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PubMed1988

First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype.

Four rapid extensive metabolizers (EM), four slow EM, and three poor metabolizers (PM) of sparteine were given single intravenous doses of 50 mg imipramine and desipramine. All subjects had previously taken single oral doses (100 mg) of imipramine and desipramine. The first-pass metabolism of imipramine and desipramine ranged from 23% to 73% and 0% to 48%, respectively, and was more pronounced for both drugs in EM than in poor metabolizers. The study suggested saturable 2-hydroxylation of imipramine and desipramine during the first-pass through the liver, especially in EM.

Adult↗

PubMed2001

Chronic desipramine treatment selectively potentiates somatostatin-induced dopamine release in the nucleus accumbens.

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin-14 (10(-4) M) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin-induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Utility of crossover designs in clinical trials: efficacy of desipramine vs. placebo in opioid-dependent cocaine abusers.

The utility of the crossover design in substance abuse research was examined in a 26-week, double-blind clinical trial that evaluated the efficacy of desipramine (0 or 150 mg/day) in 109 male and female cocaine- and opiate-dependent patients maintained on buprenorphine (12 mg/day) or methadone (65 mg/day). After being stabilized on buprenorphine or methadone (weeks 1-2), half of the patients were randomly assigned to receive desipramine for the first half of the trial and placebo for the second, with the order reversed for the second half. Analyses using hierarchical linear models (HLM) indicated that desipramine reduced the use of opiates only when administered at the start (rather than the middle) of the trial, whereas cocaine use was reduced when desipramine was introduced at either time.

Adult↗

PubMed1999

Analgesic effect of intrathecal desipramine on carrageenan-induced thermal hyperalgesia in the rat.

We examined if intrathecal desipramine, a selective norepinephrine reuptake inhibitor, would modulate peripheral inflammation-induced hyperalgesia. Rats were chronically implanted with a lumbar intrathecal catheter and paw withdrawal latency (PWL) to noxious heat stimuli was assessed. Unilateral hindpaw inflammation was induced by intraplantar carrageenan injection. Carrageenan injection significantly (P < 0.05) reduced PWL of the injected paw (from mean 11.4 (SEM 0.6) s to 3.5 (0.2) s, 3 h after carrageenan), but not of the contralateral side (from 11.6 (0.2) s to 11.2 (0.5) s). Intrathecal desipramine 10, 30, 60 and 100 micrograms, which did not produce analgesic effects in untreated rats, dose-dependently reversed the shortened PWL on the ipsilateral side (3.3 (0.2), 5.3 (0.4), 6.2 (0.3) and 9.6 (0.2) s, respectively) without affecting the contralateral side. Pretreatment with intrathecal yohimbine 10 micrograms did not antagonize the anti-hyperalgesic effects of desipramine (from 9.6 (0.2) to 9.8 (0.3) s). Our results suggest that the mechanism underlying the analgesic effect of desipramine on inflammation-induced hyperalgesia is unlikely to be inhibition of norepinephrine reuptake within the spinal cord.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Comparison of a new GLC-AFID method with a GLC-MS selected ion monitoring technique and a radioimmunoassay for the determination of plasma concentrations of imipramine and desipramine.

A gas-liquid chromatographic procedure employing an alkali flame ionization detector (GLC-AFID) for the quantitation of imipramine and its major active metabolite, desipramine, in plasma was developed. This method validated a previously reported radioimmunoassay for imipramine and desipramine. The GLC-AFID method was also compared with a GLC-mass spectrometric procedure which employed selected ion monitoring (GLC/MS-SIM) in which specific ions for imipramine and desipramine were monitored. The two methods using gas chromatographic separation were shown to be suitable for therapeutic monitoring of these drugs in patients. The direct immunoassay, which measures the total imipramine plus desipramine, is very useful when large numbers of samples are to be analysed rapidly and it compares favorably with the other two analytical procedures.

Desipramine↗

PubMed1999

The antinociceptive effects of morphine, desipramine, and serotonin and their combinations after intrathecal injection in the rat.

