SEARCH · PubMed Health

Results for “DESIPRAMINE”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed1983

Desipramine-induced increase in efflux of endogenous dopamine from rat hypothalamus in vitro: mechanism and specificity.

In vitro exposure of minced rat hypothalamus to desipramine (DMI) resulted in a significant elevation of the net efflux of endogenous norepinephrine (NE) and dopamine (DA) at a drug concentration as low as 10 nM. The net efflux of epinephrine was increased only by a 1000-fold greater concentration of desipramine. The increase in efflux of DA was not secondary to changes in the efflux of NE since nisoxetine elevated the efflux of NE but not of DA and the removal of calcium from the incubation medium blocked the effect of desipramine on the efflux of DA but not of NE. Elimination of calcium did not alter the "spontaneous" hypothalamic efflux of catecholamine. In contrast, desipramine did not affect the net efflux of either DA or NE from the olfactory tubercle or striatum at concentrations of less than 100 microM. At this concentration, the efflux of DA was significantly increased only in the striatum, while the efflux of NE was reduced in the striatum but increased in the olfactory tubercle. Again, in contrast to the hypothalmus, the removal of calcium from the medium markedly reduced "spontaneous" efflux of catecholamine and the desipramine induced efflux of NE, but not the increase in striatal DA efflux produced by desipramine. The results indicate that marked regional differences exist in brain in the ability of desipramine or calcium removal to alter the efflux of both endogenous DA and NE, and suggest that hypothalamic DA and NE neurons are uniquely sensitive to the effects of desipramine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Design of a desipramine dosing regimen for the rapid induction and maintenance of maximal cortical beta-adrenoceptor downregulation.

Chronic administration of desipramine to rats causes a gradual reduction in cortical beta-adrenoceptor density. We examined the relationship between the duration of treatment with desipramine, and the rate and intensity of cortical beta-adrenoceptor downregulation. Male Sprague-Dawley rats were administered a 3.75 mg/kg/12 hr dose of desipramine for 4, 8 or 16 days. After 4 and 8 days of treatment, cortical beta-adrenoceptor density was reduced by 14 and 26% respectively. After 16 days of treatment, cortical beta-adrenoceptor density was maximally reduced by 36%. In our next series of experiments, we tested the hypothesis that the dose of desipramine required to rapidly induce maximal beta-adrenoceptor downregulation was higher than the dose required to maintain maximal beta-adrenoceptor downregulation. Initially, cortical beta-adrenoceptors were rapidly, and maximally downregulated with a four day, 10 mg/kg/12 hr induction regimen of desipramine. Trough, steady-state brain/cortical concentrations of desipramine plus desmethyldesipramine at the end of this regimen were approx 4000 ng/gm. Subsequently, maintenance desipramine regimens of 3.75 mg/kg/12 hr and 1.87 mg/kg/12 hr or vehicle were initiated for the next four days. Inspite of a 20-fold drop in brain/cortical concentrations of desipramine plus its metabolite, the 3.75 mg/kg maintenance regimen sustained maximal cortical beta-adrenoceptor downregulation. The 1.87 mg/kg maintenance regimen did result in a marked (25%) but non-significant recovery in the density of beta-adrenoceptors. Animals administered a vehicle maintenance regimen showed a large (50%) and statistically significant recovery of cortical beta-adrenoceptor density.

Animals↗

PubMedDate not supplied

Chronic desipramine alters stress-induced behaviors and regional expression of the immediate early gene, c-fos.

This experiment examined the effects of acute or chronic administration of the antidepressant drug desipramine on conditioned stress-induced behaviors and regional c-fos expression in the brain. To this end, rats were exposed to three sequential daily sessions of uncontrollable foot-shock and matched, on the basis of crouching, into one of four groups. Two of these groups were exposed to saline injections twice daily and two were exposed to injections of desipramine (5 mg/kg, SC) twice per day, for 9 days. On the 10th day one of the saline groups received saline and the other received desipramine before being exposed to the shock chamber without shock. Likewise, on the 10th day one of the desipramine groups received saline and the other received desipramine before being exposed to the shock chamber without shock. Detailed behavioral analysis showed that compared to the saline-treated controls only the group treated chronically with desipramine, including on the test day, exhibited statistically significant reductions in crouching and increases in exploration during the test session. Similarly, Fos immunohistochemistry revealed that the chronic desipramine group showing positive behavioral effects was the only group in which there were significant reductions in the number of stress-induced Fos-positive neurons in five of 60 structures surveyed. These structures included the anterior cingulate cortex, anterior claustrum, central nucleus of the amygdala, dentate gyrus of the dorsal hippocampus, and paraventricular nucleus of the thalamus. To the extent that repeated exposure to uncontrollable stress is an animal model of depression, these and previous results suggest that these structures are potentially important neural targets for the antidepressant effects of desipramine.

