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PubMed1991

Determination of imipramine, desipramine and their hydroxy metabolites by reversed-phase chromatography with ultraviolet and coulometric detection.

A reversed-phase high-performance liquid chromatographic method is described which analyzes imipramine, desipramine and their corresponding 2-hydroxy metabolites with sequential ultraviolet and coulometric detection from a single common extraction step, so that a wider dynamic range of plasma concentrations can be measured requiring smaller sample volumes. Applicability is broader including single-dose pharmacokinetic studies as well as steady-state concentrations. The extraction procedure gives excellent recoveries for imipramine, desipramine and their metabolites (mean +/- S.D.): ultraviolet detection, imipramine 99.5 +/- 0.68%, desipramine 100 +/- 0.0%, 2-hydroxyimipramine 97.8 +/- 3.5% and 2-hydroxydesipramine 93.1 +/- 4.22%; coulometric detection, imipramine 97.5 +/- 1.9%, desipramine 98.3 +/- 1.2%, 2-hydroxyimipramine 90.3 +/- 4.0% and 2-hydroxydesipramine 86.6 +/- 7.5%.

Chromatography, High Pressure Liquid↗

PubMed1995

Simultaneous determination of lofepramine and desipramine by a high-performance liquid chromatographic method used for therapeutic drug monitoring.

A simple reversed-phase HPLC method with ultraviolet detection for the simultaneous measurement of lofepramine and desipramine is described. Only a single alkaline extraction was used, with clomipramine as internal standard. The column used was a Supelco PCN column, and the mobile phase was acetonitrile-methanol-0.015 M phosphate buffer (120:35:100, v/v). The average recoveries were 78.8% for desipramine and 103.8% for lofepramine, and limits of quantitation were 25 and 5 nmol/l, respectively. The inter-assay C.V.s for lofepramine and desipramine were 6.0 and 7.6%, respectively. The method is specific and has excellent accuracy, and has been used for therapeutic drug monitoring of patients with depressions treated with lofepramine. Mean steady-state plasma concentrations found for lofepramine and desipramine were 8.5 +/- 6.1 and 123.6 +/- 120.6 nmol/l, respectively. It is concluded that lofepramine in itself has an antidepressive effect.

Chromatography, High Pressure Liquid↗

PubMed1987

Two tricyclic antidepressant poisonings: levels of amitriptyline, nortriptyline and desipramine in post-mortem biological samples.

Two deaths due to amitriptyline and desipramine overdoses are reported. The first case deals with a 20-year-old Caucasian male who was found dead at his residence. Toxicological analysis of the blood, urine, liver and kidney revealed the presence of amitriptyline (1.7 mg/l, 0.13 mg/l, 36.0 mg/kg and 98.0 mg/kg) and nortriptyline (0.66 mg/l, 0.74 mg/l, 12.0 mg/kg and 37.0 mg/kg). The gastric content contained only 220 mg of amitriptyline. The urine also contained norverapamil, which was consistent with previous verapamil therapy. The second case involved a 19-year-old Caucasian male who attempted suicide earlier and was on desipramine medication. The blood, urine, liver and gastric content disclosed the presence of desipramine in the concentrations of 14.2 mg/l, 33.7 mg/l, 112.5 mg/kg and 180 mg, respectively. The levels of these tricyclics analyzed by high pressure liquid chromatography were in agreement with the levels reported in the literature. Though with the amitriptyline poisoning no significant anatomic changes were noted, the desipramine-caused death was further supported by the multisystem vascular congestion and ischemic changes consistent with cardiopulmonary failure.

Adult↗

PubMed1990

Plasma versus bone marrow desipramine: a comparative study.

Correlation between plasma and bone marrow tricyclic antidepressants has not been studied before. Two groups of rabbits were given 10 and 20 mg of desipramine/kg body weight, respectively. Desipramine was administered to the animals once daily by mouth for 5 days. On the fifth day the animals were sacrificed and blood and bone marrow samples were collected and analyzed using a high performance liquid chromatographic (HPLC) method. Data showed that a correlation exists between bone marrow and blood desipramine. The bone marrow desipramine concentration increased as its blood levels increased. The average ratio of bone marrow to blood desipramine +/- S.D. (standard deviation) in both dosage groups was 37.2 +/- 4.46 with a range of 30.99-44.82. This investigation is promising and shows that bone marrow could be used as an alternative tissue in the absence of a suitable blood sample.

