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PubMedDate not supplied

The production of amitriptyline from nortriptyline in formaldehyde-containing solutions.

The stability of nortriptyline in aqueous solutions containing various concentrations of formaldehyde was investigated. Amitriptyline, as a reaction product, was determined by gas chromatography/mass spectrometry (GC/MS) in these experiments. Factors that may contribute to this phenomenon, including pH, formaldehyde concentration, and incubation time were evaluated. At 40% (v/v) formaldehyde concentration and pH 4, there was a 68% decrease in nortriptyline concentration along with a concomitant formation of amitriptyline after 24 h. The N-methylated product was responsible for 48% of the total tricyclic drug present. The data also clearly indicate that the formation of amitriptyline is favored at elevated pH.

Amitriptyline↗
PubMedDate not supplied

Potential interference of cyclobenzaprine and norcyclobenzaprine with HPLC measurement of amitriptyline and nortriptyline: resolution by GC-MS analysis.

Cyclobenzaprine and its major metabolite, norcyclobenzaprine, differ from amitriptyline and nortriptyline only by the presence of a double bond in the cycloheptane ring. Three patients developed sufficient levels of cyclobenzaprine and norcyclobenzaprine because of either rapid or long-term ingestion of cyclobenzaprine to cause positive interferences in both a Syva EMIT assay and a high-performance liquid chromatographic (HPLC) assay for identification and quantitation of tricyclic antidepressants in serum. Cyclobenzaprine coeluted with amitriptyline, and norcyclobenzaprine eluted slightly earlier than, but was poorly resolved from, nortriptyline in this HPLC assay. We found that cyclobenzaprine could be distinguished from amitriptyline and that norcyclobenzaprine could be distinguished from nortriptyline on the basis of gas chromatographic retention times upon gas chromatographic-mass spectrometric analyses after derivatization with trifluoroacetic anhydride. The compounds were also distinguishable by mass spectrometric criteria.

Acetic Anhydrides↗
PubMedDate not supplied

Postmortem distribution of tramadol, amitriptyline, and their metabolites in a suicidal overdose.

A case report involving a 34-year-old white male who was found dead at home by his roommate is presented. At the time of his death, he was being treated with tramadol/acetaminophen, metaxalone, oxycodone, and amitriptyline. The decedent's mother stated that he had been taking increasing amounts of pain medication in order to sleep at night. There were no significant findings at autopsy; however, toxicology results supported a cause and manner of death resulting from suicidal mixed tramadol and amitriptyline toxicity. This case reports the tissue and fluid distribution of tramadol, amitriptyline, and their metabolites in an acutely fatal ingestion in an effort to document concentrations of these analytes in 12 matrices with respect to one another to assist toxicologists in difficult interpretations.

Adult↗
PubMed2004

Phase Ia and Ib study of amitriptyline for ulnar nerve block in humans: side effects and efficacy.

BACKGROUND: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain conditions. Among its many actions, this drug also blocks ion channels, such as Na channels. Preliminary animal studies suggested that amitripty-line would be a longer-lasting local anesthetic than bupivacaine, with potentially fewer side effects. Therefore, the authors investigated the adverse effects and effectiveness of this drug when given for ulnar nerve blockade in human volunteers. METHODS: After obtaining written institutional review board approval and informed consent, a typical phase Ia trial was conducted by administration to the ulnar nerve at the level of the wrist in an open-label, dose-escalating fashion. Amitripty-line hydrochloride, 4 ml, at concentrations of 5, 10, and 20 mM (n = 4-9/group) was used for each volunteer. If no major side effects and nerve block were encountered, comparison in a randomized, double-blinded trial of amitriptyline (20 mM) to placebo and bupivacaine (4 mM) (n = 4-9/group), was to follow. A blunt needle was used to grade the pain, and motor blockade was assessed by the Froment test. RESULTS: There was no significant statistical difference in terms of side effects (pain, swelling, erythema, and sedation) among any groups. The analgesic effects of 20 mM amitriptyline and 4 mm bupivacaine solution were significantly higher than those of the placebo solution. CONCLUSIONS: Because of the lack of evidence that amitripty-line provides better nerve blockade than current local anesthetics and the potential for neurotoxicity, its use for peripheral nerve blockade in humans seems limited.

Adult↗
PubMedDate not supplied

A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.

