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PubMed1992

Measurement of free desipramine in serum by ultrafiltration with immunoassay.

We developed an ultrafiltration method for assaying free desipramine (DMI) in serum. An ultrafiltrate of DMI-containing serum was prepared by centrifugation through an Amicon Centrifree micropartition filter. Syva DMI solid-phase extraction (SPE) columns were used to extract the DMI from the serum and ultrafiltrate. The Syva monoclonal EMIT assay was used to quantify the DMI in the extract. In some experiments, the percent free DMI was quantified with radioactivity. Nonspecific losses of DMI in serum to the ultrafilter system were low (recoveries > 91%). Extraction of [3H]DMI from phosphate-buffered saline (to mimic serum ultrafiltrate) with the Syva SPE system was quantitative (recoveries of 98.4% +/- 4.6%). Free DMI concentrations, derived from serum containing 2.5-2500 micrograms/L DMI, were determined by ultrafiltration; results agreed well with values determined by equilibrium dialysis, the average percent of free DMI being 18.4% +/- 0.25% and 15.9% +/- 0.51%, respectively. To increase the sensitivity of the free DMI assay in the therapeutic range (total DMI 125-300 micrograms/L), we increased fourfold the ultrafiltrate volume applied to the SPE column. For free DMI at 11-130 micrograms/L, the within-run and between-run CVs for the ultrafiltration method were < 9% and < 15%, respectively. Binding of DMI to serum proteins decreased over the pH range 6.0-8.0, although temperatures between 20 and 28 degrees C did not affect binding. The ultrafiltration assay is fast, accurate, simple, and adaptable to standard laboratory instrumentation.

Desipramine↗
PubMed1992

Adjunctive desipramine in the treatment of cocaine abusing schizophrenics.

Because schizophrenic patients have a lifetime prevalence rate for cocaine abuse between 15 and 50 percent, the use of adjunctive pharmacotherapy should be considered in cocaine-abuse treatment programs. This 12-week, open-label outpatient study compares 12 cocaine-abusing schizophrenic patients treated with desipramine (DMI) 100 to 150 mg and antipsychotic agents to 15 patients treated with only antipsychotic agents (no DMI). All 27 patients participated in a Dual Diagnosis Relapse Prevention (DDRP) program, which integrates traditional substance-abuse relapse prevention and psychiatric social skills training. The DMI group was more likely to complete the study (83% vs. 60%, odds ratio = 3.3, NS) and had fewer cocaine-positive urines during the last 6 weeks (20% vs. 50%, odds ratio = 4.0, p < .01). In the context of a specialized dual diagnosis treatment program, patients receiving DMI substantially decreased cocaine usage and had improved psychiatric symptoms.

Adult↗
PubMed1991

Effects of long-term desipramine administration on noradrenergic neurotransmission: electrophysiological studies in the rat brain.

The present studies were undertaken to assess in vivo the effects of repeated administration of the norepinephrine (NE) reuptake blocker desipramine (DMI) (5 or 10 mg/kg/day x 14 days) on five subsets of adrenoceptors and on the effectiveness of the NE reuptake process in the rat central nervous system. These receptors were: 1) the postsynaptic alpha-2 adrenoceptors which signal the suppressant effect of microiontophoretically applied NE on the firing activity of dorsal hippocampus pyramidal neurons; 2) the postsynaptic alpha-1 adrenoceptors which mediate the short-latency suppressant effect of endogenous NE, released by the electrical stimulation of the locus ceruleus (LC), on the firing activity of these same neurons; 3) the postsynaptic beta adrenoceptors which mediate the long-latency excitatory effect of LC stimulation on hippocampus pyramidal neurons; 4) the alpha-2 autoreceptors located on NE terminals in the hippocampus; and 5) the alpha-2 autoreceptors located on the cell body of LC NE neurons. The suppressant effect of microiontophoretic applications of NE on dorsal hippocampus pyramidal neurons was not changed by the long-term DMI treatments. The recovery time of the firing activity of these neurons after microiontophoretic application of NE, an index of the activity of the NE reuptake process, was the same in control and DMI-treated rats. However, the prolongation of this recovery time by the acute i.v. administration of DMI reached a plateau at a lower cumulative dose in long-term DMI-treated than in control rats. These results thus suggest that long-term administration of DMI did not affect the function of the NE transporter but reduced the number of DMI binding sites. The effectiveness of the 1 Hz stimulation of the LC in suppressing of the firing activity of pyramidal neurons was unchanged by either long-term DMI treatment (5 or 10 mg/kg/day), whereas that of the 5 Hz stimulation was enhanced only in rats on the 10-mg/kg regimen. This suggests that the function of terminal alpha-2 autoreceptors was decreased after this latter DMI regimen, because the reduction of the efficacy of the stimulation obtained by increasing the frequency from 1 to 5 Hz has been shown to be due to the activation of terminal alpha-2 adrenergic autoreceptors. In keeping with this interpretation, the reduction of the effectiveness of the stimulation of the LC by the systemic administration of the alpha-2 adrenoceptor agonist clonidine was attenuated in rats treated with the 10-mg/kg/day regimen of DMI, but not in those with the 5-mg/kg/day regimen.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Down-regulation of beta receptors by desipramine in vitro involves PKC/phospholipase A2.

