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At least 1,171 records · Page 65Linked to original sources
PubMed1991

A comparison of three computer models for prediction of dose in acute amitriptyline overdose.

The pharmacokinetics of amitriptyline in overdose have been reported not to fit conventional compartmental models. In this study, the dose-concentration-time relationships of amitriptyline in overdose were modeled with discriminant analysis, with an evolutionary heuristic search program, and with a decision-tree model based on the entropy of uncertainty of classification. The computer models all used the same data from dogs administered treatment (80 mg/kg), toxic (250 mg/kg), or fatal (500 mg/kg) doses directly into the surgically isolated duodenum. All the models achieved a high degree of success (77 to 93%) in assigning records to the high-, low-, or middle-dose groups. Two of the models gave a probability of the assignment. Results of this analysis suggest that blood amitriptyline and nortriptyline concentrations are most useful in estimating dose in acute amitriptyline overdose.

Amitriptyline↗
PubMed1990

Serotonergic and catecholaminergic reuptake inhibitors have opposite effects on the ultrasonic isolation calls of rat pups.

Rat pups emit a highly stereotyped and well-characterized distress call in the ultrasonic range when socially isolated. We compared the modulatory influence of catecholamines and indoleamines on rat pup ultrasonic calls using pharmacologic probes. Administration of low doses of monoamine reuptake inhibitors produced significant, selective changes in the calls emitted by isolated 10-day-old pups. Acute administration of clomipramine (CMI; relatively 5-HT specific) reduced the rate of calling at low doses (1.0 and 5.0 mg/kg [3.2 and 18.0 mmol/kg] SC) but had reduced efficacy at higher doses (10 and 20 mg/kg [32.0 and 63.7 mmol/kg] SC). Motor activity and rectal body temperature were unaffected at these doses. Similarly, low doses of other 5-HT-selective uptake inhibitors, such as paroxetine (1.0 mg/kg [3.1 mmol/kg] SC) and citalopram (1.0 mg/kg [3.09 mmol/kg] SC), virtually eliminated isolation calling. The effects of CMI were not antagonized by either naltrexone (0.1 mg/kg [0.28 mmol/kg] SC) or Ro 15-1788 (5.0 mg/kg [16.5 mmol/kg] SC). Desipramine (DMI; norepinephrine [NE] specific) significantly increased calling rates at all doses tested (1.0 to 10.0 mg/kg [3.8 to 75 mmol/kg] SC). These effects were associated with significant reductions in body temperature, but not motor activity. Similar increases in the rate of isolation calling, reduction in rectal body temperature, and an increase in motor activity were produced by low doses of mazindol (0.5 mg/kg [1.75 mmol/kg] SC) and nortriptyline (1.0 mg/kg [19 mmol/kg] SC). In an additional study, the chronic effects of CMI and desipramine were evaluated with treatment beginning within 24 hours after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacologic treatment of major depression for elderly patients in residential care settings.

A significant drug-placebo difference was found in a double-blind, placebo-controlled study of nortriptyline for treatment of major depression among frail elderly patients living in an institutional setting. This finding confirms the validity of the DSM-III-R diagnosis of major depression and establishes the need for specific psychiatric services for the chronically ill elderly living in nursing homes and congregate housing facilities. The incidence of adverse events requiring early termination of treatment was 34%, demonstrating the vulnerability of these patients and their need for careful monitoring during treatment. High levels of self-care disability and low levels of serum albumin were both associated with decreased therapeutic responses, demonstrating the need for further research on psychopathology in these settings.

Age Factors↗
PubMed1975

Inhibition of phenytoin metabolism by other drugs used in epilepsy.

Phenytoin metabolism is saturable within its normal therapeutic range and, therefore, small changes in the activity of the enzyme can lead to marked changes in serum phenytoin concentrations. The anticonvulsant drugs sulthiame and pheneturide both inhibit the metabolism of phenytoin. The mechanism of this interaction appears to be different for these two drugs. Nortriptyline produces a small increase in serum phenytoin concentrations, but this is unlikely to be of clinical importance. Case reports suggest that both chlorpromazine and chloramphenicol inhibit phenytoin metabolism to a significant degree.

Adult↗
PubMed1985

Structural analysis of the epitope recognized by a monoclonal antibody directed against tricyclic antidepressants.