UNLABELLED: Antinociception can be produced at the spinal level by activation of opioidergic, noradrenergic, and serotonergic systems. We tested the antinociceptive effects of combined activation of all three systems. Antinociception was assessed in the rat tail-flick test, and drugs were administered via an intrathecal catheter. Morphine, the norepinephrine uptake inhibitor desipramine, and serotonin produced antinociception of their own. The combination of subthreshold doses of morphine 1 microg and of desipramine 3 microg produced pronounced antinociception that was antagonized by yohimbine. The combination of subthreshold morphine with serotonin 50 microg or desipramine with serotonin caused only small antinociceptive effects. When morphine combined with desipramine was decreased to a subthreshold dose, we observed pronounced antinociception when a subthreshold dose of serotonin was added. A complex interaction can be supposed by results obtained with antagonists. The activation of all three neurotransmitter systems with small doses of agonists may represent an effective principle for pain control at the spinal level. IMPLICATIONS: Pain sensations are modulated at the spinal level by opioids, noradrenergic drugs, and serotonin. Using a rat model, we showed that the concurrent use of drugs from each of these classes produces good pain control at doses that should avoid the side effects associated with larger doses of each individual drug.

Adrenergic Uptake Inhibitors↗

PubMed1985

Interethnic dissociation between debrisoquine and desipramine hydroxylation.

Chinese and Caucasian volunteers who had previously participated in a single dose desipramine pharmacokinetic study underwent debrisoquine hydroxylation phenotyping. After a single 10-mg oral dose of debrisoquine, urinary concentrations of the drug and its major metabolite, 4-hydroxy-debrisoquine (4-OHD), from an 8-hour collection were more variable in the Caucasians. Compared to the Chinese, the Caucasian subjects tended to excrete higher mean fractions of the dose as unchanged debrisoquine (10.9 +/- 8.8% vs. 6.3 +/- 2.6%) and 4-OHD (15.9 +/- 13.0% vs. 9.7 +/- 7.7%), although given the high variability the differences did not reach significance. The "metabolic ratio" of urinary debrisoquine to 4-OHD was less than 3 in all 20 subjects, indicating extensive debrisoquine hydroxylation in every volunteer, including two Chinese individuals known to display slow clearance of desipramine. Contrary to expectation, debrisoquine hydroxylation did not correlate with total or hydroxylation clearance of desipramine in either ethnic group singly or combined. This finding is not consistent with assumptions about the genetic equivalence of the primary metabolic pathways of debrisoquine and desipramine.

Adult↗

PubMed1995

Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants.

In vitro preparations of human liver microsomes were used to study the inhibiting effects of two selective serotonin reuptake inhibitor (SSRI) antidepressants, paroxetine and fluvoxamine, on metabolism via hydroxylation of alprazolam and of desipramine. These reactions are mediated by Cytochromes P450-3A4 and P450-2D6, respectively. Paroxetine was a highly potent inhibitor of desipramine hydroxylation; the inhibition constant (Ki) value of 2.0 microM indicated greater inhibiting potency than fluoxetine or norfluoxetine. The in vitro data predicted in vivo impairment of desipramine clearance by coadministration of paroxetine which was in the same range as observed in a clinical study. Fluvoxamine, by contrast, was a much weaker inhibitor of desipramine hydroxylation, having a Ki value (16.6 microM) similar to those of sertraline and desmethylsertraline. For hydroxylation of alprazolam, paroxetine was a relatively weak inhibitor, approximately comparable to fluoxetine, whereas fluvoxamine showed inhibiting capacity similar to that of norfluoxetine. The in vitro data predicted the degree of impairment of alprazolam clearance observed in vitro model can therefore provide clinically relevant data on prediction of potential drug interactions with SSRIs.

Alprazolam↗

PubMed1991

A comparison of adinazolam and desipramine in the treatment of major depression.