Chronic treatment with a number of antidepressants results in a down-regulation and/or a desensitization of rat cortical beta-adrenergic receptors (beta ARs). Although these effects generally have been attributed to elevations in intrasynaptic norepinephrine via presynaptic mechanisms, the recent demonstration of similar changes in beta ARs following in vitro incubation of cultured cells with desipramine (DMI) suggests that direct, postsynaptic mechanisms may also be involved. To study these mechanisms, we incubated rat C6 glioma cells with 10 microM DMI for 1 or 5 days. DMI produced a significant reduction in beta AR density following chronic (but not acute) treatment (BMAX control = 1325 +/- 78 fmol/mg; DMI = 1179 +/- 96; p less than .05). Interestingly, the beta AR down-regulation was accompanied by an increase in KL/KH ratio (ratio of dissociation constants for the low- and high-affinity states of the receptor), suggesting that these drugs may stabilize the high-affinity complex. DMI treatment attenuated the cyclic adenosine monophosphate (cAMP) response to 1 microM isoproterenol (control = 540 +/- 82 pmol/mg/15 min; DMI = 335 +/- 64; p less than .05), but not to agents acting distal to the receptor (cholera toxin or forskolin). Coincubation of C6 cells with either the phospholipase A2 (PLA2) inhibitor mepacrine or the protein kinase C (PKC) inhibitor H7, during chronic treatment with DMI, blocked the down-regulation of beta ARs. Incubation of C6 cells with phorbol esters (PKC activators) also down-regulated beta ARs, effects that were nonadditive with those of DMI. Incubation with H7 alone resulted in an up-regulation of beta ARs, consistent with a tonic regulatory effect of PKC on beta ARs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Effect of chronic desipramine treatment on rat brain adrenergic alpha 2-receptor].

Clonidine has been reported to be effective as an alpha 2-adrenoceptor agonist. Locomotor activity was measured by Automex after clonidine (100 micrograms/kg ip) administration. A significant reduction of locomotor activity was found during the 30th-45th-min period of experiment. 3-Methoxy-4-hydroxyphenylethyleneglycol (MHPG)-total was decreased significantly at 60 min after clonidine administration in rat cerebral cortex, hippocampus and hypothalamus. This might suggest that MHPG content at 60 min after clonidine administration can be used as functional index of the presynaptic alpha 2-adrenergic receptor. Desipramine (DMI) (20 mg/kg) was injected ip once daily for 14 d and experiments undertaken 60 min after the clonidine administration. Chronic DMI treatment had an effect on rat brain steady state levels of serotonin (5-HT) system. Chronic DMI administration was shown to attenuate the effect of clonidine that reduced MHPG levels on rat brain. The results suggest that the chronic DMI treatment may diminish the clonidine-induced reduction of MHPG via the subsensitivity of presynaptic alpha 2-adrenergic receptor.

Animals↗
PubMed1991

[Central analgesic effects of antidepressant drugs with various mechanisms of action: desipramine, fluvoxamine and moclobemide].

Analgesic properties of antidepressants are not yet well established. The aim of this study was to investigate the analgesic effect of three antidepressants after single oral dose administration to healthy volunteers. The late spinal R-III reflex threshold (objective pain threshold) and the subjective pain threshold (numerical categorical scale) were markers of analgesic effect. Desipramine induced significant increases in both thresholds. Fluvoxamine and moclobemide also exerted a significant analgesic effect, although displaying distinct patterns depending on the analgesic marker considered. Antidepressants exert a central analgesic effect independent of their antidepressive effect and, depending on their mode of action, already detectable at spinal level.