OBJECTIVE: The involvement of ongoing peripheral activity in the generation of nociceptive input in neuropathic pain suggests that topical drug delivery may be useful as a treatment strategy. This is a pilot study providing initial information regarding the use of novel topical preparations containing amitriptyline (AMI), ketamine (KET), and a combination of both in the treatment of neuropathic pain. METHODS: The study design included a 2 day randomized, double blind, placebo controlled, 4 way cross-over trial of all treatments, followed by an open label treatment phase using the combination cream for 7 days. Twenty volunteers with chronic neuropathic pain were randomly assigned to treatment order and applied 5 mls of each topical treatment (1% AMI, 0.5% KET, combination AMI 1%/KET 0.5%, and placebo) for 2 days. Measures of pain at the end of each block included the short form McGill Pain Questionnaire (MPQ) and visual analog scales (VAS) for present pain intensity and pain relief. Eleven subjects who judged subjective improvement from any treatment in the initial trial entered the open-label trial and used the combination cream for 7 days. Pain levels were recorded daily using the same measures. Blood levels for amitriptyline and ketamine were performed at 7 days to determine whether systemic absorption had occurred. RESULTS: There was no statistically significant difference from placebo after 2 days for any treatment during the double blind component of the trial. In the 11 subjects who used the combination cream, there was a statistically significant effect, with subjects reporting significantly greater analgesia by days 3 to 7 according to measures of pain and pain relief. Blood levels revealed that there was no significant systemic absorption of amitriptyline or ketamine. Only 2 subjects experienced side effects; these were minor and did not lead to discontinuation of the cream. CONCLUSION: This pilot study demonstrated a lack of effect for all treatments in the 2 day double blind placebo controlled trial, followed by analgesia in an open label trial in a subgroup of subjects who chose to use the combination cream for 7 days. Blood analysis revealed no significant systemic absorption of either agent after 7 days of treatment, and creams were well tolerated. A larger scale randomized trial over a longer interval is warranted to examine further effects observed in the open label trial.

Administration, Topical↗
PubMed1989

Amitriptyline versus haloperidol in borderlines: final outcomes and predictors of response.

The authors report the final results of a 4-year study of amitriptyline and haloperidol in 90 symptomatic borderline inpatients. Medication trials were double-blind and placebo controlled and lasted 5 weeks. Haloperidol (4-16 mg/day) produced significant improvement over placebo in global functioning, depression, hostility, schizotypal symptoms, and impulsive behavior. Significant effects of amitriptyline (100-175 mg/day) were generally limited to measures of depression. Factor analysis identified three symptom change patterns: a global depression, hostile depression, and schizotypal symptom pattern. Medication effects favoring haloperidol were most prominent for hostile depression. Variables predicting favorable response to haloperidol included severity of schizotypal symptoms, hostility, and suspiciousness. Schizotypal symptoms and paranoia predicted poor outcome on both depression patterns with amitriptyline. Placebo effects were most prominent on acute state symptoms, with severe character traits predicting poor response.

Amitriptyline↗
PubMed2002

The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients.

We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.

Adolescent↗
PubMed1991

A comparison of fluoxetine and amitriptyline in the treatment of major depression.

Fluoxetine, a new serotonin uptake blocking antidepressant, was compared with amitriptyline in a double-blind study. Patients were diagnosed as having major depression, according to DSM-III criteria, when interviewed with the Diagnostic Interview Schedule. There was significant improvement in patient and observer ratings of depression in both groups, with no difference between groups. Recent memory improved significantly in the fluoxetine group but not in the amitriptyline group. Numbers of patients reporting side-effects were similar but the profiles of side-effects were different, with more patients on amitriptyline reporting anticholinergic and intolerable side-effects.

Adolescent↗
PubMed1992

A double-blind multicentre study of paroxetine and amitriptyline in depressed outpatients. Italian Paroxetine Study Group.

A comparative double-blind study of paroxetine and amitriptyline in the treatment of depressed hospital outpatients was undertaken at 15 centres in Italy. Three hundred and nine patients of either sex were admitted to the study. The starting dose of paroxetine was 20 mg daily and of amitriptyline 75 mg daily in divided doses; at week 3 these doses could be increased at the investigators' discretion. Efficacy was measured on the Hamilton Depression Rating Scale and on Clinical Global Impression. Both treatment groups showed significant improvement at week 6 with no significant between-group differences. Significantly fewer patients receiving paroxetine reported adverse events compared with those on amitriptyline (44% vs 62%; p < 0.01 in favour of paroxetine).

Adult↗
PubMed1996

A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone and amitriptyline and lithium.

We describe a patient treated with trazodone, amitriptyline and lithium carbonate who developed anxiety, restlessness, tremor, myoclonus, hyperreflexia, diaphoresis, rigidity and hyperthermia. The constellation of findings was diagnostic of serotonin syndrome. Although doses of trazodone and amitriptyline were relatively low, serotonin syndrome developed in this patient. It is suggested that the combination with lithium facilitated the effect of central serotonergic responses mediated by trazodone and amitriptyline.

Amitriptyline↗
PubMed1980

Trichotillomania treated wih amitriptyline.

A case of trichotillomania (compulsive hair pulling) in a young adult is presented. The patient was treated with amitriptyline in progressively increasing dosage, with marked improvement in her symptoms. Amitriptyline has a pharmacological spectrum of action analogous to chlorimipramine, a medication with reputed effectiveness in severe compulsive behaviors. Thus, a rationale for the use of amitriptyline in this and related disorders evolves.

Adult↗
PubMed1991

Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine, and mephenytoin.

