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PubMed1990

An automated method for the determination of nortriptyline and its isomeric 10-hydroxylated metabolites in plasma by high pressure liquid chromatography.

A high pressure liquid chromatography assay for determination of the tricyclic antidepressant nortriptyline (NT) and its two major metabolites, Z- and E-10-Hydroxy-NT, in plasma is described. Sample preparation included addition of internal standard and a single step extraction procedure. Run time was approximately 14 min. with a LC-18. 5 mu 250 x 4.6 mm column, a mobile phase consisting of aqueous ammonium: methanol: acetonitrile (0.8:6.2:93, v/v), and flow of 1.3 ml/min. NT, Z- and E-10-OH-NT, amitriptyline, Z- and E-10-OH-AT and the internal standard desipramine, were adequately separated within this time span. In our laboratory, the assay has been employed mainly for pharmacokinetic and toxicologic studies in experimental animals at relatively high concentrations.

Animals↗
PubMed1986

Amitriptyline and nortriptyline plasma levels, urinary 3-methoxy-4-hydroxyphenylglycol and clinical response in depressed women.

Thirty-eight depressed female inpatients, treated intramuscularly with 100 mg/day amitriptyline (AMT), were monitored to investigate the relationships between plasma levels of the drug and its metabolite nortriptyline (NT), the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), side effects and clinical response. Considering the whole group, the clinical improvement was better within an intermediate range of AMT plus NT plasma concentrations (100-200 ng/ml). A more favorable outcome was also observed at NT plasma levels below 55 ng/ml. No significantly different percent clinical response among the patient clinical subgroups was observed as well as no significant correlations between MHPG decrease and drug plasma levels.

Adult↗
PubMed1978

Prediction of individual dosage of nortriptyline.

The authors describe a technique that enables a physician to determine individual patient dosage requirements for nortriptyline from a single 24-hour blood sample. Because the technique reveals immediately those patients at the extremes of dosage ranges, toxicity and the need for time-consuming titration of the dosage regimen can be avoided.

Adult↗
PubMed1987

Prediction of response to nortriptyline and phenelzine by platelet MAO activity.

Thirty-seven depressed patients over the age of 55 were treated for 5-7 weeks with either nortriptyline, a tricyclic antidepressant, or phenelzine, a monoamine oxidase (MAO) inhibitor. Patients' platelet MAO activity was measured following a drug washout period before treatment. Patients with higher MAO activity had a better response to treatment, regardless of which drug was used.

Aged↗
PubMed1993

Treatment of nortriptyline's side effects in elderly patients: a double-blind study of bethanechol.

A double-blind, placebo-controlled study of bethanechol was conducted in 26 elderly depressed patients being treated with nortriptyline. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed a trend toward improvement on an objective measure of salivary flow. The potential use of bethanechol in older patients to reduce morbidity and improve compliance with medication regimens is discussed.

Aged↗
PubMed2004

Extended nortriptyline and psychological treatment for cigarette smoking.

OBJECTIVE: Accepted treatments for cigarette smoking rarely achieve abstinence rates of >35% at 1 year. Low rates may reflect failure to provide extended and multifocal treatment for this complex and chronic addiction. Using a chronic disease model of smoking, the authors undertook a study to determine the effects of long-term antidepressant and psychological treatment. METHOD: One hundred sixty smokers of > or =10 cigarettes/day were randomly assigned to one of four treatment conditions in a two-by-two (nortriptyline versus placebo by brief versus extended treatment) design. All subjects received 8 weeks of a transdermal nicotine patch, five group counseling sessions, and active or placebo treatment. Interventions for subjects in brief treatment ended at this point. Subjects in extended treatment continued taking drug or placebo to week 52 and received an additional 9 monthly counseling sessions, with checkup telephone calls midway through each session. Subjects were assessed at baseline and weeks 12, 24, 36, and 52. The principal outcome variables were repeated abstinence at each assessment after the first over a 1-year period and a point prevalence of 7 days of abstinence. RESULTS: At week 52, point-prevalence abstinence rates with missing subjects imputed as smokers were 30% for placebo brief treatment, 42% for placebo extended treatment, 18% for active brief treatment, and 50% for active extended treatment. With missing subjects omitted, these rates were 32%, 57%, 21%, and 56%, respectively. CONCLUSIONS: Comprehensive extended treatments that combine drug and psychological interventions can produce consistent abstinence rates that are substantially higher than those in the literature.

Administration, Cutaneous↗
PubMedDate not supplied

Nortriptyline absorption in short bowel syndrome.

Severe short bowel syndrome usually requires a period of parenteral nutrition support until gastrointestinal hypertrophy occurs. Because of the shortened length of the gastrointestinal tract, oral drug therapy can be compromised secondary to decreased absorption. In the case presented, a patient with short bowel syndrome who required parenteral nutrition was able to achieve therapeutic nortriptyline serum concentrations while receiving the drug via the oral route.

