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At least 127 records · Page 7Linked to original sources

Nortriptyline pharmacokinetic parameters in depressed children and adolescents: preliminary data.

The pharmacokinetic parameters of nortriptyline in the pediatric age group following oral administration of a single dose of 25 or 50 mg were investigated from nortriptyline plasma level assays at 12, 18, 24, 36, and 48 hours postdose. Data were analyzed separately for the nine prepubertal and 11 postpubertal subjects, all of whom were diagnosed major depressive disorder. These data were compared with studies in the literature of nortriptyline pharmacokinetics from adult and geriatric normal and depressed populations. Similar to adults, the elimination of nortriptyline in children and adolescents is apparently first order kinetics with a logarithmically linear rate of disappearance. The prepubertals had a shorter mean half-life (17.6 +/- 3.7 hours) than some adult groups and twice a day dosage would, therefore, be more appropriate for many children. Although the mean half-life (27.1 +/- 17.1 hours) for the adolescent group suggested that once a day dosage would be sufficient, some adolescents would need twice a day dosage for optimum plasma level control because there was a wide range (14.1 to 76.2 hours). The almost twofold variation in half-life in prepubertals and fivefold variation in postpubertals were similar to differences in adult groups and emphasize the value of plasma level monitoring in the clinical use of nortriptyline.

Adolescent↗

A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms.

OBJECTIVE: To determine whether the antidepressant, nortriptyline, is effective for treatment of depression, tinnitus-related disability, and tinnitus symptoms in patients with severe chronic tinnitus. DESIGN: A 12-week, double-blind, randomized controlled trial. SETTING: A university otolaryngology clinic. PATIENTS: Ninety-two subjects with severe chronic tinnitus: 38 with current major depression and 54 with depressive symptoms and significant tinnitus-related disability. INTERVENTION: Nortriptyline (maintained at 50 to 150 mg/mL for 6 weeks) or placebo. MAIN OUTCOME MEASURES: Hamilton Depression Rating Scale, Tinnitus Disability Measures, and Audiometric Measures. RESULTS: Nortriptyline was superior to placebo by multivariate analysis of covariance for depression (10.6 vs 14.3 final Hamilton Depression score), for tinnitus-related disability (1.8 vs 2.4 final MPI Tinnitus Interference), and tinnitus loudness (13.6 vs 20.0 dB final loudness match [in worst ear at tinnitus frequency]). When major depression and depressive symptoms groups were considered separately, nortriptyline was superior to placebo on these same measures but differences did not achieve statistical significance. CONCLUSIONS: The antidepressant nortriptyline decreases depression, functional disability, and tinnitus loudness associated with severe chronic tinnitus. What appears to be irreversible disability of otologic origin may, in part, be reversible disability of psychiatric origin.

Aged↗

[Insufficient effect of nortriptyline in a rapid metabolizer of sparteine].

A 61-year old woman suffering from depression was treated with 150 mg nortriptyline daily for eight weeks by her general practitioner. In spite of this dose, her S-nortriptyline was only 100 nmol/1 (recommended range: 225-600 nmol/1), and she remained depressed and was admitted to hospital. A sparteine test gave a metabolic ratio of 0.06, hence the patient was classified as a very rapid extensive metabolizer. Her nortriptyline dose was increased to 250 mg/day and the S-nortriptyline rose to 528 nmol/l. After eight weeks of sufficient nortriptyline treatment, the patient was still depressed. The patient recovered completely after a series of five electroconvulsive treatments.

Female↗

First-pass metabolism of nortriptyline in man.