After somatic cell fusion between splenocytes of immunized BALB/c mice and NS-1 myeloma cells, a clone was obtained that secreted an anti-nortriptyline antibody of the IgG1 kappa isotype. The association constant of this antibody for pharmacologically active tricyclic antidepressant drugs ranged from 0.6 X 10(7) to 3 X 10(7) M-1. From thermodynamic and binding studies as well as tridimensional structures of tested compounds, the epitope recognized by the monoclonal antibody appeared to include both a hydrophobic tricycle in which the two phenyl rings form an angle of 120 to 130 degrees, and a side chain in which the amino group is separated from the two lateral rings of the tricyclic structure by a distance of approximately 5.9 A and 7.5 A, respectively. This conformation seems to be the one interacting with muscarinic acetylcholine brain receptors.

Amino Acid Sequence↗
PubMed1989

Tricyclic antidepressants for medically ill geriatric patients.

The author reviews available data on tricyclic antidepressant (TCA) use in medically ill geriatric patients and data from controlled trials performed with physically healthy but depressed geriatric patients. Although these data point to the conclusion that medical illness appears to limit the use of TCAs in elderly patients, such agents as nortriptyline, desipramine, and doxepin can be used effectively. Guidelines are suggested to assist the clinician when confronted with this often complex and challenging patient population.

Aged↗
PubMed1987

Inhibition of 22Na influx by tricyclic and tetracyclic antidepressants and binding of [3H]imipramine in bovine adrenal medullary cells.

In bovine adrenal medullary cells we investigated the effects of antidepressants on ionic channels and secretion of catecholamines. Tricyclic (imipramine, amitriptyline and nortriptyline) and tetracyclic (maprotiline and mianserin) antidepressants inhibited carbachol-induced influx of 22Na, 45Ca and secretion of catecholamines (IC50, 14-96 microM). Influx of 22Na, 45Ca and secretion of catecholamines due to veratridine also were inhibited by these drugs (IC50, 10-17 microM). However, antidepressants did not suppress high concentration of K-induced 45Ca influx and catecholamine secretion, suggesting that antidepressants do not inhibit voltage-dependent Ca channels. [3H]Imipramine bound specifically to adrenal medullary cells. Binding was saturable, reversible and with two different equilibrium dissociation constants (13.3 and 165.0 microM). Tricyclic and tetracyclic antidepressants competed for the specific binding of [3H]imipramine at the same concentrations as they inhibited 22Na influx caused by carbachol or veratridine. Carbachol, d-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom did not inhibit the specific binding of [3H]imipramine. These results suggest that tricyclic and tetracyclic antidepressants bind to two populations of binding sites which are functionally associated with nicotinic receptor-associated ionic channels and with voltage-dependent Na channels, and inhibit Na influx. Inhibition of Na influx leads to the reduction of Ca influx and catecholamine secretion caused by carbachol or veratridine.

Adrenal Medulla↗
PubMed1989

Automated determination of drugs in serum by column-switching high-performance liquid chromatography. IV. Separation of tricyclic and tetracyclic antidepressants and their metabolites.

We describe automated column-switching high-performance liquid chromatography for determining nine tricyclic and tetracyclic antidepressants (TCAs) and their metabolites in human serum. TSKgel ODS-80TM and TSKprecolumn PW (Tosoh Co., Tokyo) are used in the analytical column and the precolumn, respectively. A 200-microL serum sample is directly injected onto the precolumn. After washing the serum proteins from the precolumn with potassium phosphate buffer, the precolumn connection is switched to introduce the retained substances onto the analytical column. The drugs are then eluted within 30 min with an acetonitrile/potassium phosphate buffer mixture containing sodium 1-heptanesulfonate. The analytical recoveries (95-104%), reproducibilities (within-run CV less than 3%), and detection limits (10 micrograms/L) indicate that this HPLC system is suited for therapeutic drug monitoring. Correlations were good between the TCA concentrations in serum and administered dose (r = 0.713, n = 41), and between 10-hydroxynortriptyline and nortriptyline in serum (r = 0.691, n = 24).

Amitriptyline↗
PubMed1988

Results compared for tricyclic antidepressants as assayed by liquid chromatography and enzyme immunoassay.

The tricyclic antidepressants amitriptyline, nortriptyline, imipramine, and desipramine in serum of patients taking one of the drugs were quantified in two laboratories by high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay (EMIT; Syva). Results for split samples were highly correlated, but EMIT gave higher results in most cases, and the slopes of the correlation lines for each analyte were greater than 1. Detection limits for the two procedures were such that 18% of the EMIT results for the drug(s) were considered negative, as compared with 4% of the HPLC results. Additional assay of desmethyl or hydroxy antidepressant metabolites by HPLC did not explain the higher EMIT results. The relatively high detection limit for EMIT greatly limits its use in therapeutic drug monitoring, where low concentrations of tricyclic antidepressants are as important as high ones for dose adjustment or determination of compliance. Other problems with EMIT measurement of tricyclic antidepressants are discussed.

