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PubMed2000

Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine.

Leptin, tumor necrosis factor-alpha (TNF-alpha), and soluble TNF receptors are involved in weight regulation. Antipsychotic agents, such as clozapine, induce weight gain and increase circulating levels of these cytokines. To assess whether obesity-inducing antidepressants have a similar effect, we measured plasma cytokine levels in depressive inpatients during the first six weeks of treatment with tricyclic agents (amitriptyline or nortriptyline, n = 12), with paroxetine (n = 10), or without medication (n = 14). There was an increase in the body mass index at week 6 of treatment with the tricyclics, which was preceded by a significant increase in soluble TNF receptor p75 plasma levels. Circulating levels of leptin were not affected. Paroxetine and drug-free treatment did not affect any of these parameters. We conclude that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin. However, activation of the TNF-alpha system might be an early and sensitive marker of ensuing weight gain.

Adult↗
PubMed2000

Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption.

Mice with a genetic disruption (knockout) of the multiple drug resistance (Mdr1a) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein at the blood-brain barrier on the uptake of amitriptyline (AMI) and fluoxetine (FLU) and their metabolites into the brain. One hour after intraperitoneal injection of AMI or FLU, knockout (-/-) and wild-type (+/+) mice were sacrificed and drug concentrations of brain, kidney, liver, testis, and plasma were measured. The plasma concentrations of the AMI metabolites and the brain:spleen ratios of AMI, nortriptyline (NOR), 10-OH-AMI and 10-OH-NOR were significantly higher in the -/- mice, demonstrating that AMI and its metabolites are substrates of the P-glycoprotein and that mdr1a activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, tissue distributions of FLU and its metabolites among the various tissues tested were indistinguishable between groups. The herein reported differences in brain penetration of antidepressant drugs depending on the presence of the mdr1a gene may offer an explanation for differences in the treatment response at a given plasma concentration. Moreover, individual differences in mdr1 gene activity may account for variable response patterns at different episodes and development of therapy resistance.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1976

Comparative trial of L-tryptophan and amitriptyline in depressive illness.

Depressed patients who were suitable for drug treatment were allocated randomly to treatment for four weeks with either amitriptyline in doses reaching 150 mg daily or with L-tryptophan in a maximal dose of 8 G daily. Both in-patients and out-patients were included. The trial was double-blind and ratings were made at the start of treatment and weekly for the subsequent four weeks: the patients were then followed for a further six months. Both groups of patients improved steadily over the course of four weeks and there were no marked differences between the treatment groups though there was some tendency for the improvement of the tryptophan-treated patients to fade between the third and fourth weeks. Within the tryptophan group anxious patients improved least. It is concluded that L-tryptophan probably has some antidepressive action in patients with depressive illness of moderate severity.

Adult↗
PubMed2005

Effects of chronic administration of olanzapine, amitriptyline, haloperidol or sodium valproate in naive and anhedonic rats.

Although in bipolar patients the main therapeutic indication of atypical antipsychotics is the management of acute mania, several observations suggest that these agents may exert antidepressant as well as anti-manic effects. The main goal of the present work was to evaluate the putative antidepressant effect of chronic olanzapine (Ola) (0.02-0.1 or 0.5 mg/kg.d), in comparison to haloperidol (Hal) (0.2 mg/kg.d) and sodium valproate (VPA) (5 or 30 mg/kg.d), in rats exposed to a protocol of chronic mild stress. The tricyclic compound amitriptyline (Ami) (5 mg/kg.d) was used as reference drug. The results indicate that Ola, in a rodent model of depression, has protective effects against the stress-induced anhedonia. Compared to Hal and VPA, Ola shows a greater antidepressant activity and is as effective as Ami in preventing the anhedonic state. The effects of Ola and Ami, however, have a different time-course. A full reversion of the anhedonia by Ami appears after a latency of 4 wk, whereas the effect of Ola is already evident 1 wk after the beginning of the chronic treatment. Moreover, the recovery from anhedonia at the end of the stress protocol and after drug cessation was more rapid in groups of rats pretreated with Ola or VPA than in the group of saline-pretreated rats. In conclusion, the results indicate that 0.02 mg/kg.d Ola causes a rapid and sustained antidepressant-like effect, while all other anti-manic treatments show loss of efficacy at 3 wk. Taken together, these observations support the hypothesis that Ola has a broader pharmacotherapeutic profile than solely as an antipsychotic or anti-manic agent.