Thirty-one patients with a DSM-III (R) diagnosis of Major Depression received adinazolam (n = 16) or desipramine (n = 15) during a 6 week double-blind randomized controlled trial. Both groups showed a significant decline in Hamilton Rating Scale for Depression scores (21.8 +/- 4.5 to 10.7 +/- 8.5 for adinazolam and 23.5 +/- 5.5 to 12.9 +/- 8.6) for desipramine. Melancholic and anxiety symptoms were reduced equally by both drugs. Initial sedation was the most common side-effect with adinazolam. Plasma levels of desipramine and hydroxy-desipramine correlated highly with oral dose after 3 weeks of treatment.

Adult↗

PubMed1993

Simultaneous high-performance liquid chromatography-electrochemical detection determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine N-oxide in human plasma and urine: preliminary application to oxidation pharmacogenetics.

This assay method allows a simultaneous determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine-N-oxide in 0.5 ml of plasma or 0.1 ml of urine within 35 min by an ion-paired, reversed phase (C18) high-performance liquid chromatography (HPLC) with electrochemical detection. The analytes are extracted from alkalinized plasma or urine with 5 ml of a 90/10 mixture (by vol) of diethyl either/2-propanol, back-extracted into 0.5 ml of 0.1 mol/L phosphoric acid. Urine samples are enzymatically treated with beta-glucuronidase/arylsulfatase before extraction. The electrochemical detection is performed with a glassy carbon electrode set at +0.85 V against the Ag/AgCl reference electrode. Recoveries for the analytes and the internal standard (propericiazine) from plasma or urine ranged from 66.4 to 105.7% with coefficients of variation (CVs) of < 6.8%. The intra- and interassay CVs for the analytes were < 17.4% in plasma and < 14.2% in urine. The limits of determination (a signal-to-noise ratio of 3) for imipramine, desipramine, 2-hydroxyimipramine, 2-hydroxydesipramine, and imipramine-N-oxide were 0.5, 0.3, 0.02, 0.02, and 1.0 microgram/L, respectively. Only four of the 23 psychotropic drugs, which might be coadministered with imipramine or desipramine, were considered to be the possible sources to interfere with the assay. We evaluated clinical applicability of this method by determining plasma concentration- and urinary excretion-time courses of the respective analytes in an extensive and a poor metabolizer of the debrisoquine/sparteine-type oxidation after a single oral dose of imipramine HCl (25 mg). The present method appears to be suitable not only for the therapeutic drug monitoring of imipramine and its active metabolites but also for studying the pharmacogenetically related metabolism of imipramine or desipramine.

Arylsulfatases↗

PubMed2004

Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics.

This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D6*3, *4, *5 and *6 alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D6*2, *9, *10, *17, *41 and x2). Genotypes of individuals heterozygous for two or three of *2, *17 and *41 alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) *9 allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with *1/*1, *1/*2 and *2/*2 genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6 IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6 genotype-phenotype relationships.

Alleles↗

PubMed1985

Desipramine binding: relationship to central and sympathetic noradrenergic activity.

We examined the effects of treatments affecting norepinephrine release on the number of norepinephrine reuptake recognition sites as reflected by desipramine binding. To do this, we used manipulations having similar presynaptic but contrasting postsynaptic effects. Presynaptic inhibition by 6-hydroxydopamine lesion or by clonidine, and postsynaptic receptor stimulation by isoproterenol, reduced desipramine binding. Presynaptic stimulation by d-amphetamine and postsynaptic receptor blockade by prazosin increased desipramine binding. Similar effects and binding properties were seen in cerebral cortex, heart, and soleus muscle. After unilateral noradrenergic lesions, reduction in desipramine binding correlated with reduction in norepinephrine uptake. These results show that norepinephrine reuptake appears to be regulated by transmitter release regardless of effects on postsynaptic transmission, and that this regulation is analogous in the central and sympathetic nervous systems.

Animals↗

PubMed1988

Possible involvement of pertussis toxin substrates (Gi, Go) in desipramine-induced refractoriness of adenylate cyclase in cerebral cortices of rats.

