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PubMed1980

Symptoms as predictors of response to amitriptyline and nortriptyline -- the plasma level variable.

Data collected to define therapeutic plasma levels for amitriptyline and nortriptyline were re-analyzed to test endogenous and non-endogenous symptoms as response predictors while controlling for plasma level variable. The selection criteria limited the range of historical predictors. Initial symptom quality was not predictive of outcome for the entire group of 44 patients or for the 27 with therapeutic plasma levels. Delusions were not associated with poor outcome. The authors conclude that historical components of the endogenous--non-endogenous distinction (e.g., premorbid personality, stability of symptoms over time, quality of remissions) may be more important as response predictors.

Amitriptyline↗
PubMed1985

Cerebrospinal fluid levels of amitriptyline, nortriptyline, imipramine and desmethylimipramine. Relationship to plasma levels and treatment outcome.

Fifty-five (55) depressed patients were treated with amitriptyline (AMI) or imipramine (IMI). Concentrations of AMI, IMI, and their metabolites, nortriptyline (NT) and desmethylimipramine (DMI), were measured in cerebrospinal fluid (CSF) and plasma at steady state by gas chromatography mass spectrometry (GC/MS). Highly significant correlations between CSF and plasma levels of AMI, NT, IMI, and DMI were found (r greater than 0.75; P less than 0.0001 in all cases). There were no significant sex, diagnostic subgroup, or geographic difference in any of the drug parameters measured. An evaluation of the relationship between CSF levels of drug variables and clinical response showed essentially no significant correlations between these various parameters. The results obtained do not support the concept of a 'therapeutic window' for levels of plasma NT in AMI-treated patients. Furthermore, the highly significant correlations between CSF and plasma compartments in terms of drug and metabolite levels would argue against the need to measure CSF levels of these parameters in clinical practice. Plasma level measurements should be equally informative, and simpler to obtain.

Amitriptyline↗
PubMedDate not supplied

Plasma nortriptyline and clinical response in depression.

Plasma levels of nortriptyline below 50 ng/ml or above 150 ng/ml have been reported to yield results inferior to intermediate levels. In the present study, patients with uncomplicated primary, nonbipolar depression were randomly assigned to 12 weeks of treatment with NT alone or with cognitive therapy. Nine of 35 patients had mean NT plasma levels less than 50 ng/ml. Five of them improved clinically to the criterion level of less than or equal to 7 on the Hamilton Rating Scale for Depression. This improvement rate was not at all different from that of patients with mean plasma levels within the presumed therapeutic window. The upper limit of 150 ng/ml was not tested. This study is presented in the hope of reviving the apparently dormant search for optimal therapeutic plasma levels of antidepressants.

Antidepressive Agents↗
PubMed1992

Nortriptyline response in elderly depressed patients.

1. Depressed geriatric patients were treated with nortriptyline (NT) for 6 weeks. The authors measured serum levels of NT and 10-hydroxynortriptyline (10-OH-NT) using a column-switching HPLC method, and examined aging effects on NT steady-state levels to NT doses (doses/kg) ratios and NT levels to 10-OH-NT levels ratios as well as clinical response and propensity for side effects. 2. There was no significant relationship between the ages and the NT serum levels to NT doses (doses/kg) ratios, the ages and the 10-OH-NT levels to NT levels ratios, or the ages and the clinical response or the %improvement of Hamilton Scores. 3. Then the authors divided the subjects into two groups: a younger group and an elderly group with the cut off age of 60. The elderly group received significantly smaller doses of NT and had significantly lower serum levels of NT. The elderly group had tendency to have lower serum levels of 10-OH-NT. However, no significant difference was found in the improvement scores or the %improvement of depression. The elderly patients did not have higher propensity for unnegligible side effects.

Adult↗
PubMed1990

The effect of nortriptyline-specific active immunization on amitriptyline toxicity and disposition in the rabbit.

Rabbits were actively immunized by a conjugate of nortriptyline (NT) to study the effect of specific anti-NT antibodies on toxicity and disposition of amitriptyline (AT). Control and immunized rabbits received 115 mg/kg AT intraperitoneally (i.p.). The lethality dose (LD) profile exhibited a gentle slope; LD100 and LD0 were separated by 100 mg/kg. Mortality was significantly reduced from LD67 to LD43 (P less than 0.05). Total plasma concentrations of the toxin were increased in the immunized group compared to the control group. AUC0.5-24 h value was 5-fold higher in the immunized group than in the control group. Moreover, a smaller fraction of unbound toxin in plasma was observed in the immunized group than in the control group. These observations indicate that AT was actively sequestered by antibodies. The intensity of this phenomenon was a function of both the antibody affinity constant (10(9) M-1) and the neutralizing capacity (varying from 0.005 to 0.2 mg/kg) of the circulating antibodies in each immunized rabbit. Results clearly show that anti-NT antibodies are able to effectively sequestrate AT.

Amitriptyline↗
PubMed1985

Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study.

A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried out in patients with painful diabetic polyneuropathy. A visual analog scale was used to evaluate the relief of pain or paresthesia. Significant relief of both pain and paresthesia was obtained with this combination. The differences were statistically significant. Side effects were frequent but not usually severe enough to lead to cessation of these medications.

Adult↗
PubMed1994

Chlorimipramine and nortriptyline but not fluoxetine and fluvoxamine inhibit human polymorphonuclear cell chemotaxis in vitro.

We examined the ability of antidepressant drugs belonging to different classes to interfere with human polymorphonuclear cell migration in vitro. 1. The tricyclic antidepressant drugs chlorimipramine and nortriptyline were able to block, in a dose related fashion both spontaneous and formyl-methionyl-leucyl-phenylalanine stimulated migration. This effect was already evident at very low concentrations (10(-7)M). 2. The atypical non-tricyclic antidepressant drugs fluoxetine and fluvoxamine did not affect polymorphonuclear cell mobility. 3. The ability of antidepressant drugs to interfere with polymorphonuclear cell physiology seems to depend on their chemical structures.

Antidepressive Agents↗
PubMed1987

Two tricyclic antidepressant poisonings: levels of amitriptyline, nortriptyline and desipramine in post-mortem biological samples.

Two deaths due to amitriptyline and desipramine overdoses are reported. The first case deals with a 20-year-old Caucasian male who was found dead at his residence. Toxicological analysis of the blood, urine, liver and kidney revealed the presence of amitriptyline (1.7 mg/l, 0.13 mg/l, 36.0 mg/kg and 98.0 mg/kg) and nortriptyline (0.66 mg/l, 0.74 mg/l, 12.0 mg/kg and 37.0 mg/kg). The gastric content contained only 220 mg of amitriptyline. The urine also contained norverapamil, which was consistent with previous verapamil therapy. The second case involved a 19-year-old Caucasian male who attempted suicide earlier and was on desipramine medication. The blood, urine, liver and gastric content disclosed the presence of desipramine in the concentrations of 14.2 mg/l, 33.7 mg/l, 112.5 mg/kg and 180 mg, respectively. The levels of these tricyclics analyzed by high pressure liquid chromatography were in agreement with the levels reported in the literature. Though with the amitriptyline poisoning no significant anatomic changes were noted, the desipramine-caused death was further supported by the multisystem vascular congestion and ischemic changes consistent with cardiopulmonary failure.

Adult↗
PubMed1995

Kinetic determination of nortriptyline in pharmaceutical samples by use of photometric and fluorimetric detection.

A fast kinetic method is proposed for the photometric and fluorimetric determination of nortriptyline hydrochloride. The method involves measuring the rate of formation of an adduct with 4-chloro-7-nitrobenzofurazan, which exhibits light absorption and fluorescent properties, and the use of a stopped-flow mixing technique, which facilitates application to automatic routine analyses. The reaction rate is measured within only 30 s. The detection limit is 0.12 micrograms ml-1 (photometry) and 0.18 micrograms ml-1 (fluorimetry) and the calibration graph is linear up to 60 micrograms ml-1 in both cases. The precision (as RSD) is less than 1.5%. The proposed method was satisfactorily used for direct analysis of pharmaceutical preparations and a mean recovery near 100% was obtained with both photometric and fluorimetric detection.

Hydrogen-Ion Concentration↗
PubMed1994

Recurrent hypotension immediately after seizures in nortriptyline overdose.

Cardiovascular deterioration after seizures in tricyclic overdose has long been suspected. The investigators studied a patient with a nortriptyline HCI level of 1,205 ng/mL who had four generalized grand mal seizures, each lasting between 60 and 90 seconds that were immediately followed by hypotension requiring norepinephrine support. When the seizures were controlled with midazolam, the hypotension subsided and norepinephrine was decreased. The metabolic acidosis associated with the seizures may have caused hypotension by direct cardiotoxicity, an increase in bioavailability of tricyclic antidepressant because of changes in protein binding, an alteration of the effects of tricyclic antidepressant on cardiac membrane sodium channels, or a combination of these mechanisms.

Biological Availability↗
PubMed1994

Aspiration of nortriptyline.

Unintentional aspiration of medication capsules is a rare event. A case report of a neurologically impaired 23-year-old woman who aspirated a 50-mg nortriptyline capsule is presented. This resulted in progressive respiratory distress necessitating ventilatory support. Bronchoscopy showed severe airway inflammation and edema.

Adult↗
PubMed1997

The dexamethasone suppression test and treatment outcome in elderly depressed patients participating in a placebo-controlled multicenter trial involving moclobemide and nortriptyline.

The dexamethasone suppression test (DST) was conducted in 95 elderly DSM-III-R depressed patients randomized for treatment with moclobemide (MOC; 400 mg daily), nortriptyline (NT; 75 mg daily), or placebo (PBO) in a 7-week double-blind multicenter study. Patients were assessed weekly using various clinical scales, including the 17-item Hamilton Depression Rating Scale. The DST was administered at baseline and at the end of treatment. At baseline, no relationship was found between DST status and the various clinical scales used. At the end of treatment, suppressors (DST-) had significantly improved clinical ratings compared to nonsuppressors (DST+), and were mostly found among those treated with NT (71%) as compared to MOC (41%) or PBO (33%) (p < .03). On the other hand, baseline DST measures influenced treatment outcome; DST+ patients had a greater number of treatment responders to NT (48%) than MOC (19%) or PBO (20%) (p < .07). For DST- patients, the situation was reversed: NT, 7%; MOC, 31%. Postdexamethasone cortisol levels were lower in MOC responders (p < .07). An interaction was found between DST and drug-specific response. The DST may be a useful adjunct for predicting and evaluating the outcome of antidepressant therapy.

Aged↗
PubMed2001

Sex-related differences in nortriptyline-induced side-effects among depressed patients.

1. Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants (TCAs), in a number of autonomic indices, and in various adrenergic receptor mediated responses. Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion, relative to men. However, sex-related differences in TCA-induced side-effects, including increases in heart rate (HR), dry mouth, constipation, and difficulty urinating, has not been systematically investigated. 2. The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline (NT), a TCA that is still widely used. Seventy-eight healthy outpatients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a double-blind, randomized parallel trial of NT versus placebo. 3. Each subject was acutely challenged with either placebo or 50 mg NT prior to and after a 6-week treatment with NT. NT doses were adjusted weekly to maintain therapeutic plasma levels. Patients were assessed at multiple time points to detect the presence of NT-induced side-effects. 4. The initial, single (50 mg) dose of NT significantly increased supine HR. Six-week treatment with NT was found to significantly increase supine and sitting HRs, irrespective of sex. In rechallenge with the single NT dose, there were no significant effects on HR. 5. When sex-related differences were examined, HR increases were greater in men than women during weeks 4 through 6 of the NT treatment, although no sex-related differences were present in plasma NT levels or metabolites. In addition, there was a significant NT to placebo difference in self-rated dry mouth for women during all 6-weeks of treatment, whereas men showed a significant NT-placebo difference during weeks 3 and 5. 6. The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment. Depressed men may be more susceptible to NT-induced increases in supine HR than women.

Adult↗
PubMed1982

Simultaneous determination of amitriptyline, nortriptyline and their respective isomeric 10-hydroxy metabolites in plasma by liquid chromatography.

An ion-pair reversed-phase liquid chromatographic method for the determination of the tricyclic antidepressant amitriptyline, the demethylated metabolite nortriptyline, and their respective cis- and trans-hydroxylated metabolites in plasma is presented. After extraction from 1 ml of plasma, the reconstituted residue was chromatographed on a trimethylsilyl packed column using a mobile phase of acetonitrile and acetate buffer with sodium heptane-sulfonate and triethylamine. Recovery of the drugs and its metabolites from plasma ranged from 56 to 99%. The method is suitable for determining plasma concentrations as low as 5 ng/ml (C.V. less than 9%) for all six compounds. Plasma concentrations of amitriptyline and its metabolites from eleven different patients are presented.

Amitriptyline↗
PubMed1978

Determination of amitriptyline and nortriptyline in human plasma by quantitative thin-layer chromatography.

A thin-layer chromatographic method for simultaneous determination of amitriptyline (AT) and nortriptyline (NT) in human plasma is described. Both substances are extracted from biological material by means of a single extraction. The extract is evaporated until dry and the residue quantitatively applied to a silica gel thin-layer plate. AT and NT are separated from interfering plasma components by chromatography. The spots are visualized by nitration, reduction and coupling with N-(1-naphtyl)ethylenediamine on the plate. The intensity of the azo-dyes formed can be measured densitometrically. Using 1 ml of plasma, the sensitivity limit was 0.5 ng/ml for both substances. About 10--15 plasma samples can be analysed per day. The method is applicable to pharmacokinetic studies after a single oral dose of 25 mg AT as hydrochloride in man.

Amitriptyline↗
PubMed1980

Determination of amitriptyline-N-oxide, amitriptyline and nortriptyline in serum and plasma by high-performance liquid chromatography.

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

Amitriptyline↗
PubMed1980

Factors influencing nortriptyline steady-state kinetics: plasma and saliva levels.

Proportionality between dose and steady-state nortriptyline (NT) plasma levels was found both during initial treatment and after long-term treatment (years) within the NT Plasma level range of 20 to 296 ng/ml. There were day-to-day variations of 10% to 20% (coefficient of variation) but no systematic changes in plasma levels over time. A significant age variation in NT plasma levels was found in 116 patients. Patients over 70 yr of age (n = 23) had higher levels than other age groups (p < 0.001) dose corrected; p < 0.0001 dose and weight corrected). It was found that during episodes of acute inflammatory diseases NT steady-state plasma levels rose after a change in sedimentation rate. Our data show that the use of saliva rather than plasma in therapeutic drug level monitoring of NT cannot be recommended because the saliva/plasma ratio varied both intra- and interindividually by factors of from 2 to 4.

Adult↗