Analgesics↗
PubMed1991

Effect of desipramine on inositol phosphate formation and inositol phospholipids in rat brain and human platelets.

To examine the mechanism of action of antidepressant drugs, we studied the effect of desipramine (DMI) in vitro on agonist-stimulated inositol phosphate formation and inositol phospholipids in rat brain and human platelets. We observed that DMI inhibited thrombin-stimulated 3H-inositol bisphosphate (IP2) and 3H-inositol trisphosphate (IP3) but not 3H-inositol monophosphate (IP1) formation in human platelets. DMI also inhibited norepinephrine (NE) and serotonin (5-HT) stimulated 3H-IP1 formation in rat cerebral cortex. DMI increased levels of all three 3H-inositol phospholipids, 3H-phosphatidyl inositol (PI), 3H-PI-4-phosphate (PIP), and 3H-PI 4,5-bisphosphate (PIP2), in both platelets and rat cortex. The decreased formation of inositol phosphates and increased levels of [3H]-PI, [3H]-PIP, and [3H]-PIP2 by DMI appears to be due to the inhibition of the enzyme phospholipase C rather than its effects on receptors. It is thus possible that interaction of tricyclic antidepressant drugs with the PI-signaling system may be related to their mechanism of action.

Animals↗
PubMed1991

Saliva and plasma desipramine levels in Asian and Caucasian volunteers.

Thirty-seven healthy volunteers (18 Asian, 19 Caucasian) ingested a single desipramine (DMI) dose of 1.0 mg/kg of body weight. Saliva and plasma samples were obtained at 1, 3, 5, 7, 12, 24, 48, 72, and 96 hrs after dosing. A nested repeated-measures analysis of variance (ANOVA) design was used to determine if the plasma/saliva DMI ratio varied between Asians and Caucasians over time. Regression analysis was used to assess the ability of saliva DMI to predict plasma DMI at any time point. The ANOVA results indicated no significant differences in DMI plasma/saliva ratios between Asians and Caucasians. There was a major effect of sampling time on the DMI plasma/saliva ratio (p = 0.0001), with the ratio falling from 1.78 at 1 hr to 0.15 at 96 hrs. At any given time at least 24 hrs after the dose, there was a significant relationship between saliva and plasma levels across individuals. However, across subjects, the 95 percent confidence limits for predicting plasma DMI from saliva DMI levels were relatively large. The potential roles and limitations of saliva DMI in pharmacokinetic studies and clinical drug monitoring are discussed.

Adult↗
PubMedDate not supplied

[Clinical usefulness of monitoring serum levels of imipramine and desipramine in patients treated for endogenous depression].

Fifteen patients with endogenous unipolar and bipolar depression were treated with imipramine and, if necessary, one of benzodiazepine or neuroleptic. Total serum concentrations of imipramine (IMI) and its active metabolite desipramine (DMI) were measured in steady-state by FPIA method . Severity of depression was assessed using the Hamilton Depression Rating Scale. IMI + DMI serum concentration monitoring appeared to be useful in every case. It helped to arrive more quickly at the optimal dosage, confirmed the suspicion of overdosage or noncompliance. In nonresponders group, it helped with the earlier decision of changing brands of tricyclic antidepressant or it contributed to intensify the diagnostic process which detected the additional pathology.

Adult↗
PubMed1991

Response to desipramine treatment in adolescent major depression.

Thirty adolescents (ages 15-20) who met DSM-III-R criteria for major depressive disorder completed a double-blind, placebo-controlled, 6-week, fixed-dose (200 mg daily) study of desipramine (DMI). Thirty-three percent of the placebo group and 50 percent of the DMI group improved (greater than or equal to 50% change on the Hamilton Rating Scale for Depression). Subjective reports of adverse effects did not significantly differentiate the two groups. Major adverse effects, necessitating study discontinuation, occurred solely in the DMI group.

Adolescent↗
PubMed1991

Desipramine treatment of alcoholism.

