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PubMed1988

Compliance during tricyclic antidepressant therapy: pharmacokinetic and analytical issues.

Information on steady-state concentrations of parent tricyclic antidepressants (TCAs) and their major metabolites in plasma is useful in ascertaining compliance, for possible pharmacokinetic changes during longer treatment, and for prospective individualized dosing procedures. Adequate response can be maintained when there are relatively small fluctuations in drug concentration from visit to visit, but large fluctuations increase the liklihood of relapses during the acute-treatment phase and recurrences afterwards. Changes in the individualized in dosage regimens complicate measurement of concentrations in plasma at steady state. Longitudinal examinations of concentration/dosage (L/D) values in our three-year imipramine (IMI) maintenance study reveal that patients having large intra-individual fluctuations can be classified as noncompliers, likely to have recurrences. The time course and magnitude of L/D values reflect higher accumulation of both components, IMI and desipramine (DMI), in plasma. Evidently, dose-dependent kinetics lead to higher steady-state concentrations in plasma than previously observed with similar dosages in shorter-term treatment. With amitriptyline (AMI), in a 12-month study, the mean total concentrations of both AMI and nortriptyline (NT) progressively increased, by 22% and 33%, respectively. The pharmacokinetic linearity of AMI and (or) NT, i.e., (L/D)high/(L/D)low, is maintained over much wider dosage and age range than with IMI or DMI. We advocate concurrent use of the L/D method and co-administration of riboflavin for identification of noncompliers. We describe our current experience with various analytical procedures in this regard, concluding that high-performance liquid-chromatographic methods, with appropriate selection among ultraviolet, enhanced fluorescence, and electrochemical detectors for each TCA under specified therapeutic conditions, are most suitable and versatile, having superior analytical parameters. A suitable alternative procedure is gas-chromatography (N/P mode). Although immunoassays (EMIT, radiochemical) are most convenient for toxicological screens, their significant cross reactivities with several phenothiazines and the detection limits, requiring higher concentrations for EMIT, restrict their usage during research and (or) clinical monitoring.

Amitriptyline↗

PubMed1987

A comparative double-blind controlled study of trimipramine and amitriptyline in major depression: lack of correlation with 5-hydroxytryptamine reuptake blockade.

Thirty-four hospitalized patients with major depression were enrolled in a 3-week double-blind parallel comparative study of trimipramine and amitriptyline. Following a 1-week washout period, patients randomly received one of the two drugs up to 100 mg twice daily on a fixed increment dosage schedule. Both treatments produced a rapid significant clinical improvement that occurred in a predominantly linear fashion. The pattern of improvement was very similar with both drugs. There was no significant correlation between plasma levels of trimipramine and desmethyl-trimipramine and clinical improvement. A negative correlation between amitriptyline plasma levels and clinical improvement was found, whereas a positive correlation occurred with the nortriptyline levels. Amitriptyline, and to a lesser extent trimipramine, prolonged intracardiac conduction. In the amitriptyline group only, this effect was accompanied by significant increases of heart rate and blood pressure. Platelet serotonin content was decreased by 57% by the amitriptyline treatment but remained unchanged in the trimipramine group. This finding constitutes the first clinical evidence that trimipramine does not exert its antidepressant effect through 5-hydroxytryptamine reuptake blockade. It is proposed that neuronal sensitization to 5-hydroxytryptamine might mediate the therapeutic effect of tricyclic antidepressant drugs.

Adult↗

PubMed1987

Reduced serum tricyclic levels due to gel separators.

Sixty-three blood samples were obtained from 48 subjects taking tricyclic antidepressants. Samples were simultaneously collected in Becton-Dickinson Vacutainer tubes for measurement of serum and plasma tricyclic antidepressant concentrations. Serum was drawn into red stopper tubes (without gel separator) and into speckled stopper serum separator tubes (with gel separator), while plasma was collected in green stopper tubes (heparinized). Imipramine, desipramine, amitriptyline, and nortriptyline concentrations were all significantly lower in serum separator samples than in either plasma or red stopper serum collection tubes. Serum and plasma concentrations were similar.

Antidepressive Agents, Tricyclic↗

PubMed1978

[Nomifensine: clinical data (author's transl)].

