rod test, spontaneous motility or inspection activity, as revealed by the hole board test. The present results demonstrate that central antinociception induced by amitriptyline and clomipramine involves the opening of different subtypes of K(+) channels (voltage-gated, K(ATP) and Ca(2+)-gated) which, therefore, represent a step in the transduction mechanism of tricyclic antidepressant analgesia.

Amitriptyline↗
PubMed2003

Dynamic changes in AP-1 transcription factor DNA binding activity in rat brain following administration of antidepressant amitriptyline and brain-derived neurotrophic factor.

The present study was undertaken to examine the effects of the antidepressant, amitriptyline, and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA binding activity in the rat brain. Acute administration of amitriptyline (5 or 10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in the rat frontal cortex and hippocampus. Chronic administration of amitriptyline (5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity but ultimately resulted in its persistent elevation in the rat frontal cortex. In contrast, the chronic administration of amitriptyline did not affect the low activity of AP-1 DNA binding in the hippocampus. However, chronic administration of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct infusion of BDNF (1 microg) into the hippocampal dentate gyrus significantly increased hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription factor may be modulated by BDNF and that it may be an important target for the action of antidepressants.

Amitriptyline↗
PubMed1997

Prevention of amitriptyline-induced avoidance impairment by tacrine in mice.

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

Amitriptyline↗
PubMed1999

Amitriptyline-induced loss of tight junction integrity in a human endothelial--smooth muscle cell bi-layer model.

Tricyclic antidepressants can, when taken in overdose, cause serious pulmonary failure such as the adult respiratory distress syndrome (ARDS). In this study we have examined the effects of some tricyclic antidepressants (amitriptyline, imipramine, nortriptyline and desipramine) on the viability and morphology of human endothelial and smooth muscle cells derived from umbilical cord. Effects of amitriptyline on endothelial cell fluidity, as well as permeability changes to an endothelial-smooth muscle cell bi-layer, were also studied. The tricyclic antidepressants induced acute, sub-lethal toxicity in both cell types above 100 microM as assessed by the MTT reduction assay. Morphological changes were also observed at these concentrations. Such changes were, however, absent at 33 microM and below. Amitriptyline did, however, cause a concentration-dependent fall in the electrical resistance of an endothelial-smooth muscle cell bi-layer, with significant effects already evident at 33 microM. All of these observed effects were fairly rapid and appeared within 5-15 min of exposure. The rapidity of these permeabilisation effects suggests potential membrane perturbations, since tricyclic antidepressants are lipophilic molecules with affinity for cell membranes. However, fluorescence anisotropy measurements showed no significant difference in membrane fluidity between amitriptyline-treated and control endothelial cells. Collectively, these data point to specific mechanisms of action of amitriptyline, and probably also the other tricyclic antidepressants studied, on endothelial permeability, which is a hallmark of ARDS. The data suggest that increased endothelial permeability could be due to impaired tight junction function.

Amitriptyline↗
PubMed1997

Amitriptyline: a potent inhibitor of butyrylcholinesterase from human serum.

1. The effect of amitriptyline on human serum butyrylcholinesterase (acylcholine acylhydrolase E.C.3.1.1.8) has been investigated. From the Lineweaver-Burk plot and the plot of v versus amitriptyline concentration, it was concluded that amitriptyline inhibition is partially competitive, and the kinetic parameters have been calculated as Ks = 0.11 mM, alpha = 1425 and Ki = 0.01 mM. 2. Because amitriptyline is a partial competitive inhibitor of butyrylcholinesterase, acquired deficiency may be seen in patients treated with amitriptyline and may cause complications in operations.

Adrenergic Uptake Inhibitors↗
PubMed1977

Determination of amitriptyline and some of its metabolites in blood by high-pressure liquid chromatography.

Conditions for the determination of amitriptyline and some of its metabolites in serum on a reversed-phase material (C-8) by high-pressure liquid chromatography with UV detection at 254 nm were systematically investigated. The separation of tricyclic antidepressants is best carried out on a phase system consisting of C-8 bonded-phase material as the stationary phase and water--methanol--dichloromethane--propylamine as the mobile phase. The precision and detection limit of the method and the extraction efficiency were established. A chromatogram of a serum extract from a patient treated with amitriptyline is shown. Serum levels of amitriptyline and its four main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxy-amitriptyline and trans-10-hydroxy-nortriptyline) in a patient receiving 150 mg of amitriptyline daily, are reported.

Amitriptyline↗
PubMed1999

Cost-effectiveness of mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in austria.

This study estimated the cost-effectiveness of mirtazapine, compared to amitriptyline and fluoxetine, in the management of moderate and severe depression in Austria, as well as the costs related to the discontinuation of antidepressant treatment from the perspective of the Austrian Sick Funds (Gebietskrankenkassen). The economic analyses were based on a meta-analysis of four randomised clinical trials comparing mirtazapine with amitriptyline, and on a six week comparative trial of mirtazapine and fluoxetine which was extrapolated to six months using assumptions derived from the literature. Decision models of the treatment paths and associated resource use attributable to managing moderate and severe depression in Austria were developed from clinical trial data, information on Austrian clinical practice obtained from interviews with an Austrian Delphi panel (comprising psychiatrists and GPs), and from published literature. The models were used to estimate the expected costs to the Gebietskrankenkassen of managing a patient with moderate or severe depression, and the indirect cost per patient to Austrian society due to lost productivity. The expected cost to the Gebietskrankenkassen of healthcare resource use attributable to managing a patient suffering from moderate or severe depression who discontinues antidepressant treatment was estimated to be ATS 4,088 over five months, of which hospitalisations accounted for nearly 69% of the cost. Using mirtazapine instead of amitriptyline for 28 weeks increases the proportion of successfully treated patients by 21% (from 19.2 to 23.2%), and reduces the expected cost to the Gebietskrankenkassen by ATS 1,112 per patient (from ATS 31,411 to ATS 30,299). Patients treated with mirtazapine and amitriptyline for 28 weeks are expected to miss 4.76 and 5.01 weeks of work respectively, due to their depression. Hence, the expected indirect cost to Austrian society over this period was estimated to be ATS 58, 787 and ATS 61,851 per patient respectively. Using mirtazapine instead of fluoxetine for six months increases the proportion of successfully treated patients by 22% (from 15.6 to 19.1%), albeit for a negligible additional cost to the Gebietskrankenkassen of ATS 408 per patient (from ATS 29,205 to ATS 29,613). Patients treated with mirtazapine and fluoxetine for six months are expected to miss 4.53 weeks of work, due to their depression. Hence, the expected indirect cost to Austrian society due to lost productivity was estimated to be ATS 55,900 per patient with either antidepressant. In conclusion, this study suggests that despite the differences in acquisition costs, mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine, supporting the adoption of this treatment in the management of moderate and severe depression in Austria.

Amitriptyline↗