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PubMed1996

[3H]8-OH-DPAT binding and serotonin content in rat cerebral cortex after acute fluoxetine, desipramine, or pargyline.

Cortical serotonin1A (5-HT1A) receptors in the rat were studied following acute (24 hours) intraperitoneal administrations of the 5-HT uptake inhibitor fluoxetine (10 mg/kg), the antidepressant desipramine (20 mg/kg), or the monoamine oxidase (MAO) inhibitor pargyline (75 mg/kg). The 5-HT1A receptors were labelled in total cortex membrane homogenates with [3H]8-OH-DPAT, and the monoamines measured in cingulate cortex by high-performance liquid chromatography. As expected, after pargyline administration tissue concentrations of 5-HT, noradrenaline (NA) and dopamine (DA) were markedly increased due to MAO inhibition with a concomitant decrease of the metabolites 5-hydroxyindole-3-acetic acid and homovanillic acid. However, neither desipramine nor fluoxetine changed monoamine concentrations. Saturation binding with [3H]8-OH-DPAT revealed that, for the control animals (saline treated), the curves were best fitted to a 2-site model. Following drug administration, the saturation curves were still best fitted to a 2-site model, with no changes in affinities or bonding capacities. In competition experiments with 5-HT, buspirone, and pindolol, the curves were always best fitted to a 2-site model. Following fluoxetine administration, the inhibition curves revealed decreases in the affinity of the low-affinity site (KiL) for the agonist buspirone, and in the relative proportion of these sites. In addition, following pargyline, there was an increase in the affinity of the high-affinity site (KiH) for 5-HT but with a decrease of the relative proportion of high-affinity sites. The results confirm that [3H]8-OH-DPAT binding is to a 2-site model, and reveal an absence of downregulation of 5-HT1A receptors following increases in tissue 5-HT after MAO inhibition or antidepressant administrations. Moreover, the data may reflect an alteration of the coupling efficacy between cortical 5-HT1A receptors and their associated G proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1997

Death of two subjects due to imipramine and desipramine metabolite accumulation during chronic therapy: a review of the literature and possible mechanisms.

In two unrelated cases, a 7-year-old boy and a 21-year-old woman died suddenly while receiving chronic imipramine therapy. In the boy, concentrations of imipramine were: Left femoral blood 0.5 mg/L, right femoral blood 1.2 mg/L, aorta blood 1.0 mg/L, liver 68 mg/Kg, and for the active metabolite, desipramine, left femoral blood 6.7 mg/L, right femoral blood 9.9 mg/L, aorta blood 8.7 mg/L, liver 400 mg/Kg. In the woman, the imipramine concentrations were: Femoral blood 0.6 mg/L, liver 37 mg/Kg, and of the active metabolite, desipramine, femoral blood 3.74 mg/L, liver 261 mg/Kg. In both cases, the scene investigation strongly indicated that neither individual had ingested an acute overdose. The very high ratios of desmethyl metabolite to parent drug are consistent with this observation. Impaired metabolism due to a genetically determined "slow metabolizer" phenotype of cytochrome CYP2D6, and/or concurrent therapy with phenothiazines, is suggested as a possible mechanism for the apparent fatal accumulation of these tricyclic antidepressants.

Adult↗

PubMed1988

Analysis by liquid chromatography of desipramine in aqueous solutions and plasma application of dichlorotriazinylaminofluorescein (DTAF) as a pre-column fluorescent derivatising agent for selected secondary amines.

Dichlorotriazinylaminofluorescein (DTAF) has been proposed as a fluorescent derivatising agent for secondary aliphatic amines. In this report, its applicability as a pre-column reagent is demonstrated by its use in the analysis of aqueous solutions and plasma samples of the tricyclic antidepressant, desipramine. Samples were processed by liquid-solid extraction onto XAD-2 resin, followed by DTAF derivatisation of the fraction of the column effluent containing analyte. The reaction mixture was then subjected to HPLC using a dual column switching configuration that was designed to (a) separate excess DTAF from the reaction product, and to (b) achieve the necessary analytical resolution. Fluorometric detection of the analyte in column effluent afforded a sensitivity of 150 fmol of desipramine injected on-column, a 2-3 order of magnitude increase in sensitivity relative to previously described methods. DTAF appears to be a convenient reagent for fluorescence derivatisation of N-methyl secondary amines prior to their HPLC analysis.