The kinetics of nortriptyline were studied after oral and intravenous (iv) administration of test doses of 50 mg 14C-nortriptyline. The systemic availability of orally administered nortriptyline varied from 0.46 to 0.59 in 6 subjects. The decrease in availability was due to metabolism after administration. Systemic clearance varied from 0.31 to 0.66 L/min. From these measurements indirect estimates of the hepatic blood flow could be made, and a variation from 0.6 to 1.5 L/min was found. Quantitative measurements of first-pass metabolism could also be obtained from urinary metabolite excretion data when the kinetics of metabolite formation and elimination were taken into account. From the second or third day after the test dose, the urinary excretion rate of total radioactivity declined monoexponentially with half-lives closely corresponding to the plasma half-lives of unchanged nortriptyline. Analysis of the data from the iv test according to a 2-compartment open model showed that there was a close correlation between the rate constant of distribution from central to peripheral compartment (k12) and the elimination rate constant in the central compartment (kel). Still, there was some variation in the kel/k12-ratio, and this variation corresponded to the variation of the estimated hepatic blood flow.

Administration, Oral↗

Cardiovascular effect of imipramine and nortriptyline in elderly patients.

Cardiovascular effects in elderly depressed patients (age 62-78 years) treated with imipramine (N = 11) or nortriptyline (N = 10) were recorded by monitoring of heart rate, blood pressure, systolic time intervals, standard ECG and 24-h ECG. The two drugs exhibited distinctly different cardiovascular reactions. The use of imipramine was severely limited by orthostatic hypotension occurring at subtherapeutic plasma levels, which resulted in falls with fracture in two patients. In contrast, nortriptyline at therapeutic drug levels did not significantly influence orthostatic blood pressure regulation. Nortriptyline caused moderate changes in systolic time intervals, indicating impairment in myocardial contractility. This effect was not seen with imipramine, but a majority of the patients did not reach therapeutic plasma levels because of blood pressure reactions. Neither imipramine nor nortriptyline induced changes in cardiac conduction time measurements or arrhythmias. In addition to the blood pressure reactions, the use of imipramine was complicated by dose dependent kinetics.

Aged↗

A simplified radioimmunoassay of plasma nortriptyline in depressed patients compared with high-pressure liquid chromatography and gas-liquid chromatography.

Antiserum to nortriptyline was generated in male New Zealand rabbits innoculated with n-succinylnortriptyline-bovine serum albumin conjugates. The antiserum was used at a final dilution of 1:4000 and tritiated imipramine was used as the label antigen. An accurate, sensitive, and specific radioimmunoassay of depressed patients' plasma or serum nortriptyline is described. The accuracy was good with a recovery range of 90-100% with a mean of 94%. The method can be used to measure nortriptyline concentration in the range of 0.1 microgram/liter to 100 micrograms/liter without prior extraction and purification of plasma or serum. Results of this method correlate well with those obtained by high-pressure liquid chromatography (r = 0.979) and by gas-liquid chromatography (r = 0.98). The specificity of the antiserum was examined by studying the cross-reactivity of 20 different psychopharmacological compounds, including nortriptyline's metabolites.

Antidepressive Agents↗

Effects of amitriptyline and nortriptyline on cerebral activity of the CDF-1 mouse strain.

1. Equal dose regimens of amitriptyline, a tertiary amine tricyclic antidepressant, were more potent than nortriptyline, a secondary amine derivative, in suppressing CDF-1 mouse locomotor activity. 2. A suggestive increase in dopamine turnover rate in mouse cerebral cortex and striatal brain regions was apparent by amitriptyline but not nortriptyline. 3. A suggestive increase in serotonin turnover in mouse cerebellum and striatum was determined for nortriptyline. 4. Both antidepressants increased cerebral cortex, midbrain and cerebellum serotonin levels from saline control. 5. Increases of regional brain dopamine by amitriptyline and serotonin by nortriptyline concurrent with reuptake blockade of the respective serotonin and dopamine may contribute to their differential extrapyramidal and sedating side effects.

Amitriptyline↗

Sensitive method for the quantitation of nortriptyline and 10-hydroxynortriptyline in human plasma by capillary gas chromatography with electron-capture detection.