Animals↗

PubMedDate not supplied

Desipramine, amantadine, or fluoxetine in buprenorphine-maintained cocaine users.

The clinical efficacy of promising cocaine anti-craving medications was examined in combination with buprenorphine. Twenty-one opioid-dependent cocaine abusers were enrolled in a double-blind, 12-week trial in which they received on a daily basis buprenorphine (8 mg, s.l.) plus either desipramine (150 mg, p.o.), amantadine (300 mg, p.o.), or fluoxetine (60 mg, p.o.). Urine samples and self-reported drug use were obtained 1-3 times/week. The order of greatest patient retention across the 12 weeks was desipramine (83.3%) > amantadine (66.7%) > fluoxetine (20.0%). The desipramine and amantadine groups appeared to have greater increases in opioid- and cocaine-free urines than the fluoxetine group. These results suggest that desipramine and amantadine may facilitate greater opioid and cocaine abstinence than fluoxetine.

Adult↗

PubMed2005

Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol.

This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (alpha2-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen. The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.

Adrenergic alpha-Antagonists↗

PubMed2006

Effects of acute and subchronic treatments with fluoxetine and desipramine on the memory of fear in moderate and high-intensity contextual conditioning.

Selective serotonin and noradrenalin reuptake inhibitors such as fluoxetine and desipramine, respectively, are efficacious in the treatment of depression and chronic stress. Although they inhibit the reuptake of the biogenic monoamines soon after administration, therapeutic improvements occur only after 2 or 3 weeks. Freezing response and potentiated startle are common responses to moderate fear contextual conditioning. However, freezing but not startle is increased in rats that undergo intense fear conditioning. In this study, we evaluated the effects of acute and subchronic administration of fluoxetine and desipramine on these responses in testing sessions, as indices of fear in moderate and high fear conditioning. Fluoxetine did not show any significant effect on the moderate fear conditioning but reduced freezing and restored the startle response in rats under intense fear conditioning. In comparison, desipramine had no effect on the startle response when administered acutely or subchronically while freezing of the intense fear conditioning was reduced. Our findings indicate that intense contextual fear conditioning is sensitive to subchronic treatment with fluoxetine and resistant to desipramine. Fluoxetine appears to restore the serotoninergic function in brain areas recruited by intense contextual fear conditioning. These effects of fluoxetine may underlie its reported efficacy in the pharmacotherapy of panic disorders.

Acoustic Stimulation↗

PubMed2006

Functional interaction between alpha2-adrenoceptors, mu- and kappa-opioid receptors in the guinea pig myenteric plexus: effect of chronic desipramine treatment.

The existence of a functional interplay between alpha(2)-adrenoceptor and opioid receptor inhibitory pathways modulating neurotransmitter release has been demonstrated in the enteric nervous system by development of sensitivity changes to alpha(2)-adrenoceptor, mu- and kappa-opioid receptor agents on enteric cholinergic neurons after chronic sympathetic denervation. In the present study, to further examine this hypothesis we evaluated whether manipulation of alpha(2)-adrenoceptor pathways by chronic treatment with the antidepressant drug, desipramine (10 mg/kg i.p. daily, for 21 days), could entail changes in enteric mu- and kappa-opioid receptor pathways in the myenteric plexus of the guinea pig distal colon. In this region, subsensitivity to the inhibitory effect of both UK14,304 and U69,593, respectively alpha(2A)-adrenoceptor and kappa-opioid receptor agonist, on the peristaltic reflex developed after chronic desipramine treatment. On opposite, in these experimental conditions, supersensitivity developed to the inhibitory effect of [D-Ala, N-Me-Phe4-Gly-ol5]-enkephalin (DAMGO), mu-opioid receptor agonist, on propulsion velocity. Immunoreactive expression levels of alpha(2A)-adrenoceptors, mu- and kappa-opioid receptors significantly decreased in the myenteric plexus of the guinea pig colon after chronic desipramine treatment. In these experimental conditions, mRNA levels of alpha(2A)-adrenoceptors, mu- and kappa-opioid receptors significantly increased, excluding a direct involvement of transcription mechanisms in the regulation of receptor expression. Levels of G protein-coupled receptor kinase 2/3 and of inhibitory G(i/o) proteins were significantly reduced in the myenteric plexus after chronic treatment with desipramine. Such changes might represent possible molecular mechanisms involved in the development of subsensitivity to UK14,304 and U69,593 on the efficiency of peristalsis. Alternative molecular mechanisms, including a higher efficiency in the coupling between receptor activation and downstream intracellular effector systems, possibly independent from inhibitory G(i/o) proteins, may be accounted for the development of supersensitivity to DAMGO. Increased sensitivity to the mu-opioid agonist might compensate for the development of alpha(2A)-adrenoceptor and kappa-opioid receptor subsensitivity. On the whole, the present data further strengthen the concept that, manipulation of alpha(2)-adrenergic inhibitory receptor pathways in the enteric nervous system entails changes in opioid inhibitory receptor pathways, which might be involved in maintaining homeostasis as suggested for mu-opioid, but not for kappa-opioid receptors.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Modulating sensorimotor gating in healthy volunteers: the effects of desipramine and haloperidol.