Administration, Oral↗
PubMed1977

Once-daily treatment for mixed anxiety/depressive states: a comparison of slow release amitriptyline and fluphenazine with nortriptyline.

Patients suffering from mixed anxiety/depressive states referred to a psychiatric out-patient clinic completed a four course of either a once-daily table of 30 mg nortriptyline with 1-5 mag fluphenazine, or a sustained release capsule of 50 mg amitriptyline once daily, on a double-blind basis. Depression improved satisfactorily on either treatment, but there was a greater reduction of anxiety on fluphenazine/nortriptyline, Drowsiness, however, occurred more frequently among the patients on amitriptyline, suggesting the sedative properties of this drug did not substitute adequately for a specific anxiolytic effect. Dry mouth was also noticeably more frequent with amitriptyline. As might be expected on pharmacokinetic and phsyological grounds, the results suggest that the sustained release characteristics of the amitriptyline preparation lead to a maximization of side-effects during the day without conferring any therapeutic advantage.

Adolescent↗
PubMed1998

Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial.

UNLABELLED: OBJECTIVE (BACKGROUND): Amitriptyline (AT) is a standard therapy for postherpetic neuralgia (PHN). Our hypothesis was that nortriptyline (NT), a noradrenergic metabolite of AT, may be more effective. METHODS: A randomized, double-blind, crossover trial of AT versus NT was conducted in 33 patients. RESULTS: Thirty-one patients completed the trial. Twenty-one of 31 (67.7%) had at least a good response to AT or NT, or both. We found no difference with regard to relief of steady, brief, or skin pain by visual analog scales for pain and pain relief; mood; disability; satisfaction; or preference between the two drugs. Intolerable side effects were more common with AT. Most patients (26/33) were not depressed, and most responding showed no change in rating scales for depression despite the occurrence of pain relief. CONCLUSIONS: We concluded that this study provides a scientific basis for an analgesic action of NT in PHN because pain relief occurred without an antidepressant effect, and that although there were fewer side effects with NT, AT and NT appear to have a similar analgesic action for most individuals.

Aged↗
PubMed2004

Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.

BACKGROUND: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. METHODS: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). RESULTS: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). CONCLUSIONS: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

Adult↗
PubMed2006

The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites.

The impact of P-glycoprotein (P-gp) on the distribution of nortriptyline (NT) and its metabolites between brain, liver and serum was studied experimentally. The interaction of NT with P-gp in vitro was confirmed by measurement of P-gp stimulated ATPase activity (Km = 257.6 microM, Vmax = 51.0 nmol phosphate released/mg protein-min). Administration of NT (5 mg/kg, s.c.) to mdrla knockout mice resulted in enhanced brain-serum (1.6-fold, p = 0.012) and liver-serum (1.4-fold, p = 0.019) ratios, as compared to the wild-type mice. For a series of NT doses (2.5, 5, 10, 25, 30 mg/kg, i.p.) inhibition of P-gp with cyclosporine A (CsA, 200 mg/kg, i.p.) in rats led to NT brain- and liver-serum ratios that were on average 1.3- (p = 0.005) and 2.1- (p = 0.001) fold higher than those of the controls, respectively. Verapamil (50 mg/kg) (NT, 5 mg/kg) increased the ratios by a factor of 1.6 (p <0.001) and 10.3 (p <0.001) for brain and liver, respectively. Finally, co-administration of methadone (1 mg/kg) did not alter the brain-serum ratio of NT, but in the liver a slight increase (1.5-fold, p = 0.035) was observed. In conclusion, verapamil yielded complete inhibition of P-gp at the blood-brain barrier and CsA had an effect corresponding to about 50% inhibition. The results show that P-gp influences the penetration of NT into the brain, and that drug-drug interactions may take place.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Nortriptyline plasma levels and clinical response in patients with familial pure unipolar depression and blunted TRH tests.

We studied the efficacy of nortriptyline (NT) when given in doses which produce tricyclic antidepressant (TCA) levels within the proposed therapeutic "window" in a select patient group to assess the "window" hypothesis in a group of patients that was biologically homogeneous with respect to the TRH test and clinically homogeneous with respect to RDC, DSM III, and Winokur criteria. Pharmacokinetic and dose differences were controlled for by administering a NT dose-prediction test, giving the indicated dose, allowing levels to reach steady state and changing the dose, if necessary, to maintain NT levels within the range of 90-130 ng/ml. Using this protocol nine of ten patients responded to NT. This rate of response for a severely depressed patient group is comparable to response data for ECT and recent European data using regular NT levels to change doses of NT and assess appropriate NT trial duration.

Adult↗
PubMed1991

An open trial of nortriptyline in women with chronic pelvic pain.

Although antidepressants have been used in the management of several types of chronic pain there have been no systematic trials of these medications in women with chronic pelvic pain. The authors report on the use of nortriptyline in fourteen women with chronic pelvic pain. Seven women dropped out of the study. These seven subjects were significantly different from the treated group only in lower tolerance of antidepressant side effects. Six of the seven treated subjects reported complete or partial relief from pain. Fifty seven percent of the drop-outs and the one nonresponding treated subject had histories of childhood sexual abuse. This open trial suggests that antidepressants may be effective in the treatment of some women with chronic pelvic pain. However, the frequent association of sexual abuse with this disorder indicates that accepted treatment trial designs may need to be altered.

Abdominal Pain↗
PubMed1985

Effect of hemorrhagic and nortriptyline-induced shock on the porcine pancreas as evaluated by changes in serum cationic trypsin-like immunoreactivity.

Hemorrhagic shock caused by gastrointestinal bleeding in seven pigs and by external bleeding in another six pigs and cardiogenic shock induced by intravenous infusion of the tricyclic antidepressant drug nortriptyline in yet another eight pigs caused a significant increase in serum cationic trypsin-like immunoreactivity together with formation of complexes between cationic trypsin, on the one hand, and alpha-2-macroglobulin and alpha-1-antitrypsin, on the other hand, compatible with what happens in acute pancreatitis.

Animals↗
PubMed1992

Stereoselective inhibition of nortriptyline hydroxylation in man by quinidine.

1. Four volunteers phenotyped as extensive metabolizers of sparteine took 25 mg nortriptyline hydrochloride and collected urine for 72-80 h. Total free and conjugated 10-hydroxynortriptyline (10-OH-NT) accounted for 54-58% of the dose and it was reduced to 25-40% when 50 mg quinidine sulphate was ingested on the first and second day. 2. Of the four isomers of 10-OH-NT, (-)-E-10-OH-NT was selectively decreased in quantity by quinidine coadministration, while the (+)-isomer and (-)- and (+)-Z-10-OH-NT were found in unchanged or slightly increased quantities. The contribution of (-)-E-10-OH-NT to total E-10-OH-NT and the E-/Z-ratio in total 10-OH-NT were significantly reduced. 3. The quantity of the phenol, 2-hydroxynortriptyline in urine was decreased by quinidine; the relative amounts of metabolites with a primary amino group were not affected. 4. Liver microsomes from a donor in which cytochrome P450IID6 was shown to be present by in vitro phenotyping metabolized NT to E-10-OH-NT containing 86% of the (-)-isomer. Quinidine reduced the hydroxylation rate in (-)-E-10-position much more than that in (+)-E-10-position. 5. Since quinidine selectively impairs the function of cytochrome P450IID6, it is concluded that this isoform catalyses NT hydroxylation predominantly in (-)-E-10- and in 2-position.

Adult↗
PubMed1995

Stereoselective reversible ketone formation from 10-hydroxylated nortriptyline metabolites in human liver.

1. E- and Z-10-hydroxynortriptyline are major metabolites of amitriptyline and nortriptyline in man. Upon incubation with human liver microsomes or cytosol, these metabolites were oxidized to the corresponding ketones, E- and Z-10-oxonortriptyline. (+)-E- and (+)-Z-10-hydroxynortriptyline were distinctly preferred over the (-)-isomers as substrates. NADP+ supported the oxidation in cytosol, whereas in microsomes NAD+ was the best cofactor. 2. Incubation of E- and Z-10-oxonortriptyline with NADPH and cytosol resulted in the nearly exclusive formation of (+)-E- and (+)-Z-10-hydroxynortriptyline. Kinetic analysis revealed high-affinity reduction (K(m) 1-2 microM) of the two ketones and an additional low-affinity component with the E-isomer. 10-Oxonortriptyline reduction was also catalysed by rabbit, but not by rat or guinea pig liver cytosol. 3. With [4-3H]NADPH as cosubstrate, tritium was incorporated into E- and Z-10-hydroxynortriptyline preferentially from the pro-4R position. Redox cycling of (+)-E- and (+)-Z-10-hydroxynortriptyline in cytosol in the presence of NAD- and NADPH was indicated by 3H incorporation from [pro-4R-3H]NADPH. 4. Recombinant human carbonyl reductase catalysed low-affinity reduction of E-10-oxonortriptyline with preferential transfer of the pro-4S-3H of labelled NADPH. 5. Ketone reduction in cytosol was strongly inhibited by 9,10-phenanthrenequinone and dehydrolithocholic acid and moderately by other 3-oxo steroids and some anti-inflammatory drugs. 6. The high-affinity reduction of E- and Z-10-oxonortriptyline and the oxidation of the alcohols in cytosol are probably mediated by a member of the aldo-keto reductase family of enzymes.

Adult↗