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PubMed1990

Effect of amitriptyline or phenobarbital on the activities of the enzymes involved in rat liver.

The effect of phenobarbital (PB) or amitriptyline (AMT) on phospholipid metabolism was studied in rat liver. Administration of PB or AMT caused a marked increase in the microsomal phosphatidylcholine (PC) content. In this context, the activities of glycerophosphate acyltransferase (GAT), phosphatidate cytidylyltransferase (PCT), phosphatidate phosphohydrolase (PPH) and choline phosphotransferase (CPT) in the liver were all increased by PB. In contrast, the activities of GAT and PCT were little affected by AMT, while those of PPH and CPT were significantly increased by AMT. These findings suggest that AMT or PB would increase hepatic microsomal PC synthesis through inducing PPH and then CPT.

Amitriptyline↗
PubMed1974

Comparison of cardiovascular toxicities induced by dimetacrine, imipramine and amitriptyline in isolated guinea pig atria and anesthetized dogs.

Cardiovascular toxicity induced by dimetacrine (DMC), an antidepressant, was investigated in isolated guinea pig atria and anesthetized dogs, and compared with those of imipramine (IMP) and amitriptyline (AMT) which have been widely used as antidepressants. In the electrically driven guinea pig left atria, these three agents depressed the atrial contraction; a statistically significant differences from non-treated control atria was observed in IMP and AMT, 3 times 10- minus 6M, and DMC, 10-5 minus M. The following order of potency was obtained; AMT greater than IMP greater than DMC. In the anesthetized dogs treated with the increasing doses of each agent, hypotensive response were observed in the doses more than 1 mg/kg i.v.; the order of potency was as follows, AMT greater than IMP greater than DMC. A pronounced tachycardia was induced by IMP and AMT, 0.1-3 mg/kg i.v., and DMC, 1-3 mg/kg i.v., and the maximum response was observed in the doses of 1, 1 and 3 mg/kg i.v., respectively. When infused at the rate of 1 mg/kg/min i.v., the agents elicited hyperpnoea, tachycardia (except DMC) and hypotension, followed by respiratory arrest and cardiac arrest. Various changes in the ECG, including extrasystoles and supraventricular or ventricular tachycardia were also observed 10 to 15 min after the onset of infusion of AMT and IMP. However, DMC caused no visible modification in the ECG. The doses of AMT, IMP and DMC required to produce cardiac arrest were 25.4 plus or minus 1.2 (S.E.M.), 27.5 plus or minus 3.8 and 64.0 plus or minus 2.2 mg/kg i.v., respectively. The present study confirmed that fewer cardiovascular complications are caused by clinical use of DMC as compared to other tricyclic antidepressants such as IMP or AMT.

Acridines↗
PubMed1989

Acute effect of amitriptyline, phenobarbital or cobaltous chloride on delta-aminolevulinic acid synthetase, heme oxygenase and microsomal heme content and drug metabolism in rat liver.

Cobaltous chloride (CoCl2) caused very marked decreases of cytochrome P-450, b5 and total heme contents and an increase of heme oxygenase activity. On the contrary, phenobarbital (PB) increased hepatic drug-metabolizing enzymes, but the total heme content remained unchanged. On the other hand, amitriptyline (AMT) caused a marked increase of delta-aminolevulinic acid (delta-ALA) synthetase activity at 12 and 24 hr. In addition, the contents of total heme and cytochrome b5 and the activities of aminopyrine (AM) N-demethylase and aniline (AN) hydroxylase at 24 hr were also increased by AMT, whereas cytochrome P-450 content did not change. This may be explained by the fact that AMT would increase hepatic heme synthesis through the prolonged induction of delta-ALA synthetase, but it may not cause an increase in cytochrome P-450 heme because there are increases in the contents of cytochrome b5 and total heme.

5-Aminolevulinate Synthetase↗
PubMed2004

Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.