In schizophrenia both an involvement of a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity have been suggested. In addition, patients suffering from schizophrenia show reduced sensorimotor gating and reduced habituation. If there is a causality between these neurotransmitters and these processes, then either a reduction in dopaminergic activity or an enhanced noradrenergic activity in healthy volunteers would result in reduced sensorimotor gating and reduced habituation. In the present study, a group of 12 healthy male volunteers was tested four times in a prepulse inhibition (PPI) paradigm 2.5 h following administration of placebo/placebo, placebo/desipramine (50 mg), placebo/haloperidol (2 mg) and desipramine (50 mg)/haloperidol (2 mg). A significant reduction of percentage PPI was found in all active treatments compared with placebo/placebo, while no treatment effects on habituation were found. Furthermore, a significant increase in heart rate was found in both desipramine treatments, from 120 min following oral intake onwards. Both desipramine and haloperidol reduced PPI, which suggests that an enhanced noradrenergic activity and a reduced dopaminergic activity lead to a reduction in sensorimotor gating. Since reduced sensorimotor gating is found in schizophrenia, these results supply further evidence for a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity in schizophrenia. Furthermore, the combination of haloperidol and desipramine did not have a synergistic effect on PPI, which indicates an interaction between the compounds. The site for this interaction is most likely located in the prefrontal cortex, since evidence is accumulating that extracellular dopamine concentration is regulated by noradrenergic terminals, particularly in the frontal areas of the brain. Since no effects on habituation were found, this suggests that neither enhanced noradrenergic nor decreased dopaminergic activity is involved in this process.

Adrenergic Uptake Inhibitors↗

PubMed2000

Exploratory behaviour and grooming after repeated restraint and chronic mild stress: effect of desipramine.

In a previous study, we have recently shown that chronic treatment with desipramine either reduced or potentiated the locomotor response to the dopamine D(2)-like receptor agonist quinpirole, a behavioural response mediated by the mesolimbic dopamine system, depending on whether the animals were subjected, respectively, to repeated restraint or to chronic mild stress (different stressors randomly presented). In this study, we examined the interaction between prolonged exposure to either repeated restraint stress or chronic mild stress with the chronic administration of the antidepressant desipramine on two spontaneous behaviours, in which an involvement of the mesolimbic dopamine system has been suggested: novelty-induced exploratory activity and grooming. Exploratory activity in the open field was reduced by chronic mild stress regardless of the drug treatment, while it was not influenced by restraint stress. Desipramine reduced exploratory activity in rats subjected to restraint stress. Restraint stress increased grooming and desipramine reversed this effect, while increasing grooming in the chronic mild stress group. These findings suggest that antidepressants exert their effect by opposing the modifications induced by stress. The available experimental evidence is consistent with the hypothesis that an important role in the observed behavioural changes is played by the mesolimbic dopamine system.

Animals↗

PubMed2002

Inhibition of SK3 channels in the TE671 human medulloblastoma cell line by desipramine and imipramine.

The TE671 human medulloblastoma cell line endogenously expresses SK3 channels. Using patch clamp, we tested the effects on this current of desipramine and imipramine. In both cases, we observed a complete, reversible and concentration-dependent block. The interaction of desipramine with the selective SK3 blocker, apamin, was studied in more detail. Co-application of desipramine and apamin at concentrations close to their IC(50) produced an additive effect that was significantly higher than that of each compound alone. This effect was also observed at IC(25) concentrations. Collectively, these data provide evidence against a common site of action for desipramine and apamin.

Desipramine↗

PubMed1997

Effects of clomipramine and desipramine on a C-fiber reflex in rats.

