Antidepressants inhibit human acetylcholinesterase and butyrylcholinesterase activity.

This study examines the effect of the antidepressants Fluoxetine ( Prozac ), Sertraline HCL ( Zoloft )and Amitriptyline ( Elavil ) on cholinesterase (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) activities in human serum and erythrocyte membrane (ghost). The concentrations used range from 3 to 60 microM for Fluoxetine ( Prozac ) and Amitriptyline ( Elavil ) and 0.3 to 12 microM for Sertraline HCL ( Zoloft ). At the micromolar range concentration, different classes of antidepressants, including Fluoxetine ( Prozac ) and Sertraline HCL ( Zoloft )(selective serotonin reuptake inhibitors (SSRIs)) and Amitriptyline ( Elavil ) (tricyclic antidepressant) inhibited human serum cholinesterase. The order of inhibitory potency was Sertraline HCL ( Zoloft )>Amitriptyline ( Elavil )>>Fluoxetine ( Prozac ) and the IC(50) values were 4.05, 9.43 and 62 microM, respectively. Analysis of kinetic data indicated that the inhibition caused by all the antidepressants was mixed in nature. At the micromolar range concentration, Sertraline HCL ( Zoloft )(60-120 microM) and Amitriptyline ( Elavil ) (60-180 microM) inhibited human erythrocyte AChE. The order of inhibitory potency was Sertraline HCL ( Zoloft )>Amitriptyline ( Elavil ) and the IC(50) values were 80 and 134 microM, respectively. Analysis of kinetic data indicated that the inhibition caused by all the antidepressants in AChE human erythrocyte membrane (ghost) was mixed in nature. The interaction of Sertraline HCL ( Zoloft )with the cholinesterase is labile since the removal of inhibitor by gel filtration recovered completely the enzyme activity. Our results demonstrate that the usual clinical antidepressants are inhibitors of the cholinesterases on human serum and erythrocyte membrane.

Comparative single-dose kinetics of Amitriptyline ( Elavil ) and its N-oxide in a volunteer.

Plasma drug levels and urinary metabolites were measured in a volunteer for 28 h after ingestion of Amitriptyline ( Elavil ) hydrochloride or Amitriptyline ( Elavil ) N-oxide (amitriptylinoxide) equivalent to 100 mg of Amitriptyline ( Elavil ) base. The N-oxide initially produced high plasma levels and 15% of the dose was excreted unchanged within 14 h. From comparison of the metabolite excretions, it can be concluded that about 70% of the dose was reduced at the N-oxide group, while comparison of the areas under the plasma group, while comparison of the areas under the plasma level-time curves for Amitriptyline ( Elavil ) pointed to a 55% reduction to the amine. Less drowsiness was experienced after ingesting the N-oxide, and there was no depressive mood.

Column switching and high-performance liquid chromatography in the analysis of Amitriptyline ( Elavil ), nortriptyline and hydroxylated metabolites in human plasma or serum.

A column-switching system for the direct injection of plasma or serum samples, followed by isocratic high-performance liquid chromatography and ultraviolet detection, is described for the simultaneous quantitation of the tricyclic antidepressant Amitriptyline ( Elavil ), its demethylated metabolite nortriptyline and the E- and Z-isomers of 10-hydroxy Amitriptyline ( Elavil ) and 10-hydroxynortriptyline. The method included adsorption of Amitriptyline ( Elavil ) and metabolites on a reversed-phase C8 clean-up column (10 microns; 20 mm x 4.6 mm I.D.), washing of unwanted material to waste and, after on-line column-switching, separation on a cyanopropyl analytical column (5 microns; 250 mm x 4.6 mm I.D.). The compounds of interest were separated and eluted using acetonitrile-methanol-0.01 M phosphate buffer (pH 6.8) (578:188:235, v/v) within less than 20 min. Various drugs frequently co-administered with Amitriptyline ( Elavil ) or other antidepressants did not interfere with the determinations. In plasma samples spiked with 25-300 ng/ml, the recoveries were between 84 and 112% and the inter-assay coefficients of variation were 3-11%. After a minor modification, as little as 5 ng/ml could be quantitated. There were linear correlations (r greater than 0.99) between drug concentrations of 5-500 ng/ml and the detector signal. The method allows routine measurements of Amitriptyline ( Elavil ), nortriptyline and hydroxylated metabolites in blood plasma or serum of patients treated with Amitriptyline ( Elavil ) or nortriptyline, and enables the results to be reported within 1 h.

