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At least 19 recordsLinked to original sources
PubMed1992

Amitriptyline and amitriptyline metabolites in blood and cerebrospinal fluid following human overdose.

The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. Gastric lavage was performed and 50 g activated charcoal were given orally. Venous blood samples were taken on admission and at 1, 2, 4, 8, and 24 h, and in some patients at 36 and 48 h after admission. Arterial blood samples were taken at 1, 4, 8, and 24 h after admission. Lumbar punctures were performed 1 h after admission in 8 patients and again 4 h later in 5 patients. A urine sample was screened for other drugs. The bound and unbound fraction of amitriptyline and its metabolites nortriptyline, E and Z forms of 10-OH-amitriptyline and nortriptyline were analyzed in plasma, whole blood, red blood cells, and cerebrospinal fluid using an HPLC technique. The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 h respectively. The rate of elimination of amitriptyline was not dose-dependent. The arteriovenous differences in the total amitriptyline+nortriptyline concentration were maximal in patients admitted soon after intake of drugs. Amitriptyline concentrations in cerebrospinal fluid were quantitatively similar to the unbound amitriptyline concentration in blood. The highest cerebrospinal fluid amitriptyline concentration was 506 nmol/L. There were large individual differences in plasma, blood and cerebrospinal fluid concentrations between different individuals. Repeated quantitative analysis of amitriptyline and its metabolites is unlikely to contribute to the clinical management of most patients with amitriptyline overdose.

Adult↗
PubMed1980

On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients.

The antidepressant effect of amitriptyline was studied in 28 endogenous depressive patients. They received 150 mg amitriptyline once nightly in a sustained release form for 4 weeks. Blood samples were drawn 12 hrs. after medication. Amitriptyline concentrations were between 35--300 ng/ml Nortriptyline concentrations were between 20--330 ng/ml. No correlations were found between plasma concentrations of amitriptyline, nortriptyline, or their sum, and the clinical outcome of treatment. Plasma levels of amitriptyline depended on neither the age nor the sex of the patients. A significant correlation was found between the ratio of nortriptyline to amitriptyline concentrations in serum (demethylation ratio) and clinical improvement. The demethylation ratio appeared to be relatively constant after a few days of treatment. The results suggest that monitoring the demethylation ratio of endogenous depressive patients treated with amitriptyline may predict therapeutic effects of the treatment. They also suggest that a balance between noradrenergic and serotonergic mechanisms is necessary to improve antidepressant treatment with amitriptyline.

Adult↗
PubMed1995

A comparison of amitriptyline, vasopressin and amitriptyline with vasopressin in nocturnal enuresis.

Forty-five children aged 6-14 years with primary nocturnal enuresis were randomised to determine whether desmopressin is more effective than amitriptyline and whether the combination of amitriptyline/desmopressin is more effective than amitriptyline or desmopressin alone. Amitriptyline dosage was 25 mg for children 6-10 years and 50 mg for children aged 10-14 years. Desmopressin (20 micrograms) was given in the same dosage for all age groups. After a run-in period of 2 weeks, children were treated for 16 weeks and then observed for 12 weeks. In the amitriptyline group mean wet nights per week decreased from 5.8 +/- 0.9 to 3.3 +/- 1.9 (P < 0.0005); in the desmopressin group mean wet nights per week decreased from 6.0 +/- 0.9 to 4.7 +/- 1.7 (P < 0.02); in the amitriptyline/desmopressin group mean wet nights per week decreased from 6.3 +/- 0.9 to 3.3 +/- 2.5 (P < 0.0006). When comparing the groups, amitriptyline/desmopressin and amitriptyline were statistically more effective than desmopressin in week 6 (P < 0.009), week 8 (P < 0.03) and week 10 (P < 0.04). No significant side effects occurred. At this dose amitriptyline was more effective than desmopressin and the combination of desmopressin and amitriptyline did not confer any additional benefit.

Adolescent↗
PubMed1982

The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo.

