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PubMed1986

Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study.

Seventy patients with primary fibrositis satisfying Smythe's criteria were studied in a 9-week double-blind trial comparing 50 mg amitriptyline with placebo. Fifty-nine patients completed the trial: 27 were treated with amitriptyline, and 32 took a placebo. The patients who received amitriptyline improved significantly in their morning stiffness and pain analog scores at 5 and 9 weeks, compared with baseline scores, whereas no changes were noted in these parameters in the placebo group. Fibrocytic point tenderness did not improve significantly in either of the treatment groups. When compared with the placebo group, the amitriptyline group improved significantly with respect to sleep pattern and patient and physician global assessments. Our data indicate that amitriptyline has some therapeutic benefit in patients with primary fibrositis.

Adult↗

PubMed1998

Multiple-dose pharmacokinetics and pharmacodynamics of OROS and immediate-release amitriptyline hydrochloride formulations.

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate-release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled-release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration--time curve (AUC0-24) for the OROS and IR formulations were 1,265 and 1,393 ng. hr/mL, respectively. The drug-to-metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline-corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.

Adult↗

PubMed2005

Aromatic-aromatic interaction of amitriptyline: implication of overdosed drug detoxification.

The objectives of this work are to explore the pi-pi complexation of amitriptyline with pi electron-deficient aromatic rings and demonstrate the feasibility of pi-pi complexation for overdosed drug detoxification. Water-soluble oligochitosan was chemically modified with dinitrobenzenesulfonyl groups to induce selective binding toward amitriptyline through pi-pi complexation. NMR studies showed that benzenesulfonyl and dinitrobenzenesulfonyl protons were upfield shifted by the addition of amitriptyline, indicating the formation of pi-pi complexes. The pi-pi complexation of amitriptyline is driven primarily by a desolvation driving force, whereas the magnitude of interaction is dictated by the complementrary electrostatic interaction. Isolated rat heart tests revealed that dinitrobenzenesulfonyl oligochitosan prevented the amitriptyline-induced cardiotoxicity and was itself not cardiotoxic.

Adsorption↗

PubMed1992

A comparison of the effects of fluvoxamine and amitriptyline on autonomic functions in healthy volunteers.

We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design. Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis. Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg). The results suggest that fluvoxamine has some anti-muscarinic activity in man, but is considerably less potent in this respect than amitriptyline.

Administration, Oral↗

PubMed1991

Does tolerance develop to the sedative and amnesic effects of antidepressants? A comparison of amitriptyline, trazodone and placebo.

The psychomotor, sedative and memory effects of a sedative, anticholinergic antidepressant (amitriptyline), a sedative antidepressant (trazodone) and placebo were compared in a double-blind, cross-over study with 12 healthy volunteers. Amitriptyline (37.5 mg) and trazodone (100 mg) were administered for the first 7 days of treatment and in double-dosage for the next 7 days of treatment. Subjects completed a battery of tests before and 2 h after drug administration on days 1, 8 and 14. Over the 2 weeks of treatment, there was no accumulation of effects but subjects experienced marked sedation and psychomotor impairments following a daily dose of both active drugs. Although both amitriptyline and trazodone produced impairments on memory tasks, the effect of amitriptyline was significantly greater and may reflect its anticholinergic action over and above global sedative effects. Tolerance to the effects of amitriptyline built up differentially over measures of sedation, psychomotor function and memory.

Adult↗

PubMed1993

Minor and clinically non-significant interaction between toloxatone and amitriptyline.

The possibility of a pharmacokinetic interaction between amitriptyline and toloxatone (a new MAOI-A) has been studied in 17 depressed in-patients. Amitriptyline and its demethylated and hydroxylated metabolites in blood and urine were measured at steady state after the administration of amitriptyline with and without toloxatone in steady state. The metabolic status of patients was determined using the dextromethorphan phenotyping test. There was only a minor pharmacokinetic interaction between amitriptyline (AMT) and toloxatone, with a small increase in the AMT/NT (nortriptyline) plasma ratio: 0.68 before and 0.78 after toloxatone. The urinary excretion and plasma levels of AMT and its metabolites were not affected by the co-therapy. Three of the patients were poor metabolisers, but this did not predict the magnitude of the drug interaction. The interaction does not justify plasma level monitoring of amitriptyline as the change in pharmacokinetics was so small.

Adult↗

PubMed1979

A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness.

In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures. Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4. The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects.

Adult↗

PubMed1982

Amitriptyline and nortriptyline response profiles in unipolar depressed patients.

The relationship between steady-state plasma concentration and clinical response was studied in 22 hospitalized unipolar depressed patients. In a double-blind format the patients were randomly assigned to receive amitriptyline or nortriptyline. Dosage was adjusted based on plasma level with the aim of achieving a concentration of 60-180 ng/ml. By week 4 of treatment, 83% of amitriptyline patients and all nortriptyline patients were within the targeted plasma range. Based on final ratings of clinical state, the drug level adjustment improved the outcome for nortriptyline-treated patients, but not amitriptyline-treated patients. Nortriptyline patients with plasma levels of 60-230 ng/ml had lower Hamilton Rating Scale depression scores than patients outside that range. By contrast, amitriptyline plasma levels were not associated with depression ratings. After 1 week, patients treated with nortriptyline had a significantly greater mean reduction in Hamilton depression score, i.e., 55% compared to 25% for amitriptyline patients.