To evaluate the efficiency of coupling between beta-receptor and adenylate cyclase catalyst via a GTP-binding protein, Gs, in the brain membrane two parameters were employed: a beta-agonist-induced increase in the membrane GTP-dependent adenylate cyclase activity and a beta-agonist-induced shortening of the lag time preceding the onset of the steady-state activation by guanyl-5'-yl-beta-gamma-imidodiphosphate [Gpp(NH)p] of the membrane cyclase. Both parameters showed lower values in membranes from desipramine-treated rats compared with untreated rats. Thus, coupling of beta-adrenergic receptors to adenylate cyclase in the brain membrane was impaired by the desipramine treatment. Rats once injected intraventricularly with islet-activating protein (IAP), pertussis toxin, were subjected to desipramine treatment, for the purpose of studying effects of another kind of the GTP-binding protein (Gi), which loses its function as a signal transducer on being ADP-ribosylated selectively by the toxin. IAP treatment did not impair the beta-receptor coupling by itself, since neither of the above two parameters for the coupling were reduced by IAP treatment. Moreover, the first parameter was normalized, though the second one was not, by superimposition of the IAP treatment upon the desipramine-treated rats. It seems likely, therefore, that Gi interacts with a Gs-adenylate cyclase coupling in an inhibitory fashion in brain membranes. The desensitization might be overcome when the inhibitory interaction of Gi on the subsequent process is attenuated by IAP treatment.

Adenosine Diphosphate Ribose↗

PubMed1989

[3H]desipramine binding to rat brain tissue: binding to both noradrenaline uptake sites and sites not related to noradrenaline neurons.

The pharmacological and biochemical characteristics of [3H]desipramine binding to rat brain tissue were investigated. Competition studies with noradrenaline, nisoxetine, nortriptyline, and desipramine suggested the presence of more than one [3H]desipramine binding site. Most of the noradrenaline-sensitive binding represented a high-affinity site, and this site appeared to be the same as the high-affinity site of nisoxetine-sensitive binding. The [3H]desipramine binding sites were abolished by protease treatment, a result suggesting that the binding sites are protein in nature. When specific binding was defined by 0.1 microM nisoxetine, the binding was saturable and fitted a single-site binding model with a binding affinity of approximately 1 nM. This binding fraction was abolished by lesioning of the noradrenaline neurons with the noradrenaline neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). In contrast, when 10 microM nisoxetine was used to define the specific binding, the binding was not saturable over the nanomolar range, but the binding fitted a two-site binding model with KD values of 0.5 and greater than 100 nM for the high- and low-affinity components, respectively. The high-affinity site was abolished after DSP4 lesioning, whereas the low-affinity site remained. The binding capacity (Bmax) for binding defined by 0.1 microM nisoxetine varied between brain regions, with very low density in the striatum (Bmax not possible to determine), 60-90 fmol/mg of protein in cortical areas and cerebellum, and 120 fmol/mg of protein in the hypothalamus. The binding capacities of these high-affinity sites correlated significantly with the regional distribution of [3H]noradrenaline uptake but not with 5-[3H]hydroxytryptamine uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1974

Effects of imipramine and desipramine on responses of single cortical neurones to noradrenaline and 5-hydroxytryptamine.

1 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat, anaesthetized with halothane.2 Imipramine and desipramine, when applied for a brief period, did not affect the firing rate of the vast majority of the neurones tested.3 Both potentiation and antagonism of excitatory responses to noradrenaline could be observed after a brief application of either of the antidepressants. Four drug-interaction patterns could be distinguished: potentiation of immediate onset; potentiation reaching its maximum after a delay; antagonism followed by potentiation; antagonism followed by recovery.4 When different doses of the same antidepressant were applied, it was found that the drug-interaction patterns were related to the dose of antidepressant applied, a lower dose causing potentiation, and a higher dose antagonism of the response.5 Both potentiation and antagonism of depressant responses to noradrenaline could be observed.6 Both excitatory and depressant responses to 5-hydroxytryptamine were modified by imipramine and desipramine: a smaller dose of the antidepressant potentiated, and a higher dose antagonized the responses.7 Excitatory responses to glutamate were not affected by imipramine and desipramine.