Journal Article↗

PubMed2001

Maintenance desipramine for dysthymia: a placebo-controlled study.

BACKGROUND: This study examines the efficacy of maintenance pharmacotherapy in dysthymia without concurrent major depression, i.e. 'pure dysthymia'. No published data exist on this topic. METHODS: Responders to a 10-week open trial of desipramine (DMI) whose therapeutic response persisted during a 4-month continuation phase were eligible to begin a 2-year placebo-controlled maintenance phase. We analyzed the subgroup with DSM-III-R pure dysthymia (n=27) that entered maintenance. Time to recurrence during maintenance therapy was compared between the two treatment groups. RESULTS: Six of 13 patients receiving placebo and none of 14 patients receiving ongoing DMI experienced a recurrence. Risk of recurrence was significantly greater for placebo patients. Five of six placebo recurrences occurred within the first 6 months of maintenance. LIMITATIONS: Larger replication studies are needed. CONCLUSION: Desipramine was efficacious as a maintenance treatment in patients with pure dysthymia who responded to 7 months of acute and continuation DMI.

Acute Disease↗

PubMed1997

Desipramine modulates 3H-ouabain binding in rat hypothalamus.

We have previously shown that Na+, K(+)-ATPase activity in hypothalamus is increased after administration of an acute dose of desipramine, a noradrenaline uptake inhibitor (Viola et al., Cell Molec Neurobiol 9:263-271, 1989). In this report the same treatment (10 mg per kg) was applied to evaluate 3H-ouabain binding in rat brain sections by quantitative autoradiography. Results disclosed an increase in the number of ouabain binding sites in hypothalamus but not in cerebral cortex. Concomitantly, such acute DMI treatment enhanced K(+)-stimulated-p-nitrophenylphosphatase activity in hypothalamus membranes whereas it failed to modify cerebral cortex membranes. A direct interaction of DMI with the enzyme was ruled out since in vitro DMI is known to inhibit the enzyme. It may be speculated that DMI indirectly stimulates Na+, K(+)-ATPase through the increase in noradrenaline which acts in turn on the external phosphorylated site of the enzyme.

4-Nitrophenylphosphatase↗

PubMed1996

Initial increases in extracellular dopamine in the ventral tegmental area provide a mechanism for the development of desipramine-induced sensitization within the midbrain dopamine system.

In an attempt to understand the basis of the changes in the mesolimbic dopamine system that occur in response to chronic treatment with the antidepressant drug, desipramine HCl (DMI), we monitored changes in extracellular dopamine in ventral tegmental area (VTA) and nucleus accumbens septi (NAS) using in vivo microdialysis in freely moving animals. Early in treatment at a time before changes in the responsiveness of the dopamine system are observed, basal levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found to be increased in the VTA of rats treated with 5.0 mg/kg DMI twice daily for 6 days compared to those of saline-treated animals. After 12 days of treatment, and in a second group of animals after 18 days of treatment, basal levels of dopamine, DOPAC, HVA and 5HIAA, and levels in response to challenge with 1.5 mg/kg d-amphetamine sulphate were measured in the NAS. No differences in these measures taken in NAS were found between DMI- and saline-pretreated animals after 12 days of treatment. In DMI-treated animals tested after 18 days, the dopamine response to amphetamine was elevated compared to that of saline-treated animals. Furthermore, although there were no differences in basal levels of dopamine, basal levels of DOPAC and HVA were increased in DMI-treated animals. These findings lend support to the view that the time-dependent sensitization of dopaminergic function brought about by the tricyclic antidepressants may share processes in common with the development of sensitization to the indirect dopamine receptor agonist, amphetamine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Double-blind comparison of fluoxetine and desipramine in the treatment of depressed women with advanced HIV disease: a pilot study.

