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PubMed1997

Evaluation of a colloidal metal immunoassay device for the detection of tricyclic antidepressants in urine.

BACKGROUND: The sensitivity and selectivity of a colloidal metal immunoassay device (Triage Plus TCA) which is designed for the rapid detection of tricyclic antidepressant drugs in urine at a total tricyclic antidepressant concentration of 1000 ng/mL or greater were evaluated. METHODS: The sensitivity of the Triage Plus assay was determined by adding known amounts of amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin to drug free urine. The selectivity of the assay was determined by adding known concentrations of 32 drugs or drug metabolites commonly encountered in emergency department admissions to drug free urine. Triage Plus results from clinical urine specimens containing either amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin were compared to those obtained with thin layer chromatography and high performance liquid chromatography. RESULTS: Triage Plus yielded a positive response to gravimetrically prepared urines of tricyclic antidepressant at the stated cut-off value (1,000 ng/mL), and at 80% (800 ng/mL) and 50% (500 ng/mL) of the cut-off with amitriptyline, nortriptyline, imipramine, desipramine and doxepin. Other tricyclic antidepressant drugs, clomipramine and protriptyline were positive at 1000 ng/mL. Significant cross-reactivity was observed only with cyclobenzaprine at 1000 ng/mL. No significant cross reactivity was found at 1.0 g/L for 32 drugs commonly encountered in emergency department admissions. A 95% (70/74) agreement of positive tricyclic antidepressant results was observed between Triage Plus and thin layer chromatography. Discordant urines were found by high performance liquid chromatography to contain tricyclic antidepressant concentrations below the cut-off value of the colloidal metal assay. CONCLUSION: Triage Plus was found to be an accurate device for the detection of tricyclic antidepressants in urine at the stated cut-off value of 1000 ng/mL tricyclic antidepressant. With the exception of cyclobenzaprine, significant cross-reactivity was not observed with other drugs commonly encountered in emergency department admissions.

Antidepressive Agents, Tricyclic↗
PubMed1999

The extent of postmortem drug redistribution in a rat model.

The aim of this study was to investigate the postmortem redistribution of several drugs in a rat model and to examine if any of the pharmacological properties was related to the extent of this phenomenon. One of the following drugs: phenobarbital (phenobarbitone), acetaminophen (paracetamol), carbamazepine, codeine, verapamil, amphetamine, mianserin, trimeprazine (alimemazine) or chloroquine was administered together with nortriptyline orally to rats 90 min prior to sacrifice. Heart blood was sampled immediately before sacrifice and after 2 h postmortem, as it has previously been shown that this is sufficient time for postmortem concentration changes to occur in heart blood. Blood was also sampled from the clamped abdominal inferior vena cava (representing peripheral blood) and tissue samples were taken from lungs, myocardium, liver, kidney, thigh muscle, forebrain, and vitreous humor together with a specimen from the minced carcass. Drugs were analyzed by high performance liquid or gas chromatography. For phenobarbital, acetaminophen and carbamazepine the postmortem to antemortem blood drug concentration ratios were close to 1.0 and tissue concentrations were low. The postmortem to antemortem heart blood drug concentration ratio for chloroquine (6.9 +/- 1.5) was higher than for nortriptyline (3.5 +/- 0.3), and the remaining drugs (codeine, verapamil, amphetamine, mianserin, and trimeprazine) showed ratios of the same magnitude as nortriptyline. The postmortem to antemortem blood drug concentration ratios for both heart blood and blood from the vena cava and also the lung to antemortem blood drug concentration ratio were closely related to the apparent volume of distribution for the drugs studied (p < 0.001). Accordingly, an apparent volume of distribution of more than 3-4 L/kg is a good predictor that a drug is liable to undergo postmortem redistribution with significant increments in blood levels. The postmortem drug concentration in blood from vena cava was closely related to the antemortem blood level, confirming that among the postmortem samples, the peripheral blood sample was the most representative for the antemortem blood concentration.

Animals↗
PubMed2003

[The efficacy of smoking cessation methods available in the Netherlands: a systematic review based on Cochrane data].

OBJECTIVE: To obtain an overview of data from the Cochrane Library on smoking-cessation methods and aids available in the Netherlands. DESIGN: Systematic literature review. METHOD: Common smoking-cessation methods in the Netherlands in 1999 and 2000 were selected from previous research. Data from relevant Cochrane reviews about these cessation methods were collected, after which the efficacy was calculated as a pooled odds ratio and the effectiveness as a percentage of 12 months' continuous abstinence. RESULTS: The following methods were found to be more efficacious than placebo: tailored written advice, individual counselling, telephonic counselling, group courses, all forms of nicotine-replacement therapy, bupropion and nortriptyline. Acupuncture was not superior to placebo. It was not possible to draw any unequivocal conclusions about hypnotherapy. No randomised studies were found with respect to the 'Allen Carr method'. Rates of 12 months' continuous abstinence were as follows for those methods with proven efficacy: tailored advice: 7%, individual counselling: 16%, telephonic counselling: 7.5%, nicotine gum: 17%, nicotine patch: 13%, nicotine inhaler: 17%, nicotine tablets: 20%, bupropion: 17%, and nortriptyline: 24%. The success rates for nicotine tablets and nortriptyline were based on only 2 and 1 study respectively. CONCLUSION: Several effective smoking-cessation methods are available in the Netherlands. In trials the long-term effectiveness of these methods was between 7-24%.

Humans↗
PubMed1991

Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients.

The combination of carbamazepine and an antidepressant (doxepin, amitriptyline, mianserin) was given to 22 psychiatric inpatients with 29 measurements of their serum antidepressant concentrations. For comparison, sex-, age-, and dose-matched inpatients, treated with the antidepressant but not with carbamazepine, were selected as controls (N = 29). All the patients were treated with their routine daily dose for at least 7 days before the gas-chromatographic measurement of serum predose concentrations of the antidepressants. In patients with carbamazepine, serum doxepin and doxepin + nordoxepin concentrations (N = 17) were decreased significantly (p less than 0.05), on average to 46% and 45%, respectively, as compared to that in subjects without carbamazepine. Also in carbamazepine + amitriptyline patients, serum nortriptyline and amitriptyline + nortriptyline concentrations (N = 8) were significantly lower than in those not receiving carbamazepine (p less than 0.05). The mean serum antidepressant levels were decreased to 42% and 40%, respectively. The serum mianserin concentration of carbamazepine patients (N = 4) was reduced to 30% of that in patients not treated with carbamazepine (p less than 0.01). The percentage fractions of demethylated metabolites (nordoxepin, nortriptyline) from the total antidepressant levels were not influenced by carbamazepine. In patients treated with carbamazepine, serum total antidepressant concentrations remained more often below the suggested therapeutic ranges than in those patients without carbamazepine. The results suggest that serum antidepressant concentrations are reduced by concurrent carbamazepine therapy, and that the concentrations should be carefully monitored when carbamazepine is added to the antidepressant regimen.

Adult↗
PubMed1995

Comparison of the kinetic interactions of the neuroleptics perphenazine and zuclopenthixol with tricyclic antidepressives.

Using data from a therapeutic drug monitoring database, kinetic interactions between the neuroleptics zuclopenthixol and perphenazine and tricyclic antidepressives were studied. Out of 290 patients monitored for amitriptyline and 611 patients monitored for nortriptyline, 77 patients were comedicated with perphenazine and 50 patients with zuclopenthixol. Comedication with perphenazine increased the median steady-state serum concentration to daily dose ratio (C/D) of nortriptyline by 30-45%, whereas the median C/D of amitriptyline was unaffected. On the contrary, median C/D values of nortriptyline and amitriptyline were not significantly influenced by comedication with zuclopenthixol. Thus, in accordance with previous studies, perphenazine increases the concentration of tricyclic antidepressives to a moderate extent. Zuclopenthixol, on the other hand, does not exert any impact under routine therapeutic drug monitoring, even though the drug is known to partly depend on metabolism by the isozyme cytochrome P450 2D6.

Adolescent↗
PubMed1995

Biotransformation of amitriptyline by Cunninghamella elegans.

A fungal biotransformation system as an in vitro model for mammalian drug metabolism was investigated. Amitriptyline, a widely used antidepressant, was effectively biotransformed within 72 hr by the filamentous fungus, Cunninghamella elegans. Eight major metabolites in HPLC elution order (11-hydroxyamitriptyline N-oxide, 11-hydroxynortriptyline, 11-hydroxyamitriptyline, 10-hydroxyamitriptyline, 3-hydroxyamitriptyline, 2-hydroxyamitriptyline, nortriptyline, and amitriptyline N-oxide) were produced at estimated molar ratios of 2:1:10:0.6:0.1:1.2.5:0.5, respectively. These metabolites were isolated by HPLC and identified by UV/MS analyses, as well as NMR spectroscopic analysis for most of these metabolites. In some cases, they were also compared with authentic standards. Glucose, culture age, and substrate concentration significantly affected the extent of amitriptyline metabolism. Kinetic studies indicated that nortriptyline and 11-hydroxyamitriptyline were produced as initial major metabolites. The hydroxylated metabolite was excreted from mycelia, but amitriptyline and its N-demethylated metabolite, nortriptyline, were not. An 18O2 labeling experiment showed that the oxygen atoms in 11-hydroxyamitriptyline and 2-hydroxyamitriptyline were derived from molecular oxygen. The cytochrome P450 inhibitors SKF 525-A (1.5 mM), metyrapone (2.0 mM), and 1-aminobenzotriazole (1.0 mM) inhibited the biotransformations of amitriptyline by 50, 75, and 95%, respectively. A microsomal preparation was shown to catalyze the 11-hydroxylation of amitriptyline, which was inhibited by SKF 525-A and carbon monoxide. The similarities of amitriptyline metabolism in C. elegans and in humans and rats are discussed.

Amitriptyline↗
PubMed1996

Paroxetine is a novel nitric oxide synthase inhibitor.

The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.

Animals↗
PubMed1998

Economic outcomes with antidepressant pharmacotherapy: a retrospective intent-to-treat analysis.

Herein we describe a retrospective intent-to-treat evaluation designed to compare the natural course of antidepressant utilization and direct health service expenditures for the treatment of a single episode of major depression among patients enrolled in a multistate network-model health maintenance organization and initially prescribed either a tricyclic antidepressant (amitriptyline or nortriptyline) or the serotonin selective reuptake inhibitor (SSRI) fluoxetine. Patient-level paid-claims data for the period July 1, 1988, through December 31, 1991, were abstracted. During the above time frame, fluoxetine was the only SSRI available in the United States. Patients prescribed amitriptyline were more than three times as likely to require a change in antidepressant pharmacotherapy (OR = 3.27, 95% CI = 2.31 to 5.49), while patients prescribed nortriptyline were nearly four times more likely to change medication (OR = 3.82, 95% CI = 2.74 to 6.83) relative to patients initially prescribed fluoxetine. Consistent with our intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate analyses revealed that initiation of antidepressant pharmacotherapy with amitriptyline resulted in a 25.7% increase in per capita depression-related health service expenditures per year, while initiation of antidepressant pharmacotherapy with nortriptyline resulted in a 28.1% increase in per capita depression-related health service expenditures per year relative to patients initially prescribed fluoxetine. A financial break-even point was achieved at the conclusion of Month 5, at which time all three intent-to-treat cohorts had comparable health service expenditures in total. From a financial perspective, results stemming from this inquiry suggest that the initiation of antidepressant pharmacotherapy with an SSRI is warranted.

Adult↗
PubMed1980

Clomipramine treatment of obsessive-compulsive disorder. I. A controlled clinical trial.

The effect of clomipramine hydrochloride in severe obsessive-compulsive disorder (OCD) was compared with that of nortriptyline hydrochloride and placebo in a five-week randomized, double-blind trial. Clomipramine, but not nortriptyline, was superior to placebo in interview-based ratings of severity of OCD. The effect was not clear-cut until after five weeks of treatment. When clomipramine was given openly to 22 patients after the end of the controlled trial, half of the patients responded to the drug. The response could not be predicted from severity or duration of illness, sex or age of the patient, or presence or absence of secondary depressive symptoms. The amelioration with clomipramine was not sustained if the drug was withdrawn.

Adult↗
PubMed1988

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.

Adult↗
PubMed1988

How effective and safe is continuation therapy in elderly depressed patients? Factors affecting relapse rate.

Sixty elderly depressed patients who had responded to either nortriptyline hydrochloride or phenelzine sulfate were followed up under double-blind conditions during four to eight months of continuation treatment. Over 70% of patients (43) remained well during this period, while 11 (18.3%) had relapses, three (5.0%) dropped out because of side effects, and three (5.0%) prematurely terminated in good clinical condition. There was no significant difference in the relapse rate between patients receiving nortriptyline (five [16.7%]) and those receiving phenelzine (six [20.0%]). Patients receiving phenelzine were more likely to require dose reductions, and all three patients who dropped out because of side effects were receiving phenelzine. Patients with chronic depression (greater than two years' duration) accounted for all of the relapses.

Age Factors↗
PubMed2000

Executive dysfunction and long-term outcomes of geriatric depression.

BACKGROUND: This study investigated the relationship of executive and memory impairment to relapse, recurrence, and course of residual depressive symptoms and signs after remission of geriatric major depression. METHODS: Fifty-eight elderly subjects remitted from major depression received continuation nortriptyline treatment (plasma levels 60-150 ng/mL) for 16 weeks and then were randomly assigned to either nortriptyline maintenance therapy or placebo for up to 2 years. Diagnosis was made using the Research Diagnostic Criteria and the DSM-IV criteria after an interview using the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction and memory were assessed with the Dementia Rating Scale, disability and social support were rated with the Philadelphia Multiphasic Instrument, and medical burden was assessed with the Cumulative Illness Rating Scale. RESULTS: Abnormal initiation and perseveration scores, but not memory impairment, were associated with relapse and recurrence of geriatric depression and with fluctuations of depressive symptoms in the whole group and in subjects who never met criteria for relapse or recurrence during the follow-up period. Memory impairment, disability, medical burden, social support, and history of previous episodes did not significantly influence the outcome of depression in this sample. CONCLUSIONS: Executive dysfunction was found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. These observations, if confirmed, will aid clinicians in identifying patients in need of vigilant follow-up. The findings of this study provide the rationale for investigation of the role of specific prefrontal pathways in predisposing or perpetuating depressive syndromes or symptoms in elderly patients.

Age Factors↗
PubMed2000

Antidepressant-induced regulation of 5-HT(1b) mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation.

Serotonin release from dorsal raphe projections in the forebrain is regulated by terminal 5-HT(1B) autoreceptors; dysregulation of these receptors may be involved in the pathophysiology of clinical depression. Using in situ hybridization, we have previously reported that fluoxetine reduces 5-HT(1B) mRNA in rat dorsal raphe nucleus (DRN) in a time-dependent and reversible manner. In this study we examined longer term treatment (8 weeks) with several different serotonin-selective reuptake inhibitors (SSRIs) or a tricyclic antidepressant on 5-HT(1B) mRNA regulation in DRN and hippocampus, and evaluated the stability of these drugs' effects after drug discontinuation. Fluoxetine (5 mg/kg/d), paroxetine (5 mg/kg/d), sertraline (10 mg/kg/d) or nortriptyline (10 mg/kg/d) was administered to rats via subcutaneous osmotic minipumps. Paroxetine and fluoxetine reduced DRN 5-HT(1B) mRNA by 36% and 27%, respectively whereas sertraline had a no significant effect. After 3-14 days of drug washout, DRN 5-HT(1B) mRNA levels in SSRI treated rats were no longer different from control. 5-HT(1B) mRNA levels in hippocampus were not affected by SSRI drugs at any timepoint. Nortriptyline had no significant effect on 5-HT(1B) mRNA in either DRN or hippocampus. These results confirm that SSRI antidepressants reduce presynaptic 5-HT(1B) mRNA selectively, and that this effect is maintained for at least 8 weeks of antidepressant treatment but reverses rapidly after discontinuation. Furthermore, it is possible that washout after chronic antidepressant treatment, that is routinely used in functional assays of autoreceptor action in animal models, may lead to more rapid reversal of biological effects than has previously been thought.

Animals↗
PubMed1975

Effects of tricyclic antidepressants on drug metabolism.

The effects of chronic treatment with amitriptyline and nortriptyline on the elimination from plasma of warfarin, dicumarol, phenytoin, and tolbutamide were examined in man. No alteration of plasma half-life of warfarin, phenytoin, or tolbutamide was observed following dosage with the tricyclic antidepressants used. There was no consistent effect on the metabolism of dicumarol following treatment with amitriptyline or nortriptyline although the bioavailability of dicumarol appeared to be increased. In some subjects, this increased bioavailability was associated with significant prolongation of the plasma half-life of dicumarol due to its dose-dependent kinetics.

Adult↗
PubMed1981

Dose-dependent kinetics of imipramine in elderly patients.

In a group of elderly depressed patients treated with imipramine (50-200 mg/day), six patients had the dose changed after 1-3 weeks of treatment. In all cases an increased dose resulted in a considerably disproportional rise in the plasma level of the active metabolite desipramine. In a group of elderly depressed patients treated with nortriptyline (40-100 mg/day) the dose/plasma level ratio could be examined in 6 patients, and there was no tendency towards a disproportional rise in plasma level, when the dose was raised. Dose changes, thus, may result in unpredictable changes in plasma levels during imipramine treatment and therapy control by plasma level monitoring may be difficult in these patients. Additional treatment with perphenazine (8-16 mg/day) to patients on imipramine (N = 3) or nortriptyline (N = 2) caused a marked rise in drug levels for imipramine in particular affecting the desipramine levels.

Aged↗
PubMed1978

Release of noradrenaline by labetalol in the rat anococcygeus muscle.

The effects of labetalol on the accumulation and spontaneous release of (--)-[3H]noradrenaline, and on contractile responses to exogenously applied (--)-noradrenaline were studied in the isolated anococcygeus muscle of the rat. 1. Labetalol (3 x 10(-7)--10(-4)M) inhibited the accumulation of (--)-[3H]noradrenaline. 2. Labetalol (10(-6)--10(-4)M) and guanethidine (6 x 10(-6) M) increased the spontaneous release of [3H] following incubation of the muscle with (--)-[3H]noradrenaline. Nortriptyline (10(-6) M) had no effect on the spontaneous release of [3H], antagonised the increased release of [3H] produced by 6 x 10(-6) M guanethidine but not that observed with 10(-5) M labetalol. Labetalol (5 x 10(-6) M) markedly increased the loss of tritiated deminated metabolites with little change in the loss of (--)-[3H]noradrenaline. 3. Labetalol (10(-7)--10(-5)M), alone or in the presence of 10(-6) M nortriptyline, had no effect on contractile responses to (--)-noradrenaline. 4. Following pretreatment with 6-hydroxydopamine (10(-3)M for 3 h) to deplete endogenous noradrenaline stores, labetalol (10(-7)--10(-5) M) inhibited responses to exogenously applied (--)-noradrenaline. 5. These results suggest that, in the rat anococcygeus muscle, labetalol is a noradrenaline releasing agent and an alpha-adrenoceptor antogonist.

Animals↗
PubMed1979

Changes in the human light reflex as a measure of the anticholinergic effects of drugs. A comparison with other measures.

Single oral doses of atropine, nortriptyline, procyclidine and lactose dummy were administered double-blind to eight healthy young subjects in a balanced, crossover study. Television pupillometry was used to measure the anticholinergic effects of these drugs on the pupil diameter in darkness and the reflex response to light flashes. The sensitivity of this method was compared with conventional autonomic function tests, viz. salivary secretion, radial pulse, forearm sweat gland activity and distance to visual near point. Visual analogue scales were used to obtain subjective measures of sedative drug effects. The expected inhibition of parasympathetic activity was found in most instances with two exceptions: firstly, that nortriptyline failed to affect the pupil despite causing a tachycardia and secondly, that procyclidine gave a bradycardia. The results are discussed with reference to the possible advantages of television pupillometry over conventional pupil measurement in the detection of anticholinergic drug effects.

Adolescent↗
PubMed1994

Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions.

Recent reports suggest that a cholecystokinin (CCK)-related dysfunction may be a target by which drugs can modulate anxiety and panic disorders. In the present study, effects of subchronic (14 days) treatment with the monoamine uptake inhibitors nortriptyline (30 mumol/kg per day), amitriptyline (29 mumol/kg per day), clomipramine (32 mumol/kg per day) and alaproclate (39 mumol/kg per day), as well as with the benzodiazepine clonazepam (0.25 mumol/kg per day), on rat brain levels of CCK- and substance P-like immunoreactivity, were compared. The drugs were administered by continuous s.c. infusion using implanted osmotic pumps. The plasma concentrations of the monoamine uptake inhibitors were similar after 1 and 2 weeks of treatment, indicating that steady-state plasma levels had been reached during the first week. Treatment with clomipramine or clonazepam increased the CCK-like immunoreactivity level in the ventral tegmental area (by 64.4 +/- 28.8% and 105.1 +/- 28.8%, respectively) and in the cingulate cortex (by 30.3 +/- 10.1% and 36.0 +/- 11.8%, respectively) (P < 0.05 or P < 0.01). Clomipramine also significantly increased the CCK-like immunoreactivity level in the periaqueductal grey by 85.1 +/- 29.7%. Neither nortriptyline nor amitriptyline or alaproclate produced any significant alterations in the CCK- or substance P-like immunoreactivity levels in the areas examined. The present results may suggest that an altered utilization of CCK in limbic circuits could be of importance for the well documented clinical effect of clomipramine and clonazepam in panic disorders.

Amitriptyline↗