Action Potentials↗

PubMed1989

Sympathetic denervation caused by long-term noradrenaline infusions; prevention by desipramine and superoxide dismutase.

1. The effects of continuous intravenous infusion of noradrenaline (0.01 and 0.1 microgram kg-1 h-1) were studied in both the infused lateral saphenous vein and the contralateral saphenous vein of normal dogs. Noradrenaline, saline, noradrenaline + desipramine or noradrenaline + superoxide dismutase were infused using Alzet osmotic minipumps. 2. After a 5 day infusion period, the noradrenaline content in plasma and in both saphenous veins was determined, and the venous tissues submitted to light microscope morphometry and ultrastructural study and used for the determination of their O-methylation capacity (with [3H]-isoprenaline as a substrate). 3. Noradrenaline caused dose-dependent damage to the sympathetic nerve endings of the lateral saphenous veins. Concomitant changes in extraneuronal structure and function were observed (hypertrophy of smooth muscle cells, nuclear dysmorphy, thickening of the vessel wall, impairment in O-methylation capacity). 4. Desipramine and superoxide dismutase prevented or reduced the effects of noradrenaline on both the morphological and the biochemical parameters; the protection afforded by superoxide dismutase was more marked than that by desipramine. 5. It is concluded that moderately high doses of noradrenaline exert a 6-hydroxydopamine-like effect and that this chemical sympathectomy is partially or totally prevented by desipramine or superoxide dismutase. The data suggest that a substance derived from noradrenaline, in the formation of which free oxygen radicals are involved and which is subject to neuronal uptake, is the chemical entity responsible for the neurotoxic effect observed.

Animals↗

PubMed1982

Comparison between zimelidine and desipramine in endogenous depression. A cross-over study.

Depressed patients, who did not respond after 4 weeks treatment with zimelidine 100 mg b.i.d. (five patients) or desipramine 75 mg b.i.d. (11 patients) in a double-blind randomized study were crossed over, after 1 placebo week, to 4 weeks of treatment with the other drug. The three zimelidine non-responders who responded to desipramine were significantly more retarded compared with eight desipramine non-responders who responded to zimelidine. It was observed that two patients with bipolar depression developed mania during crossover treatment with desipramine, while two patients with bipolar depression who were treated with zimelidine during the second treatment period did not show any symptoms of mania. Three patients who were non-responders during both treatment periods had lower plasma concentration of the drugs compared with respective responding groups.

Antidepressive Agents↗

PubMed1981

Actions of lofepramine, a new tricyclic antidepressant, and desipramine on electrophysiological and mechanical parameters of guinea pig atrial and papillary muscles.

The effects of lofepramine on the isolated guinea pig atrial trabeculae were compared with those of desipramine. The preparations were taken from the same animal and mounted in the same tissue bath. All parameters were recorded in parallel. Lofepramine 10 microM was shown to exhibit minor changes in the transmembrane action potential duration only. The action potentials of the atrial trabeculae were prolonged, whereas they were shortened in the papillary muscles. Desipramine was about ten times more potent than lofepramine, but produced similar qualitative changes. Desipramine 10 microM and lofepramine 100 microM showed local anaesthetic properties: a decreased overshoot without a decreased resting potential, a decreased and rate-dependent Vmax, and a decrease in propagation velocity. After the addition of either drug in a lower concentration, a transient increase in force development and a concomitant increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) were recorded. The steady state effect on the force development was a decrease accompanied by a shortening of the action potential duration (papillary muscle). It is suggested that the action of lofepramine 100 microM and desipramine 10 microM on phase 0 of the action potential are produced by blockage of the fast sodium channel. The transient increase in developed force and the increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) could be caused by inhibition of the membrane re-uptake system for released noradrenaline. The steady state shortening and flattening of the plateau (papillary muscle) and the decrease in force development could be the cause of a block in the slow channel system.

Action Potentials↗