Open studies with nomifensine the placebo, and double-blind controlled comparisons of nomifensine with placebo, imipramine, amitriptyline, nortriptyline... have been carried out in various parts of the world. Daily dosage varied (50-225 mg), lenght of treatment also (226 weeks). These trials showed considerable effectiveness of nomifensine in neurotic and reactive depressions, it counteracts inhibition and restores drive. Nomifensine caused no significant cardiovascular or anticholinergic side-effects. It does not potentiate the effect of alcohol.

Adjustment Disorders↗

PubMed1987

Applications of column-switching technique in biopharmaceutical analysis. I. High-performance liquid chromatographic determination of amitriptyline and its metabolites in human plasma.

A new high-performance liquid chromatographic method for the determination of amitriptyline and its metabolites, nortriptyline, 10-hydroxynortriptyline and 10-hydroxyamitriptyline, in plasma is described which uses direct injection and a column-switching valve. The method is based on the enrichment of drugs on a reversed-phase concentration column, packed with Corasil RP. The enriched drugs were then separated, using back-flush mode on a bonded-phase CN column using an isocratic acetonitrile-acetate buffer (60:40, v/v) mobile phase. The validation of the method showed excellent sensitivity, precision and reproducibility. The limit of detection, using a 250-microliter direct injection of plasma, was between 5 and 10 ng/ml for each of the four drugs. The mean coefficient of variation for intra- and inter-assay was better than 5%. The method showed obvious advantages over conventional extraction procedures in terms of speed and ease of sample handling. The method has been successfully applied to the samples from patients receiving oral doses of amitriptyline.

Amitriptyline↗

PubMed1986

Metalloimmunoassay of tricyclic antidepressant drugs: production and characterization of antiserum.

Metalloimmunoassay is a new immunoassay using an organometallic complex as the label. For the development of this assay, antibodies were produced in rabbits immunized with N-succinyldesipramine-bovine serum albumin conjugate. Antisera thus obtained were shown to be specific for the tricyclic antidepressant group of drugs and are tested as regard as desipramine or nortriptyline labelled by an organometallic moiety (designated metallohaptens). The evaluation of the affinity constants shows that antisera cross-react almost equally well with both imipramine labelled with tritium (radiotracer) and metallohaptens using either ferrocene or cymantrene as labels (metallotracers). Detection of metallohaptens is performed by a ZEEMAN atomic absorption spectrophotometer (ZAAS).

Animals↗

PubMedDate not supplied

Modification by tricyclic antidepressants of cortical EEG changes induced by clonidine in conscious rats.

The effects of various tricyclic antidepressants on clonidine-induced electroencephalographic changes were investigated in rats. The EEG pattern of conscious rats was recorded by means of bipolar electrodes, implanted chronically. Clonidine (50, 150 and 300 micrograms/kg) not only synchronized cortical EEG pattern but also evoked signs of behavioural depression within 15 min of its administration. Pretreatment with imipramine, desipramine, trimipramine, amitriptyline, nortriptyline and doxepin reduced clonidine-induced EEG synchrony without showing any effects per se. Acute treatment with tricyclic antidepressants failed to modify but, chronic treatment abolished the clonidine-induced behavioural depressive signs. Chronic administration of tricyclic antidepressants (10 mg/kg/day) evoked more pronounced antagonism of the EEG effects of clonidine. Yohimbine (200 micrograms/kg) pretreatment inhibited both, clonidine-induced EEG synchrony and behavioural effects. Guanfacine as well as B-HT 920, elicited clonidine-like effects on cortical EEG pattern and behaviour. The present data suggests that antagonism of clonidine-induced EEG synchronization in conscious animals could serve as a useful test for screening of antidepressant drugs.