A 34-year-old man with bipolar manic depressive illness suffered from severe adverse effects during treatment with amitriptyline, 50 mg/day. It was subsequently shown that the patient was a slow metabolizer of amitriptyline. However, he tolerated a dose of 200 mg of imipramine/day, which was necessary in order to reach a therapeutic level of about 900 nM for imipramine plus desipramine. Since both antidepressants are subject to the genetic sparteine/debrisoquine oxidation polymorphism, the patient was phenotyped with sparteine. The test performed during paroxetine treatment indicated that the patient was a poor metabolizer. Subsequent tests performed during a drug-free period, however, showed the patient to be an extensive metabolizer, with a sparteine metabolic ratio (MR) of 1.7 and 2.8 and debrisoquine MR of 2.3. It was subsequently shown that paroxetine is a potent, competitive inhibitor of 1'-hydroxybufuralol formation in a human liver microsome preparation (K1 approximately 800 nM). This patient thus illustrates two problems: (a) the erroneous phenotyping due to concurrent medication, and (b) the existence of a very slow amitriptyline elimination apparently not related to the sparteine/debrisoquine oxidation polymorphism.

Administration, Oral↗
PubMed1994

Immunoassay reagents for psychoactive drugs. Part 4. Quantitative determination of amitriptyline and nortriptyline by fluorescence polarization immunoassay.

Methods for the quantitative determination of amitriptyline and nortriptyline by fluorescence polarization immunoassay (FPIA) is described. One immunoassay allows for the accurate quantification of amitriptyline in the presence of nortriptyline while the second immunoassay allows for the accurate quantification of nortriptyline in the presence of amitriptyline.

Amitriptyline↗
PubMed1977

Dopaminergic agonist nomifensine compared with amitriptyline: a double-blind clinical trial in acute primary depressions.

1. Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4,-tetrahydroisoquinoline) is a new antidepressant which displays an interesting pharmacological profile and acts as a potent dopaminergic agonist. 2. In a double-blind clinical trialnomifensine was compared with a standard and widely tested antidepressant amitriptyline. A total of 24 patients with primary acute depressions, defined by research criteria, were treated for 8 weeks and their clinical condition and laboratory values monitored at regular intervals. The dosage schedule was a flexible one, with a daily dose range from 50-200 mg for nomifensine and 50-225 mg for amitriptyline. 3. Nomifensine and amitriptyline were found to be equivalent in their antidepressant efficacy. Nomifensine, however, showed a trend towards more rapid effect and was relatively free of side-effects. 4. As nomifensine combined antidepressant activity with low frequency of adverse effects, it would seem to be suitable for wider use in the treatment of primary depressions. The results of our study have to be generalized with caution because of the limited sample size.

Adult↗
PubMed1978

Amitriptyline- and mianserin-induced changes in acquisition of paired-association learning-task.

1 The double-blind study on twenty healthy students was an attempt at assessing the effects of 2-week's treatment with amitriptyline (25 mg three times a day) and mianserin (10 mg three times a day), each alone or separatively inbibed with alcohol (0.5 g/kg) on the immediate memory and on the acquisition of a paired-association learning-task. 2 Amitriptyline impaired both the short-term memory-span and acquisition, and alcohol potentiated these effects. The action of mianserin did not deviate significantly from that of the placebo, and it also failed to interact with alcohol. 3 It is concluded that the decrement in learning capacity, that occurs after the 2-week's treatment with therapeutic doses of amitriptyline, reflects changes in both the intrinsic and the regulatory mechanisms of learning.

Adult↗
PubMed1984

Interaction between the beta-adrenoceptor blockers metoprolol and atenolol with amitriptyline and their effects on oxidative liver metabolism.

Neither the kinetics of the hydrophilic beta-adrenoceptor blocker atenolol nor those of the lipophilic metoprolol were influenced by the concurrent administration of amitriptyline. Compared with placebo, chronic administration (14 days) of atenolol and metoprolol (each as monotherapy) did not significantly reduce oxidative liver metabolism as measured by antipyrine half-life and by 6-beta-hydroxycortisol excretion. Compared with atenolol and metoprolol monotherapy, chronic administration of amitriptyline concurrently with each of the beta-adrenoceptor blockers produced an insignificant decrease (circa 10-20%) in antipyrine half-life and 6-beta-hydroxycortisol excretion. Amitriptyline appears therefore to have little enzyme-inducing activity.

Adult↗
PubMed1990

In vivo spectrophotometric determination of striatal acetylcholinesterase activity: the modulation induced by the antidepressant amitriptyline.

A new technology called in vivo spectrophotometry was applied to the quantitative determination of the variations in local acetylcholinesterase (AChE) activities. Repeated measurements of the enzyme activities in the same live animal allowed the study of the in vivo inhibition of AChE by amitriptyline. Interactions between AChE and this tricyclic antidepressant were investigated at the striatal level in anesthetized rats. In this anesthetized model, AChE assays were shown to be stable for approximately 8 h. The dose-effect relationship was explored in the 2.5- to 50-mg/kg amitriptyline range. A reversible inhibition was observed after acute amitriptyline administration. The maximum of inhibition appeared between 90 and 210 min after the intoxication and reached up to 22% for the 50-mg/kg dose. The threshold dose was established as 8 mg/kg. Evidence for an indirect interaction between tricyclic antidepressant and AChE was demonstrated when the total integrity of the biological system was preserved.

Acetylcholinesterase↗
PubMed1994

Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half-life repeated administration. Comparison with acute administration.

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z-10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

Amitriptyline↗