Amitriptyline↗
PubMed1988

High levels of tricyclic antidepressants in conventional therapy: determinant factors.

The incidence of potentially toxic serum levels (greater than or equal to 400 ng/ml) was analyzed in a group of 196 monitored patients on a standard dosage regimen (75-225 mg/day) of several antidepressants: imipramine, amitriptyline, nortriptyline, maprotiline and clomipramine. Mean incidence was 12%. The maximum antidepressants serum levels in these patients ranged from 403 to 1,776 ng/ml. The drug/metabolite ratio was 1.5 +/- 0.7. Only in 23% of the cases did the clinical symptoms allow us to suspect the presence of potentially toxic serum levels. The factors that may contribute to the appearance of high serum levels were analyzed; these are: association of neuroleptic agents to the antidepressant therapy, advanced age and administration of doses above 2.5 mg/kg/day. In 64% of the patients, the clinical criteria suggested the need for a reduction in the dose, with a mean value of 42%.

Adult↗
PubMed1986

Treating delusional depressives with amitriptyline.

Thirty-five delusional depressed patients were treated for either 28 or 35 days with amitriptyline. The 12 responders could not be differentiated from the nonresponders on a variety of demographic and clinical characteristics. Patients with amitriptyline+nortriptyline plasma levels above 250 ng/ml were significantly more likely to be responders than were patients with levels below that value (p less than .05). A review of the relevant literature revealed that, although some delusional depressives do respond to treatment with tricyclic antidepressants, the presence of delusions is a predictor of poor response to tricyclic antidepressants.

Adult↗
PubMed1986

Slow hydroxylation of tricyclic antidepressants--relationship to polymorphic drug oxidation.

There are marked interindividual differences in Css of tricyclic antidepressants. These are due mainly to corresponding differences in the rate of oxidative metabolism of these drugs. Twin, family, and cross-over studies with nortriptyline (NT) and desmethylimipramine (DMI) show that their kinetics and hydroxylation (Css, Kel, and Vd) are controlled mainly by genetic factors (in drug-free individuals). Slow hydroxylators are at risk of developing excessive plasma concentrations of NT and DMI when given per se or when formed from the tertiary amines amitriptyline and imipramine. Classic antidepressants have fairly well established concentration-effect curves in endogenous depression. Severe toxicity usually occurs at supratherapeutic plasma levels and might be prevented by tailoring the dosage according to the individual's drug hydroxylating capacity. Monitoring drug plasma levels is particularly relevant in slow hydroxylators (Sjöqvist et al, 1980). There is a strong association between an individual's ability to hydroxylate NT and DMI and his debrisoquine (D) hydroxylation phenotype. The D hydroxylation index will predict the patient's capacity to hydroxylate NT and DMI and hence Css during therapy. Possibly, similar hydroxylases are involved in the 4-hydroxylation of debrisoquine, in the stereospecific E-10-hydroxylation of NT, and in the 2-hydroxylation of DMI. By contrast, demethylation of AT (and probably other tertiary tricyclics) does not significantly correlate to debrisoquine hydroxylation except in non-smoking individuals. The increasing knowledge about the clinical pharmacokinetics of tricyclic antidepressants is a distinct advantage over that of the new generation of antidepressants, where little is known about concentration-effect relationships and factors governing their rate of metabolism. Possible interethnic differences in the metabolism of these essential drugs should be explored in epidemiologically sound investigations.

Amitriptyline↗
PubMed1987

Antiemetic combination for PAC (cisplatin-adriamycin-cyclophosphamide) chemotherapy-induced emesis in ovarian cancer.

Twenty-six patients suffering from disseminated epithelial ovarian cancer (FIGO stages III and IV) under treatment with Cisplatin (80-100 mg/m2 in 8 hours) in combination on the same day with Cyclophosphamide (500 mg/m2 IV) and Adriamycin (50 mg/m2), a severely emetogenic regimen, entered a randomized, double-blind, cross-over trial comparing the antiemetic activity of high-dose IV Metoclopramide (1 mg/kg/dose X 5 doses) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (50 mg PO X 2 doses) plus Thiethylperazine (10 mg IV X 3 doses). The antiemetic combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at the central emetic pathways (dopamine D-2, histamine H-1 and muscarinic cholinergic). This combination significantly reduced the emesis due to chemotherapy when compared with Metoclopramide alone and was also preferred by a significant number of patients after passing through both the antiemetic arms being compared.