Animals↗

PubMedDate not supplied

Nomifensine maleate: a new second-generation antidepressant.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and formulary recommendations for nomifensine maleate are reviewed. Nomifensine is a potent inhibitor of norepinephrine but has little effect on serotonin. It is unique in that it is a potent reuptake inhibitor of dopamine. Nomifensine is rapidly and completely absorbed and is widely distributed throughout the body. The major route of elimination is through the kidneys. Because of its short half-life and resultant lack of accumulation, nomifensine is usually given in divided doses. Nomifensine is approved for the treatment of depression. In clinical trials with imipramine, amitriptyline, nortriptyline, maprotiline, and various investigational antidepressant drugs, it has been found to be as effective as the standard antidepressant agents. In general, nomifensine has been well tolerated by patients and has caused few side effects. It also has not been associated with serious toxic effects in overdose situations. The usual effective dose of nomifensine maleate is 100-200 mg daily given in divided doses. It appears to be a good choice for patients with profoundly retarded depression and for those who cannot tolerate the side effects of traditional antidepressant drugs. Nomifensine should not be used alone in patients with schizoaffective disorders or in patients with agitated depression. Nomifensine is a safe and effective antidepressant with a fairly unique pharmacological profile. Because the drug is relatively safe and causes little sedation, it may offer substantial advantages over the more traditional antidepressants and should be considered for formulary addition.

Chemical Phenomena↗

PubMed1979

Recent advances in antidepressant drug treatment.

Psychiatric research has made remarkable advances in understanding the pathophysiology of depressive illnesses. Biologic depressions are now understood as neurotransmitter deficiency diseases. Certain forms of depression are treated with tricyclic antidepressant drugs, which increase the amount of available neurotransmitters. Complicating the clinical picture, however, is the problem of wide variability of levels of tricyclic drugs in the plasma of persons receiving the same dosage. Another problem is the apparent linear dose-response relationship of imipramine hydrochloride and its sister compound desipramine hydrochloride while amitriptyline and nortriptyline follow an inverted U-shaped dose-response curve. However, with newer, more sophisticated diagnostic methods, combined with monitoring of tricyclic drug levels in plasma, therapeutic efficacy can approach 90 percent. Available neurotransmitters also can be increased using monoamine oxidase (MAO) inhibitors. Although MAO inhibitors have been less popular than the tricyclic drugs, recent clinical research tends to support their efficacy. Distinct individual differences in the rate of metabolism of MAO inhibitors have been found. New methods are being devised to detect these differences and monitor directly the effects of these drugs. One of these methods, platelet MAO inhibition, shows some clinical promise. Tricyclic drugs and MAO inhibitors have recently been joined by lithium carbonate, which shows notable efficacy in removing acute manic-depressive symptoms as well as preventing their return during maintenance treatment. Its utility in treating cyclic depressions without mania is now being explored by researchers.

Antidepressive Agents, Tricyclic↗

PubMed1985

Geriatric depression: a guide to successful therapy.

In the apathetic, withdrawn patient, tricyclic secondary amines such as desipramine and nortriptyline are as efficacious as tricyclic tertiary amines, and they offer the advantage of fewer anticholinergic and sedating side effects. Depressions usually have a sudden onset, whereas degenerative dementias such as Alzheimer's disease and multi-infarct dementia are manifested gradually. However, many elderly demented patients have concomitant depression, making assessment difficult.

Aged↗

PubMed1978

[Quantitative determination of tricyclic antidepressant drugs by high-pressure liquid chromatography (author's transl)].

With regard to the increasing importance of determining plasma levels of antidepressant drugs a procedure has been worked out which makes it possible to analyze these substances in a simple and sensitive way. 5 ng )ca. 20 pmol) amitriptyline, nortriptyline, imipramine, desmethylimipramine, chlorimipramine, desmethylchlorimipramine, and protriptyline can be detected with a high-pressure liquid chromatograph and a UV-monitor without prior derivatisation. The extraction is made from 1 ml serum. Because of their retention time the substances can be identified. This fact allows simultaneous analyzation of all tricyclic antidepressants.

Antidepressive Agents, Tricyclic↗

PubMedDate not supplied

[Correlation of presynaptic components (uptake--release) in antidepressants].

Experiments on the rat brain slices were made to study the relationship between the ability of 19 antidepressants to inhibit the reverse monoamine uptake (14C-noradrenaline, 3H-serotonin, 3H-dopamine) and that to enhance their presynaptic release. Antidepressants were demonstrated to have the dual nature of the presynaptic mechanism of the aminopotentiating action, which is determined by the inhibitory effect on the uptake and stimulating action on impulse release of monoamines. It was found that imipramine-like and bicyclic antidepressants have two components of presynaptic activity, whereas iprindole, noveril, peptides, and beta-carbolines are marked by the predominant effect on impulse release of monoamines. Chlorimipramine had an identical effect on the uptake and release of all three amines. Antidepressants belonging to the LU series affected mainly serotonin, whereas desipramine and nortriptyline mainly the noradrenaline uptake and release.