A C-fiber nociceptive reflex evoked by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in urethane anesthetized rats. Intravenously administered clomipramine and desipramine produced a dose-dependent depression of the C-fiber reflex. High doses of intrathecal desipramine also inhibited the C-fiber reflex, while similar intrathecal doses of clomipramine produced only a modest inhibition of the response. Intracerebroventricular administration of clomipramine decreased dose-dependently the C-fiber reflex whereas intracerebroventricular desipramine increased this reflex. These findings suggest that tricyclic antidepressants with noradrenergic selectivity, as desipramine, inhibit the spinal processing of C inputs by acting directly at the spinal cord level, while those with serotonergic spectra, as clomipramine, depress the C-fiber-evoked spinal reflex by acting at a supraspinal modulatory site.

Animals↗

PubMed1999

Differential modulation of alpha2-adrenoceptor subtypes in rat kidney by chronic desipramine treatment.

The profile of [3H]RX821002 (2-methoxy idazoxan) binding to alpha2-adrenoceptor subtypes in rat kidney membranes was evaluated in controls and after chronic treatment with desipramine (10 mg/kg, i.p., every 12 h, 7 days) or clorgyline (2 mg/kg, i.p., every 24 h, 21 days). [3H]RX821002 recognized with high affinity (Kd=1.5+/-0.2 nM in controls) a single and saturable population of binding sites (Bmax=57+/-5 fmol/mg protein in controls). The competitions by (-)-adrenaline, the alpha2B-adrenoceptor selective drug ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3 (2H,4H)-isoquinolindione) and the alpha2A-adrenoceptor selective drug BRL44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidaz ole) suggested the existence of both alpha2A- and alpha2B-adrenoceptors together with a non-adrenoceptor binding site. After chronic desipramine but not after chronic clorgyline treatments, the density (Bmax) of alpha2-adrenoceptors was increased (46%). In the presence of ARC239 (50 nM), the density of alpha2A-adrenoceptors increased (44%) in the desipramine-treated group without changes in the clorgyline-treated group. Conversely, in the presence of BRL44408 (100 nM), the density of alpha2B-adrenoceptors was not affected by the treatments. The selective upregulation of the alpha2A-adrenoceptor subtype following chronic desipramine administration is compatible with a differential location and function of the alpha2-adrenoceptor subtypes in the rat kidney.

Adrenergic Uptake Inhibitors↗

PubMed1997

Comparison of rats selectively bred for high and low ethanol intake in a forced-swim-test model of depression: effects of desipramine.

This investigation examined if there is a relationship between selective breeding for high or low alcohol intake and immobility in a force-swim-test (i.e., "behavioral despair") model of depression. Time spent immobile in a water-filled cylinder was measured in the alcohol-preferring (P and nonpreferring (NP) lines of rats, and in the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines. Each rat was tested for 2 10-min trials administered 24 h apart, and pretreatment with saline or desipramine (10.0 or 20.0 mg desipramine/kg b.wt. i.p.) also was evaluated. Drug was administered immediately after Trial 1 and again 1 h before Trial 2. When tested without pretreatment in Trial 1 or with saline pretreatment in Trial 2, NP rats spent significantly more time immobile than did P rats, but no comparable line differences were found when HAD and LAD rats were tested. Desipramine pretreatment reduced the time spent immobile in rats of the 2 alcohol-nonpreferring lines (i.e., the NP and LAD rats), but had no significant effect in rats of the 2 alcohol-preferring lines (the P and HAD rats). These findings do not support the hypothesis that there is a functional relationship between high alcohol drinking and susceptibility to "behavioral despair" as measured by the forced-swim test. The results with desipramine suggest that selection for high alcohol intake may be associated with insensitivity to desipramine.

Alcohol Drinking↗

PubMed1987

Hypersensitivity reaction to desipramine.

Adverse reactions to the tricyclic antidepressant drugs imipramine and desipramine have been described and include eosinophilia, pulmonary infiltrates with eosinophilia, and elevated total serum IgE levels. The immunologic mechanism accounting for these adverse reactions has not been elucidated. This article describes a patient manifesting bronchospasm, profound eosinophilia, and elevated serum IgE levels after therapy with desipramine that resolved rapidly after withdrawal of the drug. Immunologic investigations failed to demonstrate specific IgE directed against a protein conjugate of desipramine but demonstrated the ability of desipramine to induce mast cell degranulation with direct intradermal skin challenges.