BACKGROUND: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. METHODS: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). RESULTS: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). CONCLUSIONS: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

Adult↗
PubMed1991

Reversible brain death. A manifestation of amitriptyline overdose.

Tricyclic antidepressants are known to cause central nervous system depression. However, a generalized depression of brainstem functions is rarely reported. We report a patient in deep coma with complete absence of brain-stem reflexes after she had taken a large quantity of amitriptyline. With continuous supportive treatment, she eventually regained all neurologic function and made a full recovery.

Amitriptyline↗
PubMedDate not supplied

Amitriptyline attenuates the febrile response to a pyrogen in rabbits.

We investigated the effect of a tricyclic antidepressant (TCA) agent on fever in rabbits. In the first series of experiments, the TCA agent amitriptyline hydrochloride (AMI) was administered intraperitoneally (i.p.) at a dose of 1 mg/kg or 10 mg/kg daily for three weeks. The rabbit's response to intravenous (i.v.) injection of 0.1 micrograms/kg of the lipopolysaccharide (LPS) of Salmonella typhosa was tested on a weekly basis. In the second series of experiments, rabbits were given simultaneous i.v. injections of either 1 mg/kg or 10 mg/kg of AMI together with 0.1 microgram/kg of LPS. After two weeks of chronic i.p. administration of 10 mg/kg AMI, and for the remainder of the experimental period, the rabbit's response to the LPS was significantly attenuated when compared to control animals. When AMI was administered simultaneously with the LPS, a significant dose-dependent antipyresis was observed from 50 minutes after injection, compared to the response of control animals. AMI had no effect on the body temperature of afebrile animals.

Amitriptyline↗
PubMed1999

[Use of amitriptyline in attention deficit hyperactivity disorder].

We studied the action of amitriptyline (AMI) in the attention deficit hyperactivity disorder (ADHD). Twenty-five children who came to consultation for ADHD were analyzed, in two groups: the group which used AMI (n = 18) at 1.6 mg/kg/day and the group which used placebo (n = 7). Both groups were submitted to two assessments in a 30 days interval, which consisted of the evolutive neurological evolution examination (ENE) and the WISC scale subtests on numbers, drawings to be completed and the code. The results showed that the AMI produced an improvement in performance in the motor persistence tests.

Amitriptyline↗
PubMedDate not supplied

Multifocal neurological impairment caused by infection-induced rise in blood lithium and amitriptyline.

We present the case of a thirty-eight-year-old woman who developed a febrile illness which was associated with a rise of blood lithium and amitriptyline, and subsequently suffered permanent neurological impairment, implicating CNS dysfunction at several levels. Medical, laboratory, radiological and neuropsychological findings are described, and the attribution of the syndrome is discussed. It is crucial to emphasize that the authors are not challenging the frequently useful combination of lithium and antidepressants. Rather, we urge psychiatrists to be vigilant when such patients develop febrile illnesses.

Adult↗
PubMed1998

Determination of amitriptyline and nortriptyline in human liver microsomes with reversed-phase HPLC in vitro.

AIM: To develop a method for simultaneous determinations of amitriptyline (Ami) and its metabolite nortriptyline (Nor) in human liver microsomes. METHODS: An incubation buffer containing microsomes, NADPH-generating system, and Ami, after termination of enzyme reaction and desipramine (Des) as internal standard (IS), was extracted with diethy ether and separated on a reversed-phase ODS column. Detection was achieved at 242 nm by ultraviolet detector. RESULTS: No potential interfering peaks were found. Ami and Nor gave rapid elution and baseline resolution. The linear curves of both analyses ranged 0.02-10 nmol and the limit of detection was 0.01 nmol. The recovery (94%-101%) had good precision with relative s of < 8.3%. CONCLUSION: This method is rapid, sensitive, and simple for studying the metabolism of Ami and Nor.