Depression has been related to relapsed drinking in alcoholics striving to maintain sobriety. Treatment with tricyclic antidepressants might reverse or prevent depressive symptoms related to relapse, and may reverse biochemical abnormalities hypothesized to underlie both depression and alcoholism, thus helping to prolong abstinence in recovering alcoholics. This is a preliminary report of the findings of an ongoing 6-month, double-blind, placebo-controlled trial of desipramine (DMI) in recently abstinent alcoholics, with stratification on the presence or absence of secondary depression and DMI plasma level monitoring. Hypotheses are that DMI will prolong sobriety and reduce depression secondary to alcoholism significantly more than placebo. Subjects were 34 males and 8 females with 19 subjects stratified as depressed after an average of 16.31 days of sobriety. Depressed DMI subjects were significantly less depressed at the time of their termination from study than depressed placebo subjects. No group differences were found in rate of nonsobriety. However, there was a trend for DMI subjects to maintain sobriety for a longer duration on the study since onset of alcoholism, with 33.3 percent depressed placebo, 9.1 percent nondepressed placebo, 60.0 percent depressed DMI, and 41.7 percent nondepressed DMI subjects having their longest period of sobriety on the study.

Adult↗
PubMed1990

Combined effects of desipramine and stress on monoamine turnover in rat brain.

Because depression is often associated with stress, it has been hypothesized that antidepressants may influence stress-related adaptive responses in the brain. This issue was addressed in the present study designed to compare the effects of desipramine (DMI) administration and stress on monoamine metabolism in rat brain. Rats were housed in crowded conditions for 3 to 14 days and injected with DMI or saline at various times during treatment. Animals were decapitated, after which norepinephrine (NE), serotonin (5-HT), and their metabolites were measured in various brain regions by high-performance liquid chromatography using electrochemical detection. The results indicate that DMI administration increased 5-HT turnover in all regions and NE turnover in the hypothalamus when administered for 14 days to animals housed under crowded conditions. In conclusion, DMI had a different effect on rat brain monoamine turnover under the crowded stress conditions when compared with control animals. In addition, the turnover of NE and 5-HT in some regions of the brain was augmented when DMI and stress were combined.

Animals↗
PubMed1990

Effect of desipramine treatment on pulmonary phospholipid metabolism in rats.

Changes in pulmonary phospholipid (PL) composition, fatty acid composition in phosphatidylcholine (PC) and the factors contributing to regulate fatty acid composition in PC were studied in rats treated with desipramine (DP). DP level and PL content in post lavage, surfactant and alveolar macrophages (AMs) showed significant increases by DP treatment, and the accumulation of DP and PL into post lavage was the largest of three pulmonary fractions. The overall increase of PL content in post lavage was mostly sustained by PC. Only palmitic acid involved in PC from post lavage was significantly increased by DP administration, and other fatty acids showed a decrease tendency. Concerning the factors affecting fatty acid composition in PC, the ratio of palmitic acid in free fatty acid pool and the uptake of palmitoyl-CoA into PC via deacylation-reacylation system were increased by DP treatment.

Animals↗
PubMed1989

Reevaluation of the regulation of beta-adrenergic receptor binding by desipramine treatment.

Treatment of rats with desipramine (DMI) has been shown to down-regulate beta-adrenergic receptor-stimulated adenylate cyclase and reduce the Bmax of beta-adrenergic receptors in some brain areas. Recent reports have indicated that the down-regulation in the number of beta-adrenergic receptors following DMI treatment does not occur if the serotonin system has been impaired following parachlorophenylalanine (PCPA) or 5,7-dihydroxytryptamine injection. We have previously shown that [3H]dihydroalprenolol ([3H]DHA), the most commonly used radioligand to measure central nervous system beta-adrenergic receptors, labels another site under normal experimental procedures, in addition to the beta-adrenergic receptors. This second site has some pharmacological characteristics of the 5-hydroxytryptamine1A receptor. The depletion of serotonin following PCPA injection was indeed able to prevent the down-regulation of [3H]DHA binding sites after DMI injection. However, PCPA alone increased the density of [3H]DHA binding sites. If the nonlinear, least squares, curve-fitting program LIGAND was allowed to define [3H]DHA nonspecific binding or if the more selective beta-adrenergic receptor radioligand [3H]CGP-1277 was used, the Bmax of beta-adrenergic receptors was not changed after PCPA injection. Importantly, PCPA did not prevent beta-adrenergic receptor down-regulation following DMI treatment. The blockade of 5-hydroxytryptamine2 receptors, via ketanserin administration, during DMI treatment did not change the response of beta-adrenergic receptors. Furthermore, if LIGAND was used to define the nonspecific binding of [3H]DHA, the down-regulation of beta-adrenergic receptors was significant 24 hr after a single DMI injection. The same rapid down-regulation was demonstrated with [3H]CGP-12177. However, if [3H]DHA was used to label beta-adrenergic receptors in the "typical" manner (nonspecific binding defined by 10 microM alprenolol), a decrease in the number of beta-adrenergic receptors was significant only after seven daily DMI injections. These data demonstrate that the use of [3H]DHA to measure beta-adrenergic receptors can be misleading, because changes in its second binding site can conceal the changes occurring in beta-adrenergic receptors. Moreover, these results suggest that a similarity in the time course of action of DMI cannot be used to support the hypothesis that its therapeutic antidepressant action is related to beta-adrenergic receptor down-regulation.