Adolescent↗

PubMed1981

Interaction of desipramine and amitriptyline with adrenergic mechanisms in the human iris in vivo.

Mydriatic responses of the pupil were evoked by locally instilled noradrenaline and methoxamine in eight healthy volunteers. The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine were compared on the mydriatic responses. Both antidepressants potentiated the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by methoxamine, amitriptyline being approximately twice as potent as desipramine. It is suggested that the potentiation of the response to noradrenaline may reflect the blockade of the uptake of noradrenaline into adrenergic nerve terminals, whereas the antagonism of the response to methoxamine may reflect the blockade of postsynaptic alpha-adrenoceptors by the antidepressants. It is argued that the interaction of the antidepressants with adrenergic mechanisms could explain why amitriptyline, a potent anticholinergic agent, causes no significant change in resting pupil diameter, while desipramine, a relatively weaker anticholinergic agent, produces a significant mydriasis.

Adult↗

PubMed1987

Lack of interaction of ranitidine with amitriptyline.

The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.

Adult↗

PubMed1992

Effects of chronic amitriptyline administration on saliva from the parotid and submandibular glands of the rat.

The effect of prolonged treatment with amitriptyline on the secretory activity of rat salivary glands evoked by parasympathetic nerve stimulation and isoprenaline administration has been studied. Low doses of amitriptyline (10 mg/kg per day for 2 or 4 weeks), did not significantly affect salivary flow evoked by either parasympathetic nerve or isoprenaline stimulation. Higher doses of amitriptyline (50 mg/kg/day for 2 or 4 weeks) however, markedly decreased parasympathetic-evoked salivary secretion (flow and volume) from both parotid and submandibular glands, while isoprenaline-evoked secretions were unaffected. Sodium, potassium, and calcium concentrations of nerve-elicited or isoprenaline-evoked saliva were not significantly altered by amitriptyline treatment. Protein concentration and amylase activity of nerve-elicited parotid saliva were, however, greatly increased by chronic amitriptyline administration. Possible mechanisms for drug-induced increase in nerve-elicited salivary protein concentration include changes in cholinergic receptor binding, release of neuropeptides and variations in phosphatidylinositol turnover, which need further study.

Amitriptyline↗

PubMed1978

Clinical response and plasma concentration of amitriptyline and its metabolite nortriptyline.

Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 mg/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug.

Adult↗

PubMed1994

Controlled comparison of nefazodone and amitriptyline in major depressive inpatients.

Nefazodone, a phenylpiperazine antidepressant, exhibits novel dual activity on serotonin (5-HT) neurons; it binds to 5-HT2 receptors and inhibits 5-HT reuptake. Flexible doses of nefazodone (100-400 mg/day) and amitriptyline (50-200 mg/day) were compared in 106 major depressive inpatients in a 6-week double-blind study. Results showed significant superiority of amitriptyline over nefazodone on all rating instruments: Montgomery and Asberg depression rating scale (P < 0.0001), Hamilton depression scale (P < 0.0006), Clinical Global Impressions (P < 0.0001) and Patient Global Assessment (P < 0.01). A total of 65% of patients under amitriptyline and 56% of patients under nefazodone reported adverse events during the study, with significantly more dry mouth in the amitriptyline group (39% versus 11%, P = 0.001). Modal daily doses within the last treatment week reached 242 mg with nefazodone and 124 mg with amitriptyline. The lower efficacy of nefazodone, which contradicts comparative trials with imipramine in US patients, is discussed with regard to the dose of nefazodone, probably below the optimal therapeutic range for melancholic patients, and to the clinical differences between the patient samples.

Adolescent↗

PubMed2000

Effect of amitriptyline on the messenger RNA of thyroid hormone-responsive genes in rat cerebral tissue.

To determine the molecular mechanisms of the potentiating effect of thyroid hormones (TH) on the therapeutic efficacy of tricyclic antidepressants (TCA), the expression of two known TH-responsive mRNAs was measured in control rats and rats treated with triiodothyronine (T3, 10 microg/100 g for 10 days), amitriptyline (10 mg/kg for 10 days), or combined T3 and amitriptyline. Northern blot analysis was carried out to measure the cerebral tissue content of a novel translational repressor (NAT-1) and another thyroid hormone-responsive (THR) mRNA. Rats treated with the combination of T3 and amitriptyline had significantly higher NAT-1 expression (2691.1+/-134.1 arbitrary units) than rats treated with T3 only (1688.5+/-77.8) or with amitriptyline only (1452.5+/-87.5) or the untreated control rats (731.3+/-23.0), P<0.01. Amitriptyline treatment did not alter the expression of THR mRNA or THR protein in either control or T3-treated rats. It is concluded that alterations in the expression of selective T3 responsive genes in cerebral tissue could be a mechanism of the known T3 potentiation of the therapeutic efficacy of TCA.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Coma blisters, peripheral neuropathy, and amitriptyline overdose: a brief report.