Amitriptyline↗
PubMed2000

Comparative N-glucuronidation kinetics of ketotifen and amitriptyline by expressed human UDP-glucuronosyltransferases and liver microsomes.

Like other basic amphiphilic drugs, the (S)-enantiomer of the antiallergic drug ketotifen exhibited biphasic kinetics when it was converted to two isomeric quaternary ammonium-linked glucuronides in human liver microsomes. For (R)-ketotifen this applied when incubations were carried out in the absence of a detergent. Two UDP-glucuronosyltransferases (UGTs) present in human liver, UGT1A4 and UGT1A3, were previously shown to catalyze tertiary amine N-glucuronidation when expressed in HK293 cells. Therefore, the conjugation kinetics of (R)- and (S)-ketotifen were investigated with the two expressed proteins. When homogenates of HK293 cells expressing UGT1A4 were incubated without detergent, N-glucuronidation kinetics were monophasic with K(M) values of 59 +/- 5 microM for (R)- and 86 +/- 26 microM for (S)-ketotifen. In experiments with membranes containing expressed UGT1A3, somewhat higher K(M) values were obtained. These values correspond to the high rather than to the low K(M) components of ketotifen glucuronidation in liver microsomes, the latter exhibiting K(M) values around 2 and 1 microM, respectively, with (R)- and (S)-ketotifen. With amitriptyline as the substrate, N-glucuronidation kinetics in the absence of detergent were biphasic in human liver microsomes and monophasic with a high K(M) value in cell homogenates containing UGT1A4. The results suggest that UGT1A4 and UGT1A3 catalyze high-K(M) N-glucuronidation of tertiary amine drugs, whereas the low-K(M) reaction requires either an alternative enzyme or a special conformation of UGT1A4 or UGT1A3 that can be attained in liver microsomes, but not in HK293 cell membranes.

Amitriptyline↗
PubMed2000

Comparison of three in vitro assays at evaluation of IC50 of acetylsalicylic acid, ferrous sulfate, amitriptyline, methanol, isopropanol and ethylene glycol in human cancer cells HeLa.

Evaluation of the 50% inhibitory concentration (IC50) of acetylsalicylic acid, ferrous sulfate, amitriptyline, methanol, isopropanol and ethylene glycol was done on human cancer cells cultured in in vitro conditions. Three different in vitro assays were used in this study: the plating efficiency test, the microprotein test and the neutral red uptake test. Obtained results were evaluated by statistical methods. All used methods seem to be useful for screening a cytotoxic potential of the tested chemicals. The knowledge of cytotoxic effects of frequently used chemicals on mammalian cells is important not only for necessary in vitro genotoxicity and carcinogenicity studies but also for assessing the toxicity of chemicals to find out possible hazards to the human health. Results presented in this paper underline the usefulness of the wider methodological approach for the comparison of the different endpoints as well as a necessity for selection of a battery of in vitro cytotoxicity tests allowing to estimate the possible harmful effects of xenobiotics.

2-Propanol↗
PubMed2001

Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes: studies on amitriptyline as a model substrate.

The relative activity factor (RAF) approach is being increasingly used in the quantitative phenotyping of multienzyme drug biotransformations. Using lymphoblast-expressed cytochromes P450 (CYPs) and the tricyclic antidepressant amitriptyline as a model substrate, we have tested the hypothesis that the human liver microsomal rates of a biotransformation mediated by multiple CYP isoforms can be mathematically reconstructed from the rates of the biotransformation catalyzed by individual recombinant CYPs using the RAF approach, and that the RAF approach can be used for the in vitro-in vivo scaling of pharmacokinetic clearance from in vitro intrinsic clearance measurements in heterologous expression systems. In addition, we have compared the results of two widely used methods of quantitative reaction phenotyping, namely, chemical inhibition studies and the prediction of relative contributions of individual CYP isoforms using the RAF approach. For the pathways of N-demethylation (mediated by CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and E-10 hydroxylation (mediated by CYPs 2B6, 2D6, and 3A4), the model-predicted biotransformation rates in microsomes from a panel of 12 human livers determined from enzyme kinetic parameters of the recombinant CYPs were similar to, and correlated with the observed rates. The model-predicted clearance via N-demethylation was 53% lower than the previously reported in vivo pharmacokinetic estimates. Model-predicted relative contributions of individual CYP isoforms to the net biotransformation rate were similar to, and correlated with the fractional decrement in human liver microsomal reaction rates by chemical inhibitors of the respective CYPs, provided the chemical inhibitors used were specific to their target CYP isoforms.