Involvement of potassium channels in Amitriptyline ( Elavil ) and clomipramine analgesia.

The effect of the administration of modulators of different subtypes of K(+) channels on antinociception induced by the tricyclic antidepressants Amitriptyline ( Elavil ) and clomipramine was evaluated in the mouse hot plate test. The administration of the voltage-gated K(+) channel blocker tetraethylammonium (0.01-0.5 microg per mouse i.c.v. ) prevented antinociception induced by both Amitriptyline ( Elavil ) (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.). The K(ATP) channel blocker gliquidone (0.1-1.0 microg per mouse i.c.v.) prevented antinociception produced by Amitriptyline ( Elavil ) and clomipramine whereas the K(ATP) channel openers minoxidil (10 microg per mouse i. c.v.) and pinacidil (25 microg per mouse i.c.v.) potentiated tricyclic antidepressant-induced analgesia. The administration of the Ca(2+)-gated K(+) channel blocker apamin (0.1-1.0 ng per mouse i. c.v.) completely prevented Amitriptyline ( Elavil ) and clomipramine analgesia. At the highest effective doses, none of the drugs used induced behavioural side effects or impaired motor coordination, as revealed by the rota-rod test, spontaneous motility or inspection activity, as revealed by the hole board test. The present results demonstrate that central antinociception induced by Amitriptyline ( Elavil ) and clomipramine involves the opening of different subtypes of K(+) channels (voltage-gated, K(ATP) and Ca(2+)-gated) which, therefore, represent a step in the transduction mechanism of tricyclic antidepressant analgesia.

Determination of Amitriptyline ( Elavil ) and some of its metabolites in blood by high-pressure liquid chromatography.

Conditions for the determination of Amitriptyline ( Elavil ) and some of its metabolites in serum on a reversed-phase material (C-8) by high-pressure liquid chromatography with UV detection at 254 nm were systematically investigated. The separation of tricyclic antidepressants is best carried out on a phase system consisting of C-8 bonded-phase material as the stationary phase and water--methanol--dichloromethane--propylamine as the mobile phase. The precision and detection limit of the method and the extraction efficiency were established. A chromatogram of a serum extract from a patient treated with Amitriptyline ( Elavil ) is shown. Serum levels of Amitriptyline ( Elavil ) and its four main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxy-Amitriptyline ( Elavil ) and trans-10-hydroxy-nortriptyline) in a patient receiving 150 mg of Amitriptyline ( Elavil ) daily, are reported.

Inhibition of monoamine oxidase A and B in the heart and brain of the rat with Amitriptyline ( Elavil ), pargyline and pirlindol

The inhibition of monoamine oxidase (MAO) A and B by Amitriptyline ( Elavil ), pargyline and pirlindole was measured in heart and brain homogenates of rats with tryptamine and beta-phenylethylamine as substrates. The tricyclic antidepressant Amitriptyline ( Elavil ) inhibited MAO B stronger in the brain (Ki = 8.41 X 10(-6) mol/l) as well as in the heart (Ki = 7.03 X 10(-5) mol/l) compared to the A-form (1.51 X 10(-4) and 1.03 X 10(-4) mol/l, respectively). Pargyline diminished the activity of both enzyme forms of the heart in the same range (4.29 and 1.60 X 10(-6) mol/l), whereas in the brain the B-form was blocked in a more pronounced manner, too (5.80 X 10(-8) and 4.01 X 10(-6) mol/l, respectively). In contrast to Amitriptyline ( Elavil ) and pargyline pirlindole inhibited the MAO with tryptamine as a substrate in the brain 100 times (2.49 X 10(-7) mol/l) and in the heart nearly 1000 times (3.42 X 10(-8) mol/l) more than with phenylethylamine as a substrate (5.21 and 5.99 X 10(-5) mol/l, respectively). These results show that Amitriptyline ( Elavil ) and pargyline are relatively selective inhibitors of MAO B, whereas pirlindole blocks the A-form of MAO much stronger than MAO B.

Comparison of some effects of Paroxetine ( Paxil ) with Amitriptyline ( Elavil ) on the cardiovascular system in animals.

The effects of intravenous infusions of Paroxetine ( Paxil ), a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, Amitriptyline ( Elavil ), on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, Paroxetine ( Paxil ) was less cardiotoxic than Amitriptyline ( Elavil ) in both species. Thus, Paroxetine ( Paxil ) has the advantage over Amitriptyline ( Elavil ) of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than Amitriptyline ( Elavil ) in tests for antidepressant activity.

A retrospective intent-to-treat analysis (N = 1,339) was conducted to discern the natural course of antidepressant use and direct health service expenditures for the treatment of single-episode depression (DSM-IV code 296.20) among patients initiating antidepressant pharmacotherapy with either a tricyclic antidepressant (TCA) (Amitriptyline ( Elavil ), N = 237) or a selective serotonin reuptake inhibitor (SSRI) (Citalopram ( Celexa ), N = 71; Fluoxetine ( Prozac ), N = 411; Paroxetine ( Paxil ), N = 334; or Sertraline HCL ( Zoloft ), N = 286). Data were derived from the computer archive of a network-model health maintenance organization for the period of January 1, 1996, through April 30, 1999. Comparisons at the end of the 6-month post-period (180 days) were undertaken between cohorts initiating antidepressant pharmacotherapy with Citalopram ( Celexa ) and each SSRI or TCA. Consistent with the intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate models were adjusted for patient's age, gender, number of concomitant disease state processes, use of health services in the 6-month time frame (180 days) before initiating antidepressant pharmacotherapy, specialty of physician recording a diagnosis of single-episode depression, and the presence or absence of a previous diagnosis of single-episode depression and receipt of antidepressant pharmacotherapy. Patients initiating antidepressant pharmacotherapy with Citalopram ( Celexa ) were far more likely to (1) have been diagnosed by a psychiatrist (37%; p < or = 0.05); (2) continue with the original pharmacotherapeutic option (79%) compared with patients originally prescribed Amitriptyline ( Elavil ) (51%; chi2 = 17.29, df = 1, p < or = 0.05) or Sertraline HCL ( Zoloft )(65%; chi2 = 36.91, df = 1, p < or = 0.05); no significant difference was found compared with patients initiating antidepressant pharmacotherapy with Paroxetine ( Paxil ) (72%; p = not significant [NS]) or Fluoxetine ( Prozac ) (83%; p = NS); (3) obtain 90 days or more of antidepressant pharmacotherapy (86%) compared with those prescribed Amitriptyline ( Elavil ) (69%; chi2 = 8.09, df = 1, p < or = 0.05); no significant difference was found compared with Sertraline HCL ( Zoloft )(77%), Paroxetine ( Paxil ) (81%), or Fluoxetine ( Prozac ) (84%); and (4) obtain 6 months (180 days) of antidepressant pharmacotherapy (68%) compared with those prescribed Amitriptyline ( Elavil ) (39%; chi2 = 18.26, df = 1, p < or = 0.05) or Sertraline HCL ( Zoloft )(51%; chi2 = 6.02, df = 1, p < or = 0.05); no significant difference was found compared with Paroxetine ( Paxil ) (56%) or Fluoxetine ( Prozac ) (59%). Receipt of Amitriptyline ( Elavil ) or Sertraline HCL ( Zoloft )as initial medication was associated with a per capita increase (p < or = 0.05) in health service utilization (17% and 9%, respectively) relative to Citalopram ( Celexa ). No significant difference (p > 0.05) in health service utilization was discerned between Citalopram ( Celexa ) and either Fluoxetine ( Prozac ) or Paroxetine ( Paxil ). Multivariate models adjusted for nonrandom assignment to the initial pharmacotherapeutic option confirmed these findings. Further research over a longer time course is warranted.

Effects of antidepressants in adrenergic neurotransmission of human vas deferens.

OBJECTIVES: To evaluate the effects of Sertraline HCL ( Zoloft ), Fluoxetine ( Prozac ), and Amitriptyline ( Elavil ) on the contractile responses of the human vas deferens muscle elicited by norepinephrine, electrical field stimulation, and KCl, because the therapeutic action of antidepressants may be accompanied by sexual dysfunction related to the contractility of the vas deferens smooth muscle. METHODS: Ring segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of Sertraline HCL ( Zoloft ), Fluoxetine ( Prozac ), and Amitriptyline ( Elavil ) on the neurogenic and agonist-induced contractile responses. RESULTS: Amitriptyline ( Elavil ) caused concentration-dependent inhibition of neurogenic and norepinephrine-induced contractions. In contrast, only the highest concentration (10(-5) M) of Sertraline HCL ( Zoloft )and Fluoxetine ( Prozac ) reduced the adrenergic contractions. The dihydropyridine calcium antagonist nifedipine (10(-6) M) completely prevented the inhibitory effect of Sertraline HCL ( Zoloft )and Fluoxetine ( Prozac ) on neurogenic and norepinephrine-induced contractions but did not change the inhibition caused by Amitriptyline ( Elavil ). Sertraline HCL ( Zoloft ), Fluoxetine ( Prozac ), and Amitriptyline ( Elavil ) (all at 10(-5) M) attenuated contractions elicited by KCl and reduced contractions induced by CaCl(2) in KCl-depolarized preparations. CONCLUSIONS: The results indicate that Sertraline HCL ( Zoloft )and Fluoxetine ( Prozac ) inhibit vas deferens motility through inhibition of Ca(2+) entry, with no effect on the adrenergic receptors, and Amitriptyline ( Elavil ) acts as an adrenoceptor antagonist and inhibitor of the entry of calcium.

Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ store by antidepressant drugs in cultured neurons of rat frontal cortex.

The ability of antidepressant drugs (ADs) to increase the concentration of intracellular Ca2+ ([Ca2+]i) was examined in primary cultured neurons from rat frontal cortices using the Ca(2+)-sensitive fluorescent indicator fura-2. Amitriptyline ( Elavil ), imipramine, desipramine, and mianserin elicited transient increases in [Ca2+]i in a concentration-dependent manner (100 microM to 1 mM). These four AD-induced [Ca2+]i increases were not altered by the absence of external Ca2+ or by the presence of La3+ (30 microM), suggesting that these ADs provoked intracellular Ca2+ mobilization rather than Ca2+ influx. All four ADs increased inositol 1,4,5-trisphosphate (IP3) contents by 20-60% in the cultured cells. The potency of the IP3 production by these ADs closely correlated with the AD-induced [Ca2+]i responses. Pretreatment with neomycin, an inhibitor of IP3 generation, significantly inhibited Amitriptyline ( Elavil )- and imipramine-induced [Ca2+]i increases. In addition, by initially perfusing with bradykinin (10 microM) or acetylcholine (10 microM), which can stimulate the IP3 generation and mobilize the intracellular Ca2+, the Amitriptyline ( Elavil ) responses were decreased by 76% and 69%, respectively. The Amitriptyline ( Elavil )-induced [Ca2+]i increases were unaffected by treatment with pertussis toxin. We conclude that high concentrations of Amitriptyline ( Elavil ) and three other ADs mobilize Ca2+ from IP3-sensitive Ca2+ stores and that the responses are pertussis toxin-insensitive. However, it seems unlikely that the effects requiring high concentrations of ADs are related to the therapeutic action.

Relative speed of onset of the antidepressant effect of maprotiline.

In a double-blind clinical trial conducted in general practice, maprotiline was compared with Amitriptyline ( Elavil ). Thirty-three of 40 patients completed the trial, 19 on maprotiline and 14 on Amitriptyline ( Elavil ). The Hamilton Depression Rating Scale was administered on days, 0, 7, 14, and 21, and a global rating scale of improvement was administered on day 21. Although there were significant reductions in the Hamilton scores by day 21 in both groups, with no significant difference between the compounds, maprotiline produced significantly greater improvement by day 7 than did Amitriptyline ( Elavil ). A review of published double-blind clinical Amitriptyline ( Elavil ) or imipramine for treatment of depression supports our finding that maprotiline has a faster onset of action than the standard tricyclic antidepressants.

Determination of Amitriptyline ( Elavil )-N-oxide, Amitriptyline ( Elavil ) and nortriptyline in serum and plasma by high-performance liquid chromatography.

A method for the determination of Amitriptyline ( Elavil )-N-oxide, Amitriptyline ( Elavil ) 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 ( Elavil )-N-oxide was found in rat plasma after an oral dose (10 mg/kg) of Amitriptyline ( Elavil )-N-oxide.