A method for the determination of nortriptyline and 10-hydroxynortriptyline concentrations in human plasma by capillary gas chromatography with electron-capture detection is described. The procedure requires 1.0 ml of plasma and uses maprotiline as an internal standard. The compounds are extracted from alkalinized plasma with hexane-2-butanol (98:2) and back-extracted into hydrochloric acid. The acid solution is then made basic and the compounds are re-extracted into n-butyl chloride. The extract is evaporated to dryness, derivatized with heptafluorobutyric anhydride, and analyzed by gas chromatography on a fused-silica capillary column coated with phenylmethyl silicone. The calibration curves for nortriptyline and 10-hydroxynortriptyline are linear in the ranges 3-40 and 7-90 micrograms/l, respectively, with coefficients of variation for within-day and between-day precision of less than 12%. The quantitation limits for nortriptyline and 10-hydroxynortriptyline are 1 and 3 micrograms/l, respectively. This procedure was used to analyze more than 1400 samples following sub-therapeutic doses of nortriptyline in human subjects. The assay was sufficiently sensitive for use in pharmacokinetic analysis.

Chromatography, Gas↗

Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on long-term heart rate variability measures.

BACKGROUND: Studies have linked depression to sudden death and serious cardiovascular events in patients with preexisting cardiac illness. Recent studies have shown decreased vagal function in cardiac patients with depression and depressed patients without cardiac illness. METHODS: We compared 20-hour, sleeping, and awake heart period variability measures using spectral analysis, fractal dimension, and symbolic dynamics in two patient groups with major depression and ischemic heart disease (mean age 59-60 years) before and after 6 weeks of paroxetine or nortriptyline treatment. RESULTS: Spectral measures showed decreases in awake and sleeping total power (TP: 0.0-0.5 Hz), ultra low frequency power (ULF: 0-0.0033 Hz), very low frequency power (VLF: 0.0033-0.04 Hz), and low-frequency power (LF: 0.04-0.15 Hz) for nortriptyline condition and a decrease in high-frequency power (HF: 0.15-0.5 Hz) for the awake condition in patients who received nortriptyline. A measure of nonlinear complexity, WC-100, significantly increased after paroxetine during the awake condition. CONCLUSIONS: These findings suggest that nortriptyline has stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Paroxetine may have some cardio-protective effects, especially in cardiac patients.

Adrenergic Uptake Inhibitors↗

Nortriptyline treatment of post-stroke depression: a double-blind study.

The efficacy of nortriptyline in the treatment of post-stroke depression was assessed by a double-blind study in thirty-four patients. Half of the patients had major depression. There was a significantly greater improvement in depression in patients treated with nortriptyline than in a similar group of placebo-treated patients. Depression was measured by the Hamilton depression scale, Zung depression scale, present state examination, and an overall depression scale. Successfully treated patients had serum nortriptyline levels in the therapeutic range. Post-stroke depressions are common, severe, and longstanding, and the demonstrated efficacy of nortriptyline provides an important addition to the treatments available for stroke patients.

Brain↗

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures.

Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

Amitriptyline↗

A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression.

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood-brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (chi(2) = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01-1.86).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Concomitant intake of nortriptyline and carbamazepine.

A 73-year-old woman with bipolar manic-depressive illness was treated with nortriptyline, 75 mg/day, for more than 2 years. At this dose her mean (+/- SD) serum nortriptyline concentration (SNT) was 355 +/- 49 nM (n = 13). Nevertheless, the patient again was depressed and was admitted to initiate prophylactic treatment with carbamazepine. During concomitant intake of 500-600 mg/day carbamazepine, the SNT decreased to 140 and 134 nM and the depression persisted. The nortriptyline dose was therefore increased to 150 mg/day; the mean SNT rose to 402 +/- 69 nM (n = 4) and the depression disappeared. This case shows that carbamazepine induces nortriptyline metabolism.

Aged↗

Saliva secretion following long-term antidepressant treatment with nortriptyline controlled by plasma levels.

Eight patients undergoing antidepressant therapy with nortriptyline for 1--4 years were investigated. The period of the investigation was 7 weeks and included a 2-week placebo period, blind for the patients. Total saliva secretion measurement, the nortriptyline plasma level, and signs and symptoms of depression and side effects were obtained once a week during the study. The results of the investigation were: (1) long-term treatment with nortriptyline is followed by hyposecretion or xerostomia, (2) the reduction of the secretion is reversible, (3) re-establishment of treatment with dosage leading to the same serum level of nortriptyline is immediately followed by a drop in saliva secretion, and (4) the changes in salivary secretion are useful as an indicator of side effects. The practical importance of the investigation is discussed.