Animals↗
PubMed1989

Pharmacokinetics of desipramine in Asian and Caucasian volunteers.

The pharmacokinetic differences of tricyclic antidepressants (TCAs) in Asians and Caucasians remain controversial. Thirty-seven age-matched healthy volunteers (18 Asians and 19 Caucasians) ingested a single desipramine (DMI) dose of 1.0 mg/kg of body weight. Blood was obtained at 1, 3, 5, 7, 12, 24, 48, 72, and 96 hours after dosing. Serial 24-hour urine samples were collected for 5 days. There were no statistically significant differences in plasma levels between the two groups. DMI concentrations peaked a median of 5 hours after ingestion in Asians vs. 3 hours in Caucasians. Total clearances of DMI (CL DMI) and hydroxylated DMI (OH-DMI) were greater in Caucasians. These differences were no longer significant when corrected for body weight. Clearances appeared to follow tri-modal distributions. The proportions of Asians and Caucasians falling into the slow, intermediate, and rapid clearance groups were not significantly different, but there was a tendency for more Caucasians to be in the rapid clearance group.

Adult↗
PubMedDate not supplied

Chronic administration of desipramine and imipramine but not zimelidine attenuates clonidine-induced depression of avoidance behavior in rats.

Clonidine (CLO) given intraperitoneally in a dose of 0.05 mg/kg decreased the open-field behavior in rats and completely abolished avoidance acquisition. Short term (4 days) administration of desipramine (DMI) and imipramine (IMI) practically failed to change the depressive effects of CLO whilst chronic (21 days) treatment significantly reduced the CLO action on both avoidance and open-field behavior. Contrary to tricyclic antidepressants, zimelidine (ZIM) given either acutely or chronically did not affect the avoidance deficit but given chronically attenuated the CLO-induced sedation in the open field. The results suggest that "classic" tricyclic antidepressants acting strongly upon noradrenaline uptake are more potent in preventing avoidance deficit induced by the alpha 2-adrenoceptor agonist, CLO than drugs acting more selectively upon serotonin uptake.

Animals↗
PubMed1986

Pharmacologic evidence that high dose chronic amitriptyline and desipramine down-regulate alpha 2-receptor-mediated hypothermia in the rat.

The effects of a three week course of treatment of amitriptyline (AMI) and desipramine (DMI) (3.2 and 10 mg/kg, s.c., b.i.d.) were studied on the hypothermic response to clonidine (0.1 mg/kg, s.c.) in male adult albino rats. Single doses of clonidine in normal unmedicated rats produced a marked (about 2 degrees C) fall in body temperature. In contrast, 0.9% NaCl control injections had no significant effect. The clonidine-induced hypothermia was prevented by yohimbine pretreatment (3.2 mg/kg, i.p., 1/2 hr before), suggesting an alpha 2-mediated response. On days 8 and 14 of chronic tricyclic antidepressant (TCA) treatment, the hypothermic response was prolonged. Four days after the abrupt withdrawal of 20 days of TCA treatment (10 mg/kg, s.c., b.i.d.), the clonidine-induced hypothermia response was attenuated consistent with down-regulation of alpha 2-receptors. This latter effect was not observed with a dose of 3.2 mg/kg, s.c., b.i.d. of either TCA.

Amitriptyline↗
PubMedDate not supplied

On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression.

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test.

Amitriptyline↗