Animals↗

PubMed1993

Desipramine desensitizes beta-adrenergic signal transduction in salivary glands: differential regulation with age.

We previously reported that the tricyclic antidepressant, desipramine desensitizes beta-adrenergic signal transduction in parotid and submandibular salivary glands. To determine the consequences of repeated desipramine administration on beta-adrenergic signal transduction in salivary glands from aged rats and whether the recovery after drug withdrawal is impaired, we assessed the effects of 28-day desipramine administration and the reversibility of this treatment following a 15-day washout period on beta-adrenoceptors and adenylyl cyclase activity in parotid and submandibular glands from F-344 rats of 6, 12 and 24 months of age. beta-Adrenoceptors were also assessed in the cerebral cortex. Desipramine administration down-regulated receptor number and attenuated isoproterenol-stimulated adenylyl cyclase activity in all three ages of rats. However, the reduction in isoproterenol-stimulated adenylyl cyclase activity was greater than the loss of receptor number. Desipramine administration attenuated the efficacy of NaF-stimulated activity with no change in forskolin-stimulated adenylyl cyclase activity. These data suggest that in addition to desensitizing beta-adrenergic-mediated signal transduction, desipramine impaired G-protein-mediated adenylyl cyclase stimulation. The recovery from desipramine desensitization was age dependent. beta-Adrenoceptor density recovered more slowly in the cerebral cortex and the submandibular gland in 24-month-old rats than in 6-month-old rats. In contrast, in 12-month-old rats, there was a receptor up-regulation and adenylyl cyclase supersensitivity. These data indicate that the capacity for receptor modulation is age dependent and suggest that desipramine treatment may down-regulate stimulatory G protein.

Adenylyl Cyclases↗

PubMed2004

Norepinephrine transporter function and desipramine: residual drug effects versus short-term regulation.

Previous research has shown that exposure of norepinephrine transporter (NET)-expressing cells to desipramine (DMI) downregulates the norepinephrine transporter, although changes in the several transporter parameters do not demonstrate the same time course. Exposures to desipramine for <1 day reduces only radioligand binding and uptake capacity while transporter-immunoreactivity is unaffected. Recent demonstration of persistent drug retention in cells following desipramine exposures raises the possibility that previous reported changes in the norepinephrine transporter may be partly accountable by residual drug. In this study, potential effects of residual desipramine on norepinephrine transporter binding and uptake were re-evaluated following exposures of PC12 cells to desipramine using different methods to remove residual drug. Using a method that minimizes residual drug, exposure of intact PC12 cells to desipramine for 4h had no effect on uptake capacity or [(3)H]nisoxetine binding to the norepinephrine transporter, while exposures for > or =16 h reduced uptake capacity. Desipramine-induced reductions in binding to the transporter required >24 h or greater periods of desipramine exposure. This study confirms that uptake capacity of the norepinephrine transporter is reduced earlier than changes in radioligand binding, but with a different time course than originally shown. Special pre-incubation procedures are required to abolish effects of residual transporter inhibitor when studying inhibitor-induced transporter regulation.

Adaptation, Physiological↗

PubMed1993

Side effects of methylphenidate and desipramine alone and in combination in children.

OBJECTIVE: To investigate side effects of methylphenidate and desipramine alone and in combination in hospitalized children with symptoms of attention-deficit hyperactivity disorder and depression. METHOD: A double-blind placebo controlled crossover design was used to investigate each medication alone and in combination. Side effect ratings and EKGs were done weekly. Pulse and blood pressure were monitored daily. RESULTS: Nausea, dry mouth, and tremor were present in at least twice as many children on combined methylphenidate and desipramine compared with any other condition. Nausea/vomiting, headaches, other aches, refusal of food, and feeling "tired" were significantly more frequent during the combined methylphenidate plus desipramine condition when compared with either methylphenidate alone or with baseline. Significantly higher ventricular heart rate was found on combined methylphenidate plus desipramine compared with desipramine alone, methylphenidate alone, and baseline. Prolonged PR interval and significantly higher heart rate occurred during desipramine alone compared with baseline. CONCLUSIONS: During the several-month duration of the study, there were more frequent side effects during combined methylphenidate plus desipramine treatment than with either medication alone. Clinically, side effects present during combined medication appeared to be similar to and no more serious than those associated with desipramine alone.

Adolescent↗

PubMed1997

Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers.