Animals↗

PubMed1980

[Pharmacokinetics and plasma concentration of polycyclic antidepressants. General review of the product].

To date 39 studies have been published on the relationships between the plasma levels of polycyclic antidepressants and their clinical efficacy. The results of 24 of these studies show significant relationships to variable degrees. No correlation was found in the others 15. This quota does not seem to be changed by preliminary results of studies not yet published. The particular analysis of 34 of these studies indicates that plasma levels of two tricyclic (nortriptyline and imipramine) are unequivocally related to clinical efficacy (plasma levels of imipramine are the results of imipramine and desipramine cumulated levels). The correlations are the highest for non delusionnal endogenous depressions. The results are contradictory for amitriptyline, a fact which may be attributed to methodological discrepancies such as: the choice of diagnositc criteria, the choice of sampling week, the number of samples, the sensitiveness and the specificity of the analysis. More recents drugs (butriptyline, maprotiline, mianserine, etc.) have led to a limited number of studies, yet insufficient to allow conclusions. The neuroleptic association increases the plasma levels of polycyclic antidepressants. Benzodiazepines do not change them whereas all the hepatic enzymaic inductors decrease them.

Antidepressive Agents↗

PubMed1982

Recent concepts of neuromodulators in affective disorders.

Though certain controversies exist current hypotheses on the etiopathogenesis of affective disorders postulate a dysfunction in central neurotransmitter systems, mainly of the biogenic amines serotonin (5-HT) and/or noradrenaline (NA). As antidepressants have differential influence on neurotransmitter function and prediction of clinical response is unreliable, recent investigations attempt to define more "serotoninergic" or "noradrenergic" types of endogenous depression. Results of our as well as of other groups indicate that NA turnover (as measured by the excretion of 3-methoxy-4-hydroxymethylglycol-MHPG-) is low in patients who respond to imipramine and amphetamine and high in subjects who respond to amitriptyline and sleep deprivation. Conversely, 5-HT turnover (as measured by 5-hydroxyindole acetic acid concentration in cerebrospinal fluid) has been found to be low in patients who respond to clomipramine and amitriptyline and to be normal or high in those who respond tp nortriptyline. These findings suggest biochemical heterogeneity of depressions which are largely uniform in their clinical appearance. Further investigations are presented which indicate that, in addition to NA and 5-HT, acetylcholine functions contribute significantly to the regulation of mood and drive.

Antidepressive Agents, Tricyclic↗

PubMed1980

[Clinical, biochemical and psychopharmacologic correlates in patients with depressive symptomatology].

A population of 41 clinic outpatients suffering depressive symptomatology was studied. According to the presence or absense of sixteen specific symptoms it was possible to distribute these patients in three different groups. Simultaneously urinary determinations of phenethylamine (PEA), 3-methoxy-4-hydroxyphenylethylglicol (MHPG), phenylacetic acid, 5-hydroxyindolacetic acid and serum 5-hydroxytriptamine were performed. A clossed clinical-biochemical correlation was noted in each group in relation to PEA and MHPG daily output. The other determinated values were not significant. Besides the clinical data, the mentioned groups presented the following characteristic output data: group A: decreased PEA and MHPG levels, group B, decreased PEA and normal MHPG levels and group C: normal values of the two substances. Five tricyclic antidepressant drugs were tested in the three groups. It was shown that patients with low pretreatment urinary output values of PEA and MHPG responded favourably to imipramine, desipramine and nortriptyline, alone or in association. On the other side, the group B responded favourably to chlorimipramine and amitriptiline, alone or in combination. No change or clinically worse were observed in patients of these groups when medication was not administrated according to the described form. The group with normal PEA and MHPG output values worsened or did not respond to medication following administration of any of the antidepressants essayed. Only psychotherapeutic treatment in combination with ansiolitics let to an improvement of symptomatology. At least, our findings suggest a closed clinical-biochemical-psychopharmacological correlate of some classes of depression that may provide rational basis for a more predictive tricyclic antidepressant therapy.