Aged↗

Saliva secretion following long-term antidepressant treatment with nortriptyline controlled by plasma levels.

Eight patients undergoing antidepressant therapy with nortriptyline for 1--4 years were investigated. The period of the investigation was 7 weeks and included a 2-week placebo period, blind for the patients. Total saliva secretion measurement, the nortriptyline plasma level, and signs and symptoms of depression and side effects were obtained once a week during the study. The results of the investigation were: (1) long-term treatment with nortriptyline is followed by hyposecretion or xerostomia, (2) the reduction of the secretion is reversible, (3) re-establishment of treatment with dosage leading to the same serum level of nortriptyline is immediately followed by a drop in saliva secretion, and (4) the changes in salivary secretion are useful as an indicator of side effects. The practical importance of the investigation is discussed.

Aged↗

Regioselectivity and substrate concentration-dependency of involvement of the CYP2D subfamily in oxidative metabolism of amitriptyline and nortriptyline in rat liver microsomes.

Kinetic analysis of the metabolism of amitriptyline and nortriptyline using liver microsomes from Wister rats showed that more than one enzyme was involved in each reaction except for monophasic amitriptyline N-demethylation. The Vmax values particularly in the high-affinity sites for E-10-hydroxylation of both drugs were larger than those for Z-10-hydroxylations. Their E- and E-10-hydroxylase activities in Dark-Agouti rats, which are deficient for CYP2D1, were significantly lower than those in Wistar rats at a lower substrate concentration (5 microM). The strain difference was reduced at a higher substrate concentration (500 microM). A similar but a smaller strain difference was also observed in nortriptyline N-demethylase activity, and a pronounced sex difference (male > female) was observed in N-demethylation of both drugs in Wistar and Dark-Agouti rats. The reactions with the strain difference were inhibited concentration-dependently by sparteine, a substrate of the CYP2D subfamily, and an antibody against a CYP2D isoenzyme. The profiles of these decreased metabolic activities corresponded to that of the lower metabolic activities in Dark-Agouti rats. These results indicated that a cytochrome P450 isozyme in the CYP2D subfamily was involved in E- and Z-10-hydroxylations of amitriptyline and nortriptyline in rat liver microsomes as a major isozyme in a low substrate concentration range. It seems likely that the CYP2D enzyme contributes to nortriptyline N-demethylation.

Amitriptyline↗

Correlation of subjective side effects with plasma concentrations of nortriptyline.

Plasma levels of tricyclic antidepressant drugs vary considerably between individuals receiving the same amount of drug. The bearing of this variation on the occurrence of subjective side effects was investigated in 40 psychiatric inpatients with depressive disorders. Plasma levels were determined before and during four weeks of treatment with nortriptyline 50 mg. three times a day and patients were rated for subjective side effects, the assessors being unaware of the plasma levels of the drug.Plasma levels varied widely between individual patients, but in any given patient the plasma level tended to be constant over a period of time. The side effects of nortriptyline diminished significantly with time and were in most cases absent during the fourth week of treatment. There was a significant positive correlation between plasma level of nortriptyline and subjective side effects.The steady-state plasma level of a drug which is metabolized is usually a more important determinant for its effect than dosage, since it reflects the amount of drug available for biological action. Very high plasma levels of nortriptyline should presumably be avoided, since there is no evidence that they are needed for therapeutic effect and they are potentially harmful.

Adult↗

Plasma prolactin during treatment with nortriptyline.

The plasma concentrations of prolactin and nortriptyline were determined in 17 patients with endogenous depression treated for 4 weeks with nortriptyline once a day. None of the patients developed galactorrhoea. A moderate but statistically significant increase (about 25%) in the plasma prolactin was found after 3 weeks of treatment. There was no correlation between the plasma levels of prolactin and of nortriptyline. The results indicate that nortriptyline does not belong to the group of psychotropics which produce considerable increases in the plasma concentration of prolactin.

Adult↗