One hundred and fifteen patients from 5 general practices participated in a 12-week, double-blind study comparing L-tryptophan, amitriptyline, L-tryptophan-amitriptyline combination and placebo in the treatment of depression. Analysis of total score on the Hamilton Depression Scale and a global rating of depression showed that all 3 active treatments were more effective than placebo. Significantly more patients were withdrawn as treatment failures in the placebo group compared with the active treatment groups. Side-effects necessitated withdrawal of more patients from the amitriptyline group than from the other active treatment groups, but this difference was not significant. Plasma amitriptyline and nortriptyline levels were similar in the amitriptyline and combined treatment groups. Standard haematological and biochemical profiles did not alter significantly in any group, but mean heart rate was significantly increased in patients receiving amitriptyline. There was no change in free or total plasma tryptophan concentration with treatment or on remission of symptoms.

Adolescent↗
PubMed2002

Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study.

BACKGROUND AND OBJECTIVES: Antidepressants are often used to treat chronic daily headache disorders such as transformed migraine, in part because of the high prevalence of associated mood disorder. We conducted this study to evaluate the efficacy and tolerability of combined treatment with amitriptyline and fluoxetine compared with amitriptyline alone for chronic daily headache due to transformed migraine. PATIENTS AND METHODS: Thirty-nine patients, 26 women and 13 men, aged 20 to 69 years (mean, 36.4; SD, 2.5) who fulfilled criteria for transformed migraine proposed by Silberstein et al were studied prospectively. Amitriptyline was dosed as follows: 8 mg/day for 6 days, 8 mg twice a day for 6 days, 20 mg/day for 6 days, and 20 mg twice a day for 45 days. In the group receiving combination therapy, fluoxetine was dosed and administered identically. The initial and end of the study (9 weeks) headache indices (frequency x intensity) were compared between groups. RESULTS: Twenty-seven patients completed the study, 13 in the amitriptyline-alone group (group 1) and 14 in the combination-therapy group (group 2). The most frequent adverse event in both groups was dry mouth, and there was no significant difference in the occurrence of this or other adverse events between the two groups. Initial headache indices were similar for groups 1 and 2. The mean difference between the initial and final headache index for group 1 was 513.5 (P<.0005) and 893 (P<.0017) for group 2. The difference between the final headache index for the two groups was not significant (P>.207). CONCLUSIONS: We were unable to demonstrate any significant benefit from amitriptyline plus fluoxetine over amitriptyline alone in the treatment of chronic daily headache/transformed migraine. Because of the small number of subjects involved and the short duration of our study, a type II error cannot be excluded.

Adult↗
PubMed2004

P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline.

P-glycoprotein (P-gp) is a 170-kDa membrane protein and the gene product of the multiple drug resistance (MDR1 or ABCB1) gene. It constitutes an important part of the blood-brain barrier and actively exports a number of molecules across the blood-brain barrier back into the vascular space, subsequently reducing central nervous system (CNS) bioavailability of these substances. The aim of the present study was to investigate the pharmacokinetics of amitriptyline and its metabolites in P-gp (also called mdr1ab or abcb1ab) knockout mice and controls after a long-term adminstration for 10 days. Knockout mice and controls received s.c. injections of amitriptyline (10 microg/g bodyweight) twice daily for 10 days. After 10 days, the animals were sacrificed and the concentrations of amitriptyline and nortriptyline and both their E-10-OH and Z-10-OH metabolites were measured with high-performance liquid chromatography in the cerebrum, plasma, spleen, kidney, testes, lung, liver, muscle and fat. Except for amitriptyline, the brain concentrations of all other examined substances were significantly higher in the P-gp knockout mice. Compared to controls, concentrations of nortriptyline were 2.6-fold higher, E-10-OH-nortriptyline 10-fold higher, Z-10-OH-nortriptyline seven-fold higher, E-10-OH-amitriptyline two-fold higher and Z-10-OH-amitriptyline five-fold higher. The present study confirms that P-gp plays an important role in the interaction between CNS drugs and the blood-brain barrier. Without P-gp at the blood-brain barrier, the brain concentrations of the substances were up to 10-fold higher, showing that P-gp plays an active role in exporting CNS drugs out of the brain. Recent clinical studies showing different side-effects in patients with P-gp polymorphisms confirm the clinical importance of these findings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Gas chromatographic determination of amitriptyline, nortriptyline and perphenazine in plasma of schizophrenic patients after administration of the combination of amitriptyline with perphenazine.

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.

Adult↗
PubMed2004

Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy.

BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >or=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs.