Amitriptyline↗
PubMed2006

Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats.

In the present study we have investigated the effects of a chronic administration of olanzapine (Ola) on visual and spatial memory in normal and anhedonic rats. The effects of Ola have been compared to those of the typical antipsychotic Hal, the tricyclic antidepressant amitriptyline (Ami), and the mood stabilizer VPA. Anhedonia (assessed by reduction of sucrose preference) was induced by administration of a chronic mild stress (CMS) protocol, in which rats were exposed sequentially, over a period of 4 wk, to a variety of unpredictable mild stressors. The spatial memory was evaluated by testing the ability of the rats to discriminate a familiar vs. a novel environment, while the visual memory was assessed by testing the ability of the rats to discriminate familiar vs. novel objects. In CMS-free rats, VPA (5 or 30 mg/kg.d), Ola (0.02 or 0.1 mg/kg.d), Ami (2 mg/kg.d) and Hal (0.2 mg/kg.d) caused no detectable modifications of visual memory, whereas VPA (5 mg/kg.d), Ami (2 mg/kg.d) and Ola (0.02 mg/kg.d) did not modify spatial memory performance. In our experimental conditions, the administration of the CMS protocol caused an impairment of both visual and spatial memory. The chronic treatment of anhedonic rats with Ola (0.02 mg/kg.d) or Ami (2 mg/kg.d) prevented, at least in part, the stress-induced impairment of visuospatial performance. In conclusion, the results of the present preclinical study seem to indicate that the chronic administration of low doses of Ola or Ami has the potential to lead to substantial cognitive benefits in depressed patients.

Amitriptyline↗
PubMed1980

Antiarrhythmic activity of amitriptyline analogues in conscious dogs after myocardial infarction: cyproheptadinium methiodide.

The antiarrhythmic effects of amitriptyline (1), its secondary amine metabolite nortriptyline (2), as well as cyclobenzaprine (3) and cyproheptadine (4), tertiary amine analogues of 1, were studied in conscious dogs 24 h after myocardial infarction. Since the sedative side effect of 4 presents a potential problem for its clinical use, a quarternary derivative of 4, cyproheptadine methiodide (5), was prepared and its effects also studied in this model. Complete conversion to a normal sinus rhythm occurred in all animals studied after cumulative doses of 1700 micrograms/kg (6.17 mumol/kg) of 3, 1300 micrograms/kg (4.69 mumol/kg) of 1, 300 micrograms/kg (1.04 mumol/kg) of 4, and 25 micrograms/kg (0.058 mumol/kg) of 5. While 2 significantly decreased ventricular ectopic activity, it did not convert any of the animals studied to a sinus rhythm at doses up to 3000 micrograms/kg. Thus, the order of potency for conversion to a normal sinus rhythm appears to be 5 >> 4 > 1 > 3 >> 2. These data suggest that 5 is very potent in converting ventricular arrhythmias associated wtih myocardial infarction.

Amitriptyline↗
PubMed1997

Comparison of amitriptyline metabolism in hepatocytes from streptozocin-induced diabetic rats and from non-diabetic rats.

Biotransformation of amitriptyline (AMI) was studied at different intervals in freshly isolated hepatocytes from healthy or streptozocin-induced diabetic rats in order to investigate the influence of the diabetic state. Levels of free and conjugated AMI, demethylated and hydroxylated metabolites, were assessed by HPLC analysis. In hepatocytes isolated from diabetic rats, AMI was less completely metabolized and the demethylation reaction became more important than in non-diabetic rat hepatocytes. Although the proportions of hydroxylated metabolites decreased in diabetic rats, it always remained predominant. Furthermore, glucuronidation of metabolites was greater, especially for (Z)-10-hydroxynortriptyline in diabetic animals.

Amitriptyline↗
PubMed1980

Interindividual differences in amitriptyline demethylation.

Amitriptyline (AT) and its demethyl metabolite nortriptyline (NT) were given orally and intramuscularly to 6 normal subjects, and the areas under the blood concentration--time curves (AUC) were calculated. The mean unbound fraction of AT and NT in plasma was 5.4% and 8.3%, respectively. The blood-plasma ratio of NT was nearly double that of AT, which was close to unity. The mean systemic availability of oral relative to intramuscular AT and NT was 43% and 61%. The calculated mean oral blood clearance of AT as measured by dose (oral)/AUC was 1.6 1/min. The demethylation of orally administered AT varied considerably between the 6 individuals (from 25% to 89%) and correlated with oral drug clearance. Demethylation was estimated from the AUC applied to the NT metabolite. The estimated oral clearance of AT from demethylation ranged from 0.21 to 1.80 1/min.