A double-blind, placebo-controlled study was conducted to assess the relative efficacy and tolerability of fluoxetine and desipramine in depressed, human immunodeficiency virus (HIV)-positive women. Although difficulty in the recruitment and retention of participants led to insufficient power to detect differences between treatment groups, results indicated that participants experienced improvement in their depression. However, for most women, significant depressive symptoms remained after 6 weeks of treatment. In addition, although most participants reported at least one adverse event after treatment began, most of the side effects, regardless of treatment condition, were mild to moderate in severity. Important barriers to study participation and completion are discussed, as well as suggestions for increasing the involvement of depressed, HIV-positive women in future treatment studies.

Adult↗

PubMed1976

Simultaneous measurement of imipramine and desipramine by selected ion recording with deuterated internal standards.

A gas chromatographic mass spectrometric method for the quantitative determination of imipramine and its N-demethylated metabolite desipramine in plasma samples at the nanogram level is reported. The method involves derivatization of the extracted drugs with trifluoroacetylimidazole, a mild derivatizing reagent. Specificity is provided by selected ion recording of the [M + H]+ ions, formed upon chemical ionization with methane as reagent gas. Quantitation is achieved by stable isotope dilution techniques, using deuterium labeled analogs, prepared by acid-catalyzed exchange, as internal standards. Data on patient samples are presented.

Chemical Phenomena↗

PubMed1994

The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine.

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid beta-adrenergic receptor down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague-Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR-HCl (11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection for free (R)-and (S)-FLU and (R)- and (S)-NFLU after extraction and reaction with (-)-(S)-N-(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)-FLU alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Tricyclic antidepressants and the Brugada syndrome: an example of Brugada waves appearing after the administration of desipramine.

Since its initial description in the early 1990s, the Brugada syndrome has become increasingly familiar to active researchers and practicing clinicians. The Brugada wave, a characteristic electrocardiographic abnormality of downsloping ST-segment elevation in leads V1-V3 and right bundle-branch block morphology, has now been associated with an increased risk of sudden death. Currently, very little is known about the relationship between the Brugada syndrome and tricyclic antidepressants. Accordingly, we report the case of a patient who developed prominent Brugada waves with the administration of increasing doses of desipramine. We believe the mechanism of Brugada wave augmentation or production secondary to tricyclic antidepressants is consistent with the current model of early repolarization. We also speculate that the increased risk of sudden death that may occur with tricyclic antidepressants could be related to the development of the Brugada syndrome. We advocate the judicious use of tricyclic antidepressants in cardiac and elderly patients, with careful monitoring of the electrocardiogram for the development Brugada waves.

Aged↗

PubMed2006

Early response to desipramine among women with bulimia nervosa.

OBJECTIVE: Numerous trials have demonstrated the efficacy of antidepressant medications for the treatment of bulimia nervosa (BN). The current study examined whether early response to medication predicted response to medication at the end of a controlled trial. METHOD: Data from two previously published studies of desipramine (DMI) were used. Seventy-seven patients with BN were included in the analysis. Receiver operating characteristic (ROC) curves were constructed to examine the relation between the percentage reduction in symptoms at each week and failure to respond to antidepressant medication at the end of the trial. RESULTS: Eventual nonresponders to DMI could be reliably identified in the first 2 weeks of treatment. CONCLUSION: The current study provides preliminary evidence that patients with BN who will not respond to antidepressant medication can be identified in the first 2 weeks of treatment.

Adult↗

PubMedDate not supplied

Single- versus multiple-dose comparative trial of desipramine hydrochloride: a double-placebo method.

In a double-blind comparative trial utilizing the double-placebo method, depressed neurotic patients whose effective titrated dose of desipramine hydrochloride was 75, 100, or 150 mg were maintained, with equal efficacy, on once-a-day or multiple daily dose regimens. The data confirm that the safety of the once-a-day maintenance regimen (as measured by vital signs, laboratory tests, ECGs, and clinical adverse reactions) is comparable to the safety of the multiple daily dose regimen.

Adolescent↗

PubMed1987

Bromocriptine-desipramine protocol in treatment of cocaine addiction.

Thirty-six male cocaine abusers, in withdrawal, were studied for 99 days in a double-blind design. Treatment with bromocriptine was significantly more effective than placebo in alleviating withdrawal symptoms. Adding desipramine to the bromocriptine regimen was significantly more effective than either placebo or bromocriptine alone. The authors hypothesize that these results support a model of dopamine depletion and receptor supersensitivity in cocaine withdrawal.