Adult↗
PubMedDate not supplied

[Valpromide-amitriptyline interaction. Increase in the bioavailability of amitriptyline and nortriptyline caused by valpromide].

Valpromide is largely used in the therapy of affective disorders for its presumed thymoregulating activity. So, it is often associated with tricyclic antidepressant treatment. Previous clinical studies lead us to consider the possibility of an interaction between valpromide and tricyclic antidepressants, interaction which could result in an increase of antidepressant plasma concentrations. But no pharmacokinetic study has been realized up to now in order to clearly demonstrate such a phenomenon. The authors studied amitriptyline and nortriptyline plasma levels in two groups of ten patients receiving 125 mg amitriptyline, once a day, during 20 days. In the second group, patients also received 600 mg valpromide daily after ten days on amitriptyline. In the first group amitriptyline and nortriptyline plasma concentrations remained stable between the tenth and the twentieth day. In the second group, addition of valpromide resulted in a significant increase of antidepressant plasma levels: from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) for amitriptyline, and from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01) for nortriptyline.

Amitriptyline↗
PubMed1980

Determination of amitriptyline-N-oxide, amitriptyline and nortriptyline in serum and plasma by high-performance liquid chromatography.

A method for the determination of amitriptyline-N-oxide, amitriptyline and nortriptyline in serum and plasma has been developed. After extraction from serum or plasma the drugs were analysed by high-performance liquid chromatography. The detection limit was 10 ng/ml (2 ml serum or plasma actually used). The coefficient of variation for all three compounds was below 10%. Amitriptyline-N-oxide was found in rat plasma after an oral dose (10 mg/kg) of amitriptyline-N-oxide.

Amitriptyline↗
PubMed1978

Comparative trial of amitriptyline-N-oxide and amitriptyline in the treatment of out-patients with depressive syndromes.

Amitriptyline-N-oxide and amitriptyline were compared double-blind in a material of out-patients with depressive syndromes, 21 and 22 patients respectively. Both drugs had a good antidepressant effect. The globally rated effect was equal. The effect upon the various depressive symptoms was equal. Definite reversal of depression occurred somewhat earlier on amitriptyline-N-oxide on which side effects were also less marked, but those of an anticholinergic and of a sedative nature. No orthostatic reaction, nor any effect upon blood status or liver function was observed. Amitriptyline-N-oxide appears to show a tendency to a somewhat more rapid onset of effect and less side effects.

Adult↗
PubMedDate not supplied

[Double-blind study of the effects of amitriptyline and of a combination of amitriptyline and lithium on patients with chronic primary headache].

The Authors report their experience in a "double-blind" study in patients affected by chronic primitive headache. 30 patients have been examined: the first one were prescribed amitriptyline, the other one amitriptyline plus lithium association for 30 days. The study pointed out treatments have been effective in reducing frequency, duration and intensity of headache, even though the amitriptyline is more effective in the prophylaxis of chronic headache, whilst amitriptyline plus lithium association seems to be more effective in subacute headache.

Amitriptyline↗
PubMed1993

[Effectiveness and tolerance of amitriptyline oxide in chronic tension headache--a multicenter double-blind study versus amitriptyline versus placebo].

Tricyclic antidepressants, especially amitriptyline, are the medication of first choice in the treatment of chronic tension headache. Few previous studies meet modern standards of study design and statistical analysis. Tolerability and efficacy of 60-90 mg amitriptyline oxide (AO) as a single dose in the evening were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a 4-week baseline phase and 12 weeks of treatment. The 3-armed study was conducted in 7 centers. The inclusion criterion was tension-type headache on at least 15 days monthly with a duration of at least 6 months. Exclusion criteria were a migraine history, previous participation in another clinical trial within the last 3 months, drug abuse, medication with other antidepressants or tranquilizers, current use of other acknowledged prophylactic headache medication, lack of compliance, major psychiatric disorder according to DSM-III and medical contra-indications against tricyclic antidepressants. The primary study endpoint was a reduction at least 50% of the product of headache duration and frequency and a reduction at least 50% in headache intensity. Statistics used were Fisher's Exact Test and an analysis of variance. A total of 211 patients were included in this trial. One hundred ninety-seven cases, 87 males and 110 females, with a mean age of 38 +/- 13 (18-68) years, could be analysed completely (66 AO, 67 AM, 64 PL). With regard to the strictly defined primary study endpoint, no significant difference emerged between AO, AM and PL: treatment responders were 30.3% with AO, 22.4% with AM and 21.9% with PL (PAO-PL = 0.3210, PAM-PL = 1.000, PAO-AM = 0.3299 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

Amitriptyline in combination with repeated late sleep deprivation versus amitriptyline alone in major depression. A randomised study.