Administration, Oral↗
PubMed1982

Plasma binding variations of amitriptyline and nortriptyline.

The importance of variation in plasma binding in the uncertain correlation between total plasma concentration and the antidepressive effect of amitriptyline (AT) and its active metabolite nortriptyline (NT) was examined. Plasma binding of AT and NT in 131 plasma samples from 87 patients was analyzed by equilibrium dialysis at 37 degrees for 3 hr. There was a twofold variation in percent unbound AT and NT (range 3.5% to 8.6% and 5.4% to 11.3%) and there was no correlation between percent and unbound drug and total drug concentration (range 54 to 6910 nmol/l and 77 to 3420 nmol/l for AT ant NT). The correlation coefficient relating unbound drug concentration of AT and NT to total concentration in plasma was 0.99 for the whole group and 0.16 for the NT therapy control patients, with total plasma concentrations within the therapeutic range. At therapeutic concentration AT was 66.6% and 63.5% bound to purified isolated orosomucoid (alpha 1-acid glycoprotein) and albumin, at physiologic concentrations. The binding to isolated lipoproteins was not examined, but no correlation was found between percent unbound AT and NT and plasma concentration of triglycerides, cholesterol, or orosomucoid.

Adult↗
PubMed1982

Significance of lipoproteins in serum binding variations of amitriptyline, nortriptyline, and quinidine.

Using isotope technique, the serum binding of amitriptyline (AT), nortriptyline (NT), and quinidine (Q) was measured by equilibrium dialysis in sera containing varying amounts of lipoproteins. Sera were obtained from 10 fasting subjects with normal to grossly elevated levels of cholesterol, triglycerides, or both. When the lipoproteins were removed from eight of the sera by a standard ultracentrifugation technique, the ratio bound/unbound (B/F) AT decreased an average of 47% (range 30% to 68%), NT an average of 54% (range 39% to 67%), and Q an average of 6% (range 0 to 16%). This decrease in the ratio B/F correlated linearly with the sum of serum concentrations of cholesterol and triglycerides for AT (r = 0.88) and NT (r = 0.82), but not for Q (r = 0.15). In three lipoprotein-depleted sera resuspended with lipoproteins at eight different concentrations ranging from 0 to 100% of the original content, there was a linear correlation between the ratio B/F for AT and NT and the lipoproteins, as evidence by cholesterol or triglycerides concentrations (r = 0.97 to 0.99), but not for Q (r = -0.17 to 0.36). Finally, in the original 10 serum samples, there was a linear correlation between the ratio B/F and the serum lipoproteins (sum of cholesterol and triglycerides) for AT (r = 0.89) and NT (r = 0.68), whereas there was no such relationship for Q (r = -0.15). These data indicate that basic drugs differ in binding characteristics (probably depending on lipophility).

Adult↗
PubMed1982

Nortriptyline formation after single oral and intramuscular doses of amitriptyline.

Oral (50 mg) and intramuscular (25 mg) amitriptyline (AT) was given to six normal subjects and the area under the plasma concentration-time curve (AUC) for nortriptyline (NT) formed was calculated. There was no difference between the AUCs (corrected for dose) after the two routes of administration. The ratio between the AUCs (corrected for dose) after the two routes of administration. The ratio between AUCoral and AUCim averaged 0.95 (range 0.69 to 1.13). After intramuscular AT maximum NT plasma concentration was reached after 24 to 48 hr, whereas it was 8 to 24 after oral dosing.

Administration, Oral↗
PubMed1982

Steady-state plasma concentrations of cis- and trans-10-OH amitriptyline metabolites.