BACKGROUND: Coma blisters are most commonly associated with barbiturate and benzodiazepine overdose; however, they have also been described in association with many other substances, including amitriptyline. OBJECTIVE: To review the literature on the clinical manifestations of coma blisters in the setting of amitriptyline overdose. METHODS: Case report and literature review. RESULTS: Coma blisters in association with amitriptyline overdose have rarely been documented in the literature. Of the few reported cases, peripheral neuropathy has been present two (including our case report) out of four times. CONCLUSION: Amitriptyline is known to impair endothelial cell tight junction integrity. Thus, individuals with amitriptyline overdose may be predisposed to microvascular damage during the compression imposed from a comatose state. This may help to explain the tendency for patients to present with the interesting triad of coma, blisters, and neuropathy.

Adult↗

PubMed1978

The antiarrhythmic action of amitriptyline on arrhythmias associated with myocardial infarction in dogs.

The antiarrhythmic activity of amitriptyline, a tricyclic antidepressant, was evaluated in anesthetized dogs 24 h after coronary occlusion, during the period of spontaneous ventricular arrhythmias. In all experiments amitriptyline was administered i.v. in incremental doses of 0.3 mg/kg at 1 min intervals until a conversion to normal sinus rhythm was evident. Amitriptyline administration resulted in conversion of the ventricular arrhythmia to a normal sinus rhythm in 100% of the animals tested at a mean dose of 1.3 +/- 0.1 mg/kg. Smaller doses also resulted in a dose-related decrease in non-sinus nodal pacemaker activity. Lidocaine, when administered to the same group of animals, produced a reduction of ectopic pacemaker activity, but did not eliminate it at a cumulative dose of 2 mg/kg. Antiarrhythmic doses of amitriptyline did not produce significant changes in arterial blood pressure, cardiac output or electrocardiographic parameters associated with atrioventricular or intraventricular conduction. The results of this study suggest that at very low doses amitriptyline may be an effective antiarrhythmic agent in ventricular arrhythmias associated with myocardial ischemia.

Amitriptyline↗

PubMed1995

Biochemical and behaviour changes induced by acute stress in a chronic variate stress model of depression: the effect of amitriptyline.

This paper examines the biochemical and behaviour changes induced by an acute stress (five 10-s, 1-mA foot-shocks) in three groups of rats: (1) never stressed, (2) subjected to chronic variate stress for 20 days, (3) subjected to the same chronic stress and treated with 5 mg/kg per day amitriptyline. After 15 min, acute stress led to a marked reduction in cortical beta-adrenoceptor and 5-HT2 receptor density, whereas the density of the 5-HT1A receptors was unchanged. Chronic stress also increased beta-adrenoceptor and 5-HT2 receptor density and had no effect on 5-HT1A. Acute stress diminished the density of beta-adrenoceptors in chronically stressed animals, but did not alter that of the two 5-HT populations. Amitriptyline alone reduced beta-adrenoceptor and 5-HT2 receptor densities only. Acute stress applied to animals treated with amitriptyline reduced 5-HT1A receptors, and caused a further beta-adrenoceptor decrease, but had no further effect on the 5-HT2 receptors. On behaviour, chronic stress diminished reactivity to the acute stress. This reduction was fully abolished by amitriptyline. An open-field study showed that acute stress reduced motor activity, increased latency times and diminished rearing in the controls, whereas chronic stress reduced motor activity only. No significant changes in behaviour were induced by the acute stress in animals subjected to chronic stress. The combination of chronic stress with amitriptyline was accompanied by a diminution of exploratory activity that persisted after the acute stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗

PubMed1987

Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline.

The central mechanism responsible for the potentiation by antidepressant drugs of analgesia induced by morphine, was explored by measuring the levels of various neuropeptides (met-enkephalin, leu-enkephalin, dynorphin, substance P and cholecystokinin-like materials) and the density of delta and mu opioid binding sites in the spinal cord of rats treated for 14 days with amoxapine (10 mg/kg i.p., daily) or amitriptyline (10 mg/kg i.p., daily). Similar measurements were made in the hypothalamus and cerebral cortex for comparison. Chronic treatment with amoxapine or amitriptyline did not affect the levels of dynorphin, substance P and cholecystokinin, but markedly enhanced the levels of leu-enkephalin in the three structures examined. The levels of met-enkephalin were also increased after treatment with amitriptyline but only in the spinal cord and hypothalamus. No changes in opioid receptors were found in the cerebral cortex, but the densities of delta and mu opioid binding sites were increased in the spinal cord, and decreased in the hypothalamus of rats treated with amoxapine or amitriptyline. These changes induced by antidepressants in opioidergic markers at the spinal level might account for the potentiation of the action of morphine in amoxapine- or amitriptyline-treated rats. In addition, the observed alterations in the same markers in the hypothalamus could be associated with changes induced by antidepressants in neuroendocrine regulation.

Amitriptyline↗