Only few systematic studies are available on the status of sleep deprivation therapy in the overall treatment regimen of depressive patients. 51 patients suffering from a major depressive episode (ICD-10) were randomly allocated to 4 weeks' treatment with amitriptyline (150 mg/day) or to a combination of amitriptyline with six partial-sleep-deprivation treatments late in the night (at 4-5 day intervals). According to observer rating (Hamilton Rating Scale for Depression, 21- and 10-item version), a highly significant amelioration was recorded in both groups until the 14th day of treatment. A further improvement occurred, however, only in those patients treated with both antidepressants and sleep deprivation. Hence the response rate ( > or = 50% HAMD reduction) after 4 weeks' treatment was distinctly more favourable in this group than in those patients under pharmacotherapy alone. The superiority of the combined therapy cannot be confirmed statistically by self-rating (Befindlichkeitsskala: von Zerssen; Visual Analogue Mood Scale). The immediate antidepressive effect of sleep deprivation diminished in the course of the sleep deprivation series. The response to the first sleep deprivation was a predictor neither for the response to further sleep deprivation treatments nor for the overall treatment outcome.

Adult↗
PubMed1995

Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone.

The steady-state kinetics of amitriptyline (AMI), fluoxetine (FLU), and their active metabolites nortriptyline (NTRIP) and norfluoxetine (NFLU) were studied in 15 patients treated once daily for long durations with 50 mg of AMI and 20 mg of FLU. These compounds were analyzed simultaneously in plasma by liquid chromatography. The means and (SEM) of the steady-state concentrations (Css) of AMI, NTRIP, FLU, and NFLU were 80.6 (14.2), 52.6 (10.3), 85.3 (16.1), and 90 (13.6) ng/mL, respectively, and the apparent oral clearances (CLor) of AMI and FLU were 42.4 (8.6) and 14.9 (2.5) L/hr, respectively. The metabolite/drug steady-state concentration ratio (Css(m)/Css) for NTRIP/AMI was 0.75 (0.14) and for NFLU/FLU was 1.27 (0.17). There was a significant correlation (P < 0.05) between Css of FLU and that of AMI or NTRIP. The Css and Css(m)/Css values obtained for AMI were higher (P < 0.056 and P < 0.0034, respectively) than those we observed in 10 patients treated solely with the same dose of AMI. The twofold increase in Css of AMI and ninefold increase in Css of NTRIP seem to be the result of inhibition of the metabolism of these compounds by FLU, particularly the ring hydroxylation. Norfluoxetine may have a small inhibitory influence on the metabolism of NTRIP but lacks this effect on the metabolism of AMI.

Adolescent↗
PubMed1990

Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline.

The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

Amitriptyline↗
PubMed1981

Amitriptyline pharmacokinetics. A crossover study with single doses of amitriptyline and nortriptyline.

Six healthy volunteers were given single doses of amitriptyline (AT) and of nortriptyline (NT) separated by at least 10 days. Plasma concentrations of both compounds were measured at intervals for 48 or 72 h. The total areas under the concentration-time curves for the ingested drug were greater for NT, but AT concentrations showed much higher peak values and took more than 12 h to reach the terminal beta phase of elimination. Doses of 50 mg AT produced areas averaging slightly less than half those for 100 mg AT in the same subject, suggesting some saturation of the elimination process. The consumption of a large, fatty meal just before taking the AT tablets had little effect on the plasma drug concentration curves. NT half-lives, measured after ingestion of NT tablets, were used in analysing the production of NT from doses of AT in the same subject. There was a rapid early production, amounting to 30-67% of the total and presumably resulting from the first pass of AT through the liver. NT was then formed continuously at a rate always proportional to the simultaneous rate of AT elimination. The total amount of NT entering the systemic circulation was about one-quarter of the AT dose.

Adult↗