Adult↗

PubMed2006

Desipramine prevents the sustained increase in corticotropin-releasing hormone-like immunoreactivity induced by repeated immobilization stress in the rat central extended amygdala.

Clinical and experimental studies have shown that the activation of corticotropin-releasing hormone (CRH) and noradrenergic systems mediate stress-induced anxiety. Repeated immobilization stress (RIS) has been shown to induce long-lasting anxiety behavior and changes in noradrenaline turnover. The present work was aimed at studying the effect of RIS on the in situ expression of CRH-LI in the central extended amygdala and paraventricular nucleus of the hypothalamus (PVN). Our results showed that RIS for 15 days induces a significant increase of CRH-LI expression in the central extended amygdala. The increase in CRH-LI expression in the central extended amygdala was sustained even after a 25-day stress-free period. The concomitant administration of desipramine (DMI), a specific noradrenaline uptake inhibitor, fully prevented the RIS-induced increase in CRH expression. RIS also induced an increase of CRH-LI expression in the PVN that was prevented by the concomitant DMI administration. In contrast to the sustained effect observed in the central extended amygdala, the RIS-induced increase of CRH-LI expression in the PVN was nonlasting. DMI administration also prevented the RIS-induced increase of adrenal gland weight. The present findings showing that RIS induces a sustained increase of CRH expression in the central extended amygdala suggest that the repeated activation of CRH neurons and CRH receptors in the central extended amygdala may underlie the long-lasting anxiety behavior induced by RIS. Further studies should address the mechanisms involved in the effect of DMI and its eventual relevance in the therapeutic actions of DMI.

Adrenal Glands↗

PubMed1981

Simultaneous determination of imipramine, desipramine, and their 2-hydroxy metabolites in plasma by ion-pair reversed-phase high-performance liquid chromatography with amperometric detection.

An ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method, using an electrochemical detector, is presented for the simultaneous and rapid quantitation of imipramine desipramine, and their 2-hydroxylated metabolites in plasma. The drugs are extracted from 1 ml of plasma at pH 9.7 with ether, back-extracted into 0. M HCl, and reextracted into ether following alkalinization. An efficient electrochemical oxidation reaction at the detector electrode affords a low detection level of approximately 5 ng/ml in a mobile phase of acetonitrile--acetate buffer (40:60) containing 0.005 M heptanesulfonate. Patient data are presented as correlations between the plasma level of each hydroxy metabolite and its respective parent compound. The method is applicable to the laboratory experienced in HPLC.

Chromatography, High Pressure Liquid↗

PubMed1982

Study of the metabolic conversion of imipramine and desipramine to N-nitrosodesipramine by bacteria using a nitrogen-selective GC analysis.

A GC method using dual nitrogen selective and flame ionization detectors was developed for the determination of N-nitrosodesipramine using N-butyryldesipramine as the internal standard. The precision of the method was found to be +/- 5.0% and the accuracy was +/- 4.9%. The method could be used to detect 10 ng/ml of N-nitrosodesipramine in bacterial cultures. When desipramine and sodium nitrite were incubated with aerobic or anaerobic bacteria, the nitrosamine level was found to be 10-300 times higher than the controls. When imipramine and potassium nitrate were incubated with a mixed anaerobic culture, the level of N-nitrosodesipramine was found to be 4.5 times higher than the control.

Aerobiosis↗

PubMed1990

Stable isotope coadministration methodology for the estimation of the fraction of imipramine metabolized to desipramine.

The application of a stable isotope coadministration technique for estimating the fraction (fm) of imipramine (IP) that is converted to desipramine (DMI) is described. Four healthy male subjects received 25 mg of IP-d4 hydrochloride orally with 25 mg of DMI hydrochloride. The plasma concentrations of IP-d4, DMI-d4, and DMI were determined by capillary gas chromatography-mass spectrometry-selected ion monitoring using d8 analogues as internal standards. The fm values, calculated from the ratio of the area under the plasma concentration-time curve of DMI-d4 to that of DMI, varied from 0.54 to 0.85.

Adult↗

PubMed1994

Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon.

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