In vitro studies have shown that fluoxetine and paroxetine are more potent inhibitors of cytochrome CYP2D6 than sertraline. The pharmacokinetics of desipramine when coadministered with the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline were studied in 24 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossover study with a 7-day drug-free period between phases. In addition, subjects were randomly assigned to receive concomitant paroxetine (20 mg/day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20). SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (Cmax) relative to baseline increased from 37.8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the concentration-time curve (AUC[24]) increased from 634 to 3,305 ng x h/mL (+421%) with paroxetine versus from 611 to 838 ng x h/mL (+37%) with sertraline; and the mean desipramine trough value (C0) increased from 18.5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p < 0.001). An approximately 10-fold increase in the Cmax and AUC(24) of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when coadministered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively.

1-Naphthylamine↗

PubMed2002

Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine.

In a previous study, of 41 depressed patients who had not responded to fluoxetine 20 mg/day, 53% were treated with high-dose fluoxetine (40-60 mg/ day) and responded (i.e., their 17-item Hamilton Rating Scale for Depression [HAM-D-17] score was <7) versus 29% and 25% of patients treated with fluoxetine plus lithium (300-600 mg/day) or fluoxetine plus desipramine (25-50 mg/day), respectively. We wanted to assess whether these findings could be replicated in a larger sample of depressed outpatients. We identified 101 outpatients with major depressive disorder (52 men and 49 women; mean age, 41.6 + 10.6 years) who were either partial responders (n = 49) or nonresponders (n = 52) to 8 weeks of treatment with fluoxetine 20 mg/ day. These patients were randomized to 4 weeks of double-blind treatment with high-dose fluoxetine (40-60 mg/day), fluoxetine plus lithium (300-600 mg/day), or fluoxetine plus desipramine (25-50 mg/day). In the overall group of patients (N = 101), there was no significant difference in response rates across the three treatment groups (high-dose fluoxetine, 42.4%; fluoxetine plus desipramine, 29.4%; fluoxetine plus lithium, 23.5%). Dropout rates were also comparable, ranging from 9.1% (high-dose fluoxetine) to 14.7% (fluoxetine plus desipramine and fluoxetine plus lithium). There were also no significant differences in response rates across the three treatment groups among partial responders (high-dose fluoxetine, 50.0%; fluoxetine plus desipramine, 33.3%; fluoxetine plus lithium, 33.3%) and nonresponders (high-dose fluoxetine, 35.3%; fluoxetine plus desipramine, 26.3%; fluoxetine plus lithium, 12.5%). At the end of the study, the mean lithium level was 0.37 + 0.15 mEq/L (n = 27; range, 0.1-0.8 mEq/L) among lithium-treated patients, and the mean desipramine level was 104.7 + 58.8 ng/mL (n = 22; range, 25-257 ng/mL). There were no significant relationships between lithium or desipramine blood levels and degree of improvement (as measured by the change in HAM-D-17 score). We found no significant differences in efficacy among these three treatment strategies among patients who had failed to respond adequately to 8 weeks of treatment with fluoxetine 20 mg/day, although the high-fluoxetine group was associated with nonsignificantly higher response rates in both partial responders and nonresponders.

Adult↗

PubMed2004

Excess fatality from desipramine and dosage recommendations.

Higher case fatality rates (CFR) were previously reported from desipramine than for 3 other tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, and imipramine. The database of the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) for the 20 years 1983-2002 was used to evaluate the CFR of desipramine and the other TCAs. The CFR of desipramine was 2.25-, 2.31-, and 2.62-fold the CFR for amitriptyline, nortriptyline, and imipramine, respectively (P < 0.001). Mechanisms of desipramine toxicity and its dosage recommendations are discussed. Desipramine and nortriptyline have higher distribution volumes and erythrocyte/plasma ratios than their parent compounds imipramine and amitriptyline. This implies lower therapeutic plasma levels and reduced doses for desipramine and nortriptyline compared with their parent compounds. Such adjustments have been done for nortriptyline, but not for desipramine. The authors suggest that the high CFR of desipramine might be reduced by lowering its dose, therapeutic plasma level, and maximal pill content.

Amitriptyline↗

PubMed2006

Excess fatality from desipramine in children and adolescents.

OBJECTIVE: To compare the case fatality rate (CFR) from desipramine ingestion in children and adolescents with that of other tricyclic antidepressants. METHOD: All mentions of desipramine, amitriptyline, imipramine, nortriptyline, and doxepin in children and adolescents recorded in the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 to 2002 were analyzed. The CFR for each drug was defined as the ratio of the number of deaths/number of mentioned exposures. RESULTS: There were 24 fatalities in children younger than 6 years old (desipramine, n=10; amitriptyline, n=7; doxepin, n=3; imipramine, n=3; nortriptyline, n=1) and 144 fatalities in older children and adolescents (desipramine, n=56; amitriptyline, n=30; doxepin, n=16; imipramine, n=31; nortriptyline, n=11). The CFR from desipramine was significantly higher compared with the other tricyclic antidepressants in children younger than 6 years old (chi=36, p<.001) and in older children and adolescents (chