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PubMed1990

Antiarrhythmic properties of amitriptyline.

Clinical studies and case reports have shown that nortriptyline and imipramine exert type 1 antiarrhythmic properties when plasma concentrations are therapeutic, indicating that clinical reservation against their use in cardiac patients may be overstated. The clinical cardiac effects of amitriptyline have not been extensively reported. The case I have reported details the electrophysiologic record of the beneficial and safe use of amitriptyline in a patient with severe cardiac arrhythmias and organic affective disorder.

Aged↗
PubMed1979

Tricyclic antidepressants in serum by a Clin-ElutTM column extraction and high pressure liquid chromatographic analysis.

We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.

Antidepressive Agents, Tricyclic↗
PubMed1985

Evaluation of amitriptyline pharmacokinetics during peritoneal dialysis.

The pharmacokinetics of a single oral dose of amitriptyline were examined in five functionally anephric patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The concentration of the parent drug and its major metabolite nortriptyline in plasma were measured by high performance liquid chromatography. Patients on CAPD did not have a significantly extended elimination half-life (t 1/2) as compared to literature controls. However, the variation in t 1/2 was extremely large in both the CAPD and normal renal function groups (range 15-34 h and 24-70 h, respectively). No statistically significant change was observed (p less than 0.05). Although a major route of elimination was removed and there was no change in t 1/2, the drug levels in these patients should be closely monitored because of the large variability in patient metabolism.

Adult↗
PubMed1987

Homogeneous enzyme immunoassay (EMIT) protocol for monitoring tricyclic antidepressants on the COBAS-BIO centrifugal analyzer.

EMIT tests are available for quantitative determination of the tricyclic antidepressants amitriptyline (AMI), nortriptyline (NORT), imipramine (IMI), and desipramine (DMI). An extraction step before analysis eliminates cross-reacting polar metabolites. Excellent correlation between EMIT and high-performance liquid chromatography (HPLC) has been previously established. Most published protocols for using EMIT reagents on COBAS-BIO centrifugal analyzers were designed for analytes present at 1-50 mg/L in serum. AMI, NORT, IMI, and DMI are usually present at far less than 1 mg/L. We describe a COBAS-BIO EMIT protocol for assaying these analytes. Patient sample correlation between COBAS-BIO EMIT and EMIT-AutoLab were greater than 0.99. Between-run precision for single-point determinations was comparable to SYVA AutoLab performance [less than or equal to 11% at 40 micrograms/L AMI, NORT, IMI (80 micrograms/L DMI), and less than or equal to 4% at 200 micrograms/L AMI, NORT, IMI (400 micrograms/L DMI)]. With stored-curve updating, working reagents were usable for at least 14 days (AMI) or 23 days (DMI).

Antidepressive Agents, Tricyclic↗
PubMed1987

Simultaneous quantitation of eight tricyclic antidepressants in serum by high-performance liquid chromatography.

An analytical procedure has been developed for the simultaneous separation and quantitation of amitriptyline (AMI), imipramine (IMI), doxepin (DOX), trimipramine (TRI), desipramine (DES), nortriptyline (NOR), desmethyldoxepin (DMD), and protriptyline (PRO) in serum using N-propionylprocainamide (NPPA) as an internal standard. Serum samples were extracted using Bond Elute C-18 columns. A 5-mu Supelcosil LC-PCN column separated the analytes, using a mobile phase consisting of 10 mmol/L sodium phosphate (pH 7.0):acetonitrile:methanol (28:58:14) by volume at ambient temperature. Column effluents were monitored at 254 and 280 nm. Typical recoveries ranged from 81.8% to 94.0% at 50 ng/ml and from 92.0% to 102.6% at 200 ng/ml. Within-run variations were less than or equal to 10.1% at 50 ng/ml and less than or equal to 4.5% at 200 ng/ml, whereas day-to-day variations were less than or equal to 7.4% at 50 ng/ml and less than 4.8% at 200 ng/ml for n = 10. Calibration curves showed linearity over the concentration range of 25-1,000 ng/ml. Superior resolution (Rs greater than or equal to 1.0) was obtained with this column, which completely separated the eight tricyclic antidepressants (TCAs) and the internal standard in 16 min. Sensitivity limit is 25 ng/ml for all TCAs studied. Phenothiazine tranquilizers interfere with the quantitation of TCAs.

Antidepressive Agents, Tricyclic↗
PubMed1988

Measurement of antidepressants using solid-phase extraction and wide-bore capillary gas chromatography with nitrogen-selective detection.

A comprehensive method is presented for the determination of nine antidepressant drugs and metabolites in serum: (1) amitriptyline, (2) nortriptyline, (3) imipramine, (4) desipramine, (5) maprotiline, (6) doxepin, (7) desmethyldoxepin, (8) protriptyline, and (9) trimipramine. Chlorimipramine is used as the internal standard. A simple solid-phase extraction procedure utilizing disposable reversed-phase C18 columns is described. Samples are analyzed by gas chromatography with nitrogen-selective detection using a wide-bore capillary column with a permanently bonded, non-polar stationary phase. The assay possesses linearity to 800 ng/mL for maprotiline and 500 ng/mL for the other antidepressants, sensitivity to at least 25 ng/mL, recovery ranging from 96 to 107%, and between-run precision reflected by CVs of 4.4 to 8.1%. Lack of interference is documented for over 27 commonly prescribed drugs. We conclude that the method reported here is ideally suited for monitoring therapeutic and toxic levels of antidepressant drugs.

Antidepressive Agents↗
PubMed1988

Evaluation of tricyclic antidepressant plasma levels by an automated enzyme immunoassay (EMIT) in comparison to a high-performance liquid chromatographic method.

A new homogeneous enzyme immunoassay technique (EMIT) for the measurement of plasma levels of amitriptyline, nortriptyline, imipramine, and desipramine was used with an automated procedure and the results were compared to those of a high-performance liquid chromatographic (HPLC) method. Precision of the EMIT test was similar to that of the HPLC method with within-day coefficients of variation in the range of 3.9-10.9% (EMIT) and 3.9-9.6% (HPLC). The day-to-day coefficients of variation ranged from 4.4 to 11.7% for EMIT and from 6.1 to 8.4% for HPLC. Samples from 124 patients were analyzed by both methods and a good correlation was observed for all the four drugs. A paired t test indicated no significant difference for the EMIT and HPLC values. No significant interferences were observed between the tricyclics tested and other commonly associated drugs, such as benzodiazepines and neuroleptics. The new EMIT assay proved to be rapid and easy to perform and showed sufficient reliability and reproducibility to be used for either emergency or routine analysis.

Antidepressive Agents, Tricyclic↗
PubMed1992

Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.

The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Interaction of tricyclic antidepressants with cholestyramine in vitro.

The adsorption of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline onto cholestyramine was demonstrated in vitro with use of 1.2 mol/L HCl at 37 degrees C to simulate gastric fluid. Binding to cholestyramine was approximately 80% for each of the tricyclic antidepressants, and this was about the same degree of binding noted with a nonpharmaceutical, non-ionic resin widely used in the diagnostic toxicology laboratory (Amberlite XAD-2). In contrast, five other non-antidepressants (acetaminophen, chlordiazepoxide, procainamide, quinidine, and theophylline) showed only minimal binding to cholestyramine under these conditions. Activated charcoal completely bound all drugs studied. These findings suggest that cholestyramine should be used with caution in patients receiving tricyclic antidepressants. They also suggest that cholestyramine may be a potentially useful adjunctive therapy in treatment of overdose with the tricyclic antidepressants.

Adsorption↗
PubMed1998

A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants.

Although the manufacturer of the polyclonal fluorescence polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) only recommends its use in the diagnosis of overdose, the assay is nevertheless widely used in therapeutic drug monitoring. Using plasma samples from 337 patients taking one of eight different tricyclic antidepressants, the authors investigated the performance of the TDx assay procedure for eight different TCAs by comparison to specific high-performance liquid chromatography (HPLC) assay methods. The regression correlation between the TDx assay value and that for active tricyclic measured by HPLC was poor (r2 < 0.9) for amitriptyline, clomipramine, dothiepin, and doxepin. The regression line for amitriptyline also had a significant positive y-axis intercept. Moreover, the TDx method overestimated the concentration of active drug to an extent that varied considerably between different TCAs and within the usual therapeutic range for a single TCA. The authors conclude that the TDx assay is probably satisfactory for routine TDM of desipramine, imipramine, nortriptyline, and trimipramine. However, it significantly overestimates therapeutic concentrations of amitriptyline, clomipramine, dothiepin, and doxepin. The use of TDx and HPLC assay methods by different laboratories for sequential therapeutic drug monitoring of TCAs in the same patient may confuse physicians and confound dose adjustment and patient management. Although their study shows that the TDx assay can give satisfactory therapeutic drug monitoring results for some drugs, the authors conclude that its use should be restricted to the evaluation of overdose as recommended by the manufacturer.

Antidepressive Agents, Tricyclic↗
PubMed1998

Prevention of tricyclic antidepressant adsorption loss with diethylamine during solvent evaporation.

The authors evaluated the adsorption loss of tricyclic antidepressants in analytical procedures with solvent extraction and evaporation. In standard procedures with the use of triple solvent extraction between alkalinized and acidified samples before chromatographic analysis, the adsorption loss was more significant with the demethylated metabolites. As much as 50% adsorption loss can occur; this irreversible loss can be accounted for entirely during the solvent evaporation step. Because of differential adsorption loss among parent drugs, metabolites, and internal standards, the analytical methods usually had wide within-day and day-to-day variations. The authors found that the addition of as little as 0.05% diethylamine to the extract before evaporation completely eliminated the adsorption loss of amitriptyline-nortriptyline, imipramine-desipramine, and doxepin-desmethyldoxepin. with subsequent improvement in procedure performance. This simple modification can be adopted readily by all laboratories that use solvent extraction and subsequent chromatographic analysis of tricyclic antidepressants.

Adsorption↗
PubMed2000

Simultaneous determination of human plasma levels of four selective serotonin reuptake inhibitors by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography (HPLC) method with fluorimetric detection, which allows the simultaneous determination of plasma concentrations of four selective serotonin reuptake inhibitors (SSRIs) is presented. Fluvoxamine, paroxetine, sertraline, and fluoxetine were extracted from plasma with ethyl acetate and then derivatized with dansyl chloride. The analytes were separated using Hypersyl ODS C18 (5 microm) 250 x 4.6 mm column (ThermoQuest, Runcorn, UK). For continuous gradient separation, the mobile phase consists of two eluents, acetonitrile and potassium phosphate buffer (10 mmol/L, pH 7.2) at total flow rate of 1.5 mL/min. Detection was carried out at lambda exc = 366 nm and lambda em = 490 nm. The authors found recoveries of 90% to 95% for fluvoxamine, 94% to 100% for paroxetine, 88% to 95% for sertraline, 93% to 100% for fluoxetine, and 97% to 100% for internal standard (nortriptyline). Imprecision of the method ranged from 2.5% to 8.9%. The assay was linear from 10 to 1500 ng/mL for sertraline, and from 5 to 1500 ng/mL for the other drugs. The authors conclude that this method is suitable for monitoring antidepressant therapy. In addition, the authors report the effects of adding paroxetine to fluvoxamine on plasma levels in a group of patients in combined drug therapy.

Adult↗
PubMed2000

Time-dependent absorption of therapeutic drugs by the gel of the Greiner Vacuette blood collection tube.

Stability of therapeutic drugs in sera collected in Becton-Dickinson VACUTAINER serum separator SST tubes has been well studied. Recently, the Greiner Vacuette serum separator tube has become available for blood collection. However, stability of therapeutic drugs in sera when the specimen is collected in the Greiner tube has not been reported. The authors studied the stability of 15 commonly monitored drugs in sera when stored on the gel of the Greiner serum separator tubes. The drugs studied were amikacin, gentamycin, tobramycin, vancomycin, digoxin, quinidine, theophylline, carbamazepine, phenobarbital, phenytoin, valproic acid, tricyclic antidepressants, salicylate, acetaminophen, and ethanol. The authors compared the concentrations of drugs in sera stored in plain tubes (no gel) and in sera stored in the Greiner tubes containing serum separator gel. They observed a significant decline in the concentrations of tricyclic antidepressants when stored in the Greiner tubes. Interestingly, concentrations of amitriptyline declined more than its metabolite nortriptyline and concentration of imipramine also decreased more than its metabolite desipramine. The concentration of carbamazepine also decreased slightly over time when serum was stored in the Greiner tube. Although declines in carbamazepine concentrations on prolonged storage in the Greiner tubes were statistically significant, the decreases may not be clinically significant. The concentrations of the other drugs studied did not decline when stored in the Greiner tubes. The authors conclude that the Greiner brand tube is not suitable for blood collection for analysis of tricyclic antidepressants.

Absorption↗
PubMed2002

Simultaneous determination of seven tricyclic antidepressant drugs in human plasma by direct-injection HPLC-APCI-MS-MS with an ion trap detector.

A sensitive and specific direct-injection high-performance liquid chromatography-atmospheric pressure chemical ionization tandem mass-spectrometry (HPLC-APCI-MS-MS) method has been developed for the rapid identification and quantitation of seven tricyclic antidepressants-amitriptyline, nortriptyline, doxepin, dosulepin, dibenzepin, opipramol, and melitracen-in human plasma. After the addition of the internal standard lofepramine and dilution with 0.1% formic acid, plasma samples were injected into the LC-MS-MS system. Proteins and other large biomolecules were removed during an on-line sample cleanup using an Oasis extraction column (1 x 50 mm, ID, 30 microm) with a 100% aqueous mobile phase at a flow rate of 4 mL/min. The extraction column was subsequently brought in-line with the analytical column by automatic valve switching. Analytes were separated on a 5-microm Symmetry C18 (Waters) analytical column (3.0 x 150 mm, ID) using a step gradient of acetonitrile-0.1% formic acid at a flow rate of 0.6 mL/min. The total analysis time was only 12 minutes per sample. The interday and intraday coefficients of variation for all compounds were </=11%. The assay was sufficiently sensitive to monitor all seven compounds within their therapeutic ranges. The proposed method has been in routine use for more than 1 year and permits direct analysis of plasma samples without time-consuming sample preparation, which may be especially advantageous for clinical laboratories.

Antidepressive Agents, Tricyclic↗
PubMed2004

A novel system for the determination of antidepressant concentrations in human breast milk.

The high incidence of psychiatric illness in the postpartum period and the increasing percentage of women who breastfeed has focused attention on the treatment of breastfeeding women with psychotropic medications and, additionally, the exposure of nursing infants to these medications. Consequently, there has been an increased effort to develop standardized methods for quantifying psychotropic medications in breast milk. This paper details a novel method for quantifying the concentrations of multiple selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in breast milk. The method consists of a common liquid/liquid and solid-phase extraction followed by HPLC separation on a common column and UV detection. Assay system 1 measures fluoxetine, norfluoxetine, fluvoxamine, and paroxetine; assay 2 measures sertraline and desmethylsertraline; and assay 3 measures the TCAs including doxepin, nordoxepin, desipramine, imipramine, nortriptyline, and amitriptyline. The method is shown to be a highly accurate and precise technique for measuring 12 different antidepressants in human breast milk and to be free of the matrix effects often encountered in breast milk drug analyses.

Antidepressive Agents↗
PubMed2000

Relapse of depression after ECT: a review.

Relapse of severe depression after successful treatment with electroconvulsive therapy (ECT) continues to be a major problem. We review the literature on relapse after ECT and factors that predict relapse. Early studies showed that the relapse rate was approximately 50% without follow-up treatment and that the majority of these relapses occurred in the first 6 months. More recent studies have found even higher rates in delusional depression and possibly in "double depression." Studies of biological markers as predictors of relapse were examined. Six of nine studies of the dexamethasone suppression test and one study of cortisol hypersecretion show that post-ECT nonsuppressors are at higher risk; although insensitive for diagnostic purposes, this test may be useful, when persistently abnormal, as a predictor of relapse. Studies of the thyrotropin-releasing hormone stimulation test and shortened rapid eye movement sleep latency are inconclusive. Medication resistance pre-ECT has been shown to predict relapse in two studies and highlights the need for more aggressive and effective treatment in this group. Further research into the prediction and prevention of depressive relapse after ECT is needed, and the field anxiously awaits current trials comparing ECT with combination lithium and nortriptyline.

Depressive Disorder↗
PubMedDate not supplied

Nicotine and non-nicotine smoking cessation pharmacotherapies.

Cigarette smoking remains an important risk factor for premature cardiovascular disease and its complications. There are clear benefits of cigarette smoking cessation on the rate of clinical outcomes, and in addition to behavioral therapies, various pharmacologic strategies have been developed to help achieve this goal. First-line therapies include nicotine replacement and/or bupropion. Second-line treatments include clonidine and nortriptyline. Additional treatment strategies, with less proven efficacy, include monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, opioid receptor antagonists, bromocriptine, antianxiety drugs, nicotinic receptor antagonists (eg, mecamylamine), and glucose tablets. Various approaches under investigation include the use of partial nicotine agonists (eg, varenicline), inhibitors of the hepatic P-450 enzyme (eg, methoxsalen), cannaboid-1 receptor antagonists (eg, rimonabant), and nicotine vaccines.

Heart Diseases↗
PubMed2006

A fully automated turbulent-flow liquid chromatography-tandem mass spectrometry technique for monitoring antidepressants in human serum.

Antidepressants belong to a variety of chemical and pharmacologic classes. Most require therapeutic drug monitoring, at least in certain circumstances, such as unexplained inefficacy or suspected toxicity. Several types of chromatographic methods have generally been used. This paper presents a fully automated, sensitive, and specific method for the therapeutic drug monitoring of 13 antidepressants of all classes (amoxapine, amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, imipramine, maprotiline, mianserin, paroxetine, sertraline, trimipramine) and some of their respective active metabolites (nortriptyline, monodesmethylcitalopram, desmethylclomipramine, desipramine, norfluoxetine, desmethylmianserin, N-desmethylsertraline), based on the innovative turbulent-flow liquid chromatography (TFC) technology, coupled to tandem-mass spectrometry (MS/MS). The antidepressants were divided in two groups depending on their chromatographic properties, so that two injections would be necessary to screen all compounds (which is infrequent for therapeutic drug monitoring). Calibration curves ranged from 10 to 500 ng/mL. No significant memory effect was observed after the injection of a blank serum sample spiked at 500 ng/mL. The intra-assay and inter-assay precision CVs ranged from 0.4% to 12% and from 1% to 16%, respectively. The method was further validated by blindly analyzing Heathcontrol-Therapeutic Drugs Scheme samples (Cardiff Bioanalytical Services Ltd.) containing several antidepressants.

Antidepressive Agents↗