Adult↗

PubMedDate not supplied

The influence of psychotropic drugs on the phosphodiesterase activity in the rat brain meninges.

Phosphodiesterase (PDE) is present in brain meninges. Its activity is higher in the pia than in the dura mater. Phenothiazine neuroleptics: fluphenazine, trifluoroperazine, thioproperazine, chloropromazine and thioridazine at concentration 10(-5)--10(-4) M in vitro inhibit the PDE activity in the pia and dura mater. Most potent in this respect were fluphenazine and trifluoroperazine. Much less pronounced inhibition of PDE activity in brain meninges was found after in vitro administration of tricyclic antidepressant: nortriptyline, chlorimipramine, protriptyline, desipramine and imipramine in concentrations 10(-4)--10(-3) M. Administered in vivo in a dose of 0.1 mg or 5 mg/kg ip fluphenazine inhibited the hydrolysis of 32P-cAMP injected into subarachnoid space. The results indicate that PDE present in the rat brain meninges may control the cAMP level in the cerebrospinal fluid. Treatment with phenothiazine neuroleptics which inhibit the PDE activity in meninges may significantly depress the hydrolysis of cAMP in the cerebrospinal fluid.

Animals↗

PubMed1981

Membrane action of tricyclic drugs. Spectroscopic studies of a series of phenothiazines compared with tricyclic antidepressive substances in red cell membrane, using the spin labelling technique.

Previous results were extended by binding studies of drugs on red cell membrane by means of the spin labelling technique. A series of phenothiazines was investigated and compared with several tricyclic antidepressive substances. It was found that phenothiazines at concentrations below 3 mumol/l decisively increase the order parameter of spin label 618, which reports on the interface of the membrane. Thus the fluidity of the interface is decreased. Spin label 616 reports on the hydrophobic membrane interior. Within this hydrophobic phase, the order is decreased by 100 mumol to 1 mmol/l of the phenothiazines. With tricyclic antidepressive substances, a rise of order parameter of spin label 618 is observed, which, however, is less steep. At about 30 mumol/l a maximum is eventually reached. At even higher concentrations of amitriptyline, nortriptyline or imipramine with spin label 616, however, no significant change of order parameter was observed indicating that perturbation of the hydrophobic membrane interior is not sensed. These findings thus corroborate our previous results, revealing that influence of phenothiazines can be measured through the polar and apolar phases of the membrane, while the antidepressive drugs primarily act on the polar phase.

Antidepressive Agents, Tricyclic↗

PubMed1984

[Clinical chronopharmacokinetics].

Circadian (approximately or equal to 24 hours) and other endogenous biological rhythms, detectable at all levels of organisation, constitute a temporal structure in all species, including man. Circadian, circannual, and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical and chemical agents, including medications and foods, are rather common phenomena. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronopharmacokinetics of a drug (rhythmic changes in its pharmacokinetics), the chronesthesy (rhythmic changes in susceptibility of target biosystems to the drug), and the chronergy (the drug-integrated overall effects). The chronopharmacokinetics of many drugs have been evaluated in man (tables I-IV) including sodium salicylate, aspirin, indomethacin (fig. 1), sustained-release indomethacin, paracetamol (acetaminophen), phenacetin, amidopyrine, theophylline sustained-release theophylline (fig. 2), aminophylline, sustained-release aminophylline, digitalis, propranolol, clorazepate, hexobarbitone (hexobarbital), diazepam, midazolam, lithium, phenytoin (diphenylhydantoin), nortriptyline, ethanol, erythromycine , ampicillin, sulfasymazine , sulphanilamide, cis-diammine-dichloroplatinum (fig. 3), mequitazine (fig. 4), d-xylose, ferrous sulphate, potassium chloride, hydrocortisone and prednisolone, among others. The roles presumably played by circadium rhythms in drug metabolizing liver enzymes (fig. 5), and kidney function are summarized, and the practical implications of chronopharmacokinetics, aiming both to improve in a quantitative manner the metabolic fate of a drug and its effectiveness, are discussed.

Anesthesia↗