Plasma concentrations of the geometric isomers of 10-OH amitriptyline (10-OH AT) and 10-OH nortriptyline (10-OH-NT) were determined by reversed-phase high-pressure liquid chromatography. Steady-state concentrations of At, NT, and the four 10-OH metabolites were measured in 27 patients taking AT for depression. All of the unconjugated hydroxylated metabolites were usually detectable and trans-10-OH NT always predominated. Mean concentrations, expressed as percentage of the sum of all six compounds, were: AT 30%, NT 27%, cis-10-OH AT 1.1%, trans-10-OH AT 4.0%, cis-10-OH NT 4.0%, and trans-10-OH NT 33%. Repeated measurements on 10 patients over several weeks indicated that interindividual variations in absolute and relative 10-OH metabolite concentrations are much greater than day-to-day variations. Five patients who also received a phenothiazine had a lower proportion of 10-OH metabolites.

Adult↗
PubMed1983

Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation.

Amitriptyline AT demethylation to nortriptyline NT was determined in nine healthy subjects who had been phenotyped with respect to debrisoquine D hydroxylation capacity. AT demethylation was calculated from the ratio between the plasma AUCs of NT after single oral doses of AT and NT. Plasma clearance of AT by demethylation did not correlate with the ratio between D and 4-hydroxy-D in urine (rs = -0.55).

Adult↗
PubMed1983

Chronopharmacology of amitriptyline.

Side effects of decreased salivation and sedation were more marked when a single dose of amitriptyline was taken orally in the morning than in the evening. These dynamic differences were due to alteration in kinetics. Absorption of the drug was more rapid in the morning, although other kinetic parameters, especially total bioavailability, were unchanged. Thus, in the case of this drug, chronopharmacologic differences were due to a change in rate of absorption. The present practice of giving a single dose of drug in the evening is justified on the basis that it induces fewer side effects without a loss in therapeutic efficacy.

Absorption↗
PubMed1984

Amitriptyline metabolism in relation to antidepressive effect.

The relationship between amitriptyline (AT) metabolism and clinical response was studied in 14 outpatients treated with a daily dose of 150 mg AT. Riboflavin was added to the medication to check compliance. On days 0, 2, and 7 and at 3, 6, 9, and 13 wk after onset of therapy, blood samples were drawn from the patients 3 (+/- 0.5) hr after the first morning dose and a sample of the first morning urine was taken to check riboflavin. Serum levels of AT and its metabolites, nortriptyline (NT), E- and Z-10-hydroxynortriptyline (E- and Z-10-OH-NT), total (E + Z) 10-hydroxyamitriptyline (tot-10-OH-AT), and desmethylnortriptyline (DNT), were measured by means of HPLC while minimizing adsorption onto glass. On day 0 and after 6 and 13 wk the severity of the depressive disorder was scored by means of the self-rating depression scale of Zung.28 Mean steady-state concentrations of AT, NT, and E-10-OH-NT were in the order of 100 micrograms/l and tot-10-OH-AT and Z-10-OH-NT approximated 20 micrograms/l. DNT concentrations were under 15 micrograms/l. There was great variation in metabolic pattern between patients. After 6 wk concentrations of all compounds were approximately 15% lower than at 3 wk, indicating a weak autoinducible effect of AT or its metabolites. Steady-state concentrations of AT correlated well with that of NT (r = 0.64; P less than 0.05) but not with that of E-10-OH-NT.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effects of amitriptyline and imipramine on brain amine neurotransmitter metabolites in cerebrospinal fluid.

The effects of amitriptyline (AMI) or imipramine (IMI) on levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) (the major brain metabolites of the neurotransmitters norepinephrine [NE], serotonin [5-HT], and dopamine [DA]) in cerebrospinal fluid were determined in 66 subjects with unipolar and bipolar depression. There were significant reductions in MHPG and 5-HIAA levels for the depressed group taken as a whole, but levels of HVA did not change significantly. The changes were similar when subjects were grouped as treated with AMI and IMI and with unipolar and bipolar depression. Reductions in MHPG and 5-HIAA levels were greater in women than in men. In all subjects with depression and in those treated with AMI and IMI, amine metabolite changes did not differ significantly between those who had a positive clinical response to drug therapy and those who did not. Responders with bipolar depression had smaller reductions in MHPG levels than did responders with unipolar depression. The similar effects of AMI and IMI on MHPG and 5-HIAA differ from the dissimilar effects of the two drugs on NE and 5-HT amine uptake systems reported in animal and in in vitro studies. Results provide conclusive evidence of the effects of AMI and IMI on noradrenergic and serotonergic (but not dopaminergic) systems in patients with depression.

Adult↗
PubMed1986

Analgesic and antidepressive effects of low-dose amitriptyline in relation to its metabolism in patients with chronic pain.

The analgesic and antidepressive effects of amitriptyline (AT) in relation to its kinetics and metabolism were studied in 19 outpatients with chronic pain who received a daily dose of 75 mg AT for at least 6 weeks. Riboflavin was added to the medication to check compliance. On days 0, 4, and 8 and weeks 3, 6, 9, and 12 after the start of dosing, blood samples were drawn from the patients 10 +/- 1 hours after the first morning dose and a sample of the first morning urine was taken to check riboflavin. Serum levels of AT and its metabolites, especially nortriptyline (NT) and E-10-hydroxy-nortriptyline (E-10-OH-NT), were measured by HPLC. On day 0 and at 3, 6, and 12 weeks the severity of depression was scored by means of a self-rating depression scale and pain intensity scores were measured. In addition, after 6 weeks of dosing patients estimated their percentage of pain in comparison with baseline. Mean (+/- SD) steady-state concentrations of AT, NT, and E-10-OH-NT were 36 +/- 23.5, 28 +/- 14.9, and 52 +/- 23.7 micrograms/L, respectively, in male patients (n = 8; age 45 +/- 7.4 years) and 34 +/- 14.6, 45 +/- 25.1, and 40 +/- 15.6 micrograms/L, respectively, in female patients (n = 11; age 46 +/- 6.8 years). There was a significant sex-related difference in the NT/AT ratio, which was higher in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Enzyme kinetic modelling as a tool to analyse the behaviour of cytochrome P450 catalysed reactions: application to amitriptyline N-demethylation.

1. To determine kinetic parameters (Vmax, K(m)) for cytochrome P450 (CYP) mediated metabolic pathways, nonlinear least squares regression is commonly used to fit a model equation (e.g., Michaelis Menten [MM]) to sets of data points (reaction velocity vs substrate concentration). This method can also be utilized to determine the parameters for more complex mechanisms involving allosteric or multi-enzyme systems. Akaike's Information Criterion (AIC), or an estimation of improvement of fit as successive parameters are introduced in the model (F-test), can be used to determine whether application of more complex models is helpful. To evaluate these approaches, we have examined the complex enzyme kinetics of amitriptyline (AMI) N-demethylation in vitro by human liver microsomes. 2. For a 15-point nortriptyline (NT) formation rate vs substrate (AMI) concentration curve, a two enzyme model, consisting of one enzyme with MM kinetics (Vmax = 1.2 nmol min-1 mg-1, K(m) = 24 microM) together with a sigmoidal component (described by an equation equivalent to the Hill equation for cooperative substrate binding; Vmax = 2.1 nmol min-1 mg-1, K' = 70 microM; Hill exponent n = 2.34), was favoured according to AIC and the F-test. 3. Data generated by incubating AMI under the same conditions but in the presence of 10 microM ketoconazole (KET), a CYP3A3/4 inhibitor, were consistent with a single enzyme model with substrate inhibition (Vmax = 0.74 nmol min-1 mg-1, K(m) = 186 microM, K1 = 0.0028 microM-1). 4. Sulphaphenazole (SPA), a CYP2C9 inhibitor, decreased the rate of NT formation in a concentration dependent manner, whereas a polyclonal rat liver CYP2C11 antibody, inhibitory for S-mephenytoin 4'-hydroxylation in humans, had no important effect on this reaction. 5. Incubation of AMI with 50 microM SPA resulted in a curve consistent with a two enzyme model, one with MM kinetics (Vmax = 0.72 nmol min-1 mg-1, K(m) = 54 microM) the other with 'Hill-kinetics' (Vmax = 2.1 nmol min-1 mg-1, K' = 195 microM; n = 2.38). 6. A fourth data-set was generated by incubating AMI with 10 microM KET and 50 microM SPA. The proposed model of best fit describes two activities, one obeying MM-kinetics (Vmax = 0.048 nmol min-1 mg-1, K(m) = 7 microM) and the other obeying MM kinetics but with substrate inhibition (Vmax = 0.8 nmol min-1 mg-1, K(m) = 443 microM, K1 = 0.0041 microM-1). 7. The combination of kinetic modelling tools and biological data has permitted the discrimination of at least three CYP enzymes involved in AMI N-demethylation. Two are identified as CYP3A3/4 and CYP2C9, although further work in several more livers is required to confirm the participation of the latter.

Amitriptyline↗