Adult↗
PubMed1986

Antiemetic combination for cisplatin-induced emesis. Results from a controlled study.

Thirty-six patients suffering from disseminated epithelial tumors under treatment with Cisplatin alone or in combination with Vindesine entered a randomized, double-blind, cross-over study comparing the antiemetic activity of low-dose IV Metoclopramide (total dose: 0.8 mg/kg) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (2 X 50 mg PO) plus Thiethylperazine (3 X 10 mg IV). This combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at central emetic pathways (Dopamine D-2, Histamine H-1 and muscarinic cholinergic). The antiemetic combination significantly reduces the median number of emetic episodes (p less than 0.01), the median volume of vomiting (p less than 0.01) and the median time of emesis (p less than 0.01) when compared with Metoclopramide alone and was also preferred by a significant number of patients (p = 0.0001) after passing through both antiemetic treatment arms being compared.

Adult↗
PubMed1986

The pharmacological treatment of delusional depression: Part II.

This study investigated the pharmacological treatment of delusional depressives by assigning patients on a random double-blind basis to amitriptyline (AT) alone, perphenazine (PER) alone, or AT + PER. As reported in an earlier paper, the combination of AT + PER was the superior treatment with a response rate of 78% compared with 41% for AT alone and 19% for PER alone. This difference is both clinically and statistically significant (p less than 0.01). In this second article, the authors report that the patients on AT + PER had higher plasma levels of AT and its pharmacologically active metabolite nortriptyline (NT) than the patients on AT alone. Although the response rate had a direct relationship to AT + NT plasma levels, an analysis of variance showed that the group of patients treated with AT + PER still had a significantly higher response rate, even after controlling for the plasma levels of AT + NT (p less than 0.05). There was also a correlation between PER plasma levels and clinical response.

Amitriptyline↗
PubMed1985

[The use of low-dose amitriptyline in psychogeriatrics. A clinical, pharmacokinetic and pharmacogenetic study].

Two groups of six depressive psychogeriatric patients (age 69-93) have been treated for three weeks with either 25 mg or 50 mg of amitriptyline (AT) per day. Before the beginning of the treatment and after 8, 15 and 22 days of medication, the patients (7 outpatients and 5 hospitalized patients) underwent various psychopathological tests (Hamilton, Crichton) and biochemical investigations, i.e. clinical chemistry and hematology, analyses of AT and nortriptyline (NT), in the plasma. In some subjects the hydroxylated metabolites and the binding of these substances to plasma proteins were also measured. Except one patient, all responded favourably to the treatment. No difference between the two doses has been observed as regards their clinical efficacy and incidence of side effects. The plasma levels of AT and NT were below those generally recommended in the literature. The monitoring served to identify some cases of noncompliance and, in one patient, a deficiency of hydroxylation of AT, confirmed by the debrisoquine test. These results suggest that the "therapeutic window" needs redefinition and that low-dose medication with antidepressants is indicated in a psychogeriatric population.

Aged↗
PubMed1985

Determination of compliance with riboflavin in an antidepressive therapy.

In a comprehensive study on the fate of amitriptyline (At, Laroxyl) in depressive patients, it was investigated whether their compliance could be controlled in analysing the concentration of riboflavin (vitamin B2) in urine. Therefore, they were medicated for 3 weeks with special tablets (Ro 4-1575/063) containing 150 mg At and 15 mg riboflavin. Different modalities or urine samplings were designed in order to establish the optimal conditions for testing compliance. Riboflavin, creatinine, At and nortriptyline were measured in urine, the tricyclic drugs also in plasma. The results show that compliance could be tested in analysing urine before and 4 h after the intake of the drug. However, this design was associated with a considerable subjective constraint for the patient.

Adult↗
PubMed1978

Liquid-chromatographic procedure for tricyclic drugs and their metabolites in plasma.

We describe a procedure for determining amitriptyline and imipramine and their active metabolites nortriptyline and desipramine, respectively, at therapeutic concentrations in human plasma by use of liquid chromatography. The drugs are extracted at pH 10.5 into hexane/isoamyl alcohol, which is evaporated and the residue chromatographed. Protriptyline is used as the internal standard. As little as 10 microgram of each drug per liter could be detected in plasma, the limit being established by variability in drug-free plasmas. The day-to-day coefficient of variation for each drug at a concentration of about 100 microgram/liter was about 7%. Doxepin and diphenhydramine interfere with the analysis of amitriptyline. Total analysis time for a single sample is 20 min.

Amitriptyline↗