Desipramine↗

PubMed2003

Effects of desipramine on regional serotonin synthesis in the rat brain: acute and chronic autoradiographic studies.

Various studies have implicated the involvement of noradrenaline (NA) and/or serotonin (5-hydroxytryptamine (5-HT)) in the pathogenesis and treatment of depression. The aim of the present study was to investigate the effects of acute and 7 days of administration of desipramine, a NA re-uptake inhibitor, on the rate of 5-HT synthesis in the rat brain. The study was done by an autoradiographic method using alpha-[14C]-methyl-L-tryptophan as a tracer. The acute (10mg/kg, i.p., 2h before i.v. infusion of the tracer) or 7 days of desipramine (10mg/kg per day, i.p.) did not affect plasma tryptophan (Trp) concentrations, as compared to control (saline treated) rats. Acute treatment with desipramine decreased the rate of 5-HT synthesis in the brain regions that contain 5-HT cell bodies between 19 and 28%, and increased the rate of 5-HT synthesis in the majority of areas containing 5-HT terminals between 21 and 65%. In contrast to the acute treatment, a 7-day administration increased 5-HT synthesis rates in the dorsal raphe (24%), but decreased it in raphe magnus (35%), superior olive (45%), caudate (31%), superior (38%) and inferior (53%) colliculus, and in the auditory cortex (35%). This suggests that the effect of desipramine on 5-HT synthesis rate is time-dependent and differs in the cell bodies and structures containing 5-HT nerve terminals.

Adrenergic Uptake Inhibitors↗

PubMed1999

Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test.

The objective of this study was to investigate whether bilateral dopamine depletion within the medial prefrontal cortex affects depression state, as well as the antidepressant efficacy of desipramine, in the forced swimming test. The rat's behaviour was evaluated by quantifying duration of immobility, climbing, swimming and diving. Immobility latency was also quantified and proved to be a suitable novel parameter. Monoamine levels within the medial prefrontal cortex were measured by high-performance liquid chromatography during Porsolt's test, as well as one week after it. While Porsolt's test was followed by a typical depression-like profile in sham rats, depletion of prefrontocortical dopamine (86% vs sham controls) reduced immobility and enhanced swimming, which is consistent with a diminished depression tonus. The observed enhancement of swimming was correlated with a high prefrontocortical serotonergic neurotransmission. On the other hand, desipramine induced antidepression-like effects in sham rats by increasing prefrontocortical noradrenaline and serotonin neurotransmisson, but also by blocking the normal increase in dopamine activity during the swimming test. Interestingly, desipramine behaved in a quite different manner in lesioned rats. Thus, immobility duration was not further reduced and only climbing, but not swimming, was enhanced. These effects were correlated with a preferential enhancement of noradrenaline neurotransmission. In conclusion, the results indicate that: (i) dopamine neurotransmission within the medial prefrontal cortex is a factor involved in depression, since dopamine reduction led to a low depression tonus; (ii) desipramine induces antidepression not only by enhancing prefrontocortical noradrenaline and serotonin neurotransmission, but also by blocking the normal increase in dopamine neurotransmission during a depressant situation; (iii) a selective enhancement of prefrontocortical serotonin neurotransmission mediates swimming; and (iv) a selectively augmented prefrontocortical noradrenaline activity mediates climbing during Porsolt's test.

Animals↗

PubMed1997

Simultaneous determination of imipramine and its metabolite desipramine in human plasma by capillary gas chromatography with mass-selective detection.

An analytical method for the simultaneous determination of imipramine (IMI) and its N-desmethyl metabolite, desipramine (DIMI) in human plasma by capillary gas chromatography-mass selective detection (GC-MS), with D4-imipramine (D4-IMI) and D4-desipramine (D4-DIMI) as internal standards, was developed and validated. After addition of the internal standards, the compounds were extracted from plasma at basic pH into n-heptane-isoamyl alcohol (99:1, v/v), back-extracted into acidic aqueous solution and re-extracted at basic pH into toluene. Desipramine and D4-desipramine were converted into their pentafluoropropionyl derivatives. The compounds were determined by gas chromatography using a mass selective detector at m/z 234 for IMI, m/z 238 for D4-IMI, m/z 412 for DIMI and m/z 416 for D4-DIMI. The method was applied to clinical samples.

Administration, Oral↗