Amitriptyline↗
PubMed2003

[Comparative efficacy and tolerance of fluvoxamine and amitriptyline in the treatment of moderate and severe depression in mental hospital].

The aim of the study was to compare the efficacy and tolerance of fluvoxamine (FL) and amitriptyline (AM) in the treatment of patients hospitalized for moderate and severe depression and to evaluate the spectrum of antidepressive activity in FL. The study was open, randomized and comparative. Sixty patients (mean age 41 +/- 2.9 years) diagnosed as having recurrent depressive disorder, a moderate or severe depressive episode (ICD-10 F33.1, F33.2) were divided into two equal groups treated with FL or AM. The efficacies of FL and AM were comparable, with AM exhibiting an earlier clinical effect and FL having a better tolerance. FL was defined as an antidepressant with the predominantly sedative effect comparable to that of AM, but being better tolerated.

Adolescent↗
PubMed1992

On-line solid-phase extraction and high-performance liquid chromatographic determination of nortriptyline and amitriptyline in serum.

An isocratic reversed-phase high-performance liquid chromatographic method with on-line solid-phase extraction for the simultaneous determination of amitriptyline and nortriptyline in serum has been developed. A 250-microliters serum sample is injected directly onto a commercially available CN cartridge and, after a washing step, the retained solutes are backflushed onto a bonded-phase CN column using a column-switching technique and a mobile phase composed of acetonitrile (26%) and 0.05 M phosphate buffer with diethylamine. Serum is diluted with 0.1 M sodium lauryl sulphate and centrifuged before the injection. Detection at 210 nm ensures sufficient sensitivity. The recovery is almost quantitative and the relative standard deviation ranges from 2.8 to 8.0% for concentrations of 200-40 ng/ml. Being rapid and simple, the method is convenient for routine use.

Amitriptyline↗
PubMed2003

Sympathetic blockade and amitriptyline in the treatment of reflex sympathetic dystrophy.

We prospectively investigated the outcome of a combination therapy of oral amitriptyline and sympathetic ganglion blockade on 10 patients suffering from reflex sympathetic dystrophy of the upper extremity for at least three months. The efficacy of the treatment was evaluated by clinical examination, pain ratings on the visual analogue scale (VAS) and grip strength measurements using the Jamar dynamometer. The results were statistically analysed with Wilcoxon signed-ranks test for comparison of the before and after treatment grip strength measurements and with paired t-test for comparison of the mean of initial and consecutive pain ratings on the VAS. Values of p < 0.01 were considered to be statistically significant. Combination therapy proved beneficial in this particular patient population, which, as far as previously documented studies are concerned, would otherwise respond less favourably to a treatment consisting solely of sympathetic blockade.

Adult↗
PubMed1992

Amitriptyline and carbamazepine in the treatment of dysesthetic pain in spinal cord injury.

Dysesthetic pain after spinal cord injury is a common problem. The pathophysiology of this disorder is unclear and treatment modalities have been of inconsistent effectiveness. Various pharmacologic approaches have been advocated for treatment of chronic pain in spinal cord injury, including the use of either anticonvulsants or antidepressants. This case report describes the successful use of carbamazepine in conjunction with amitriptyline in the treatment of dysesthetic pain in a patient with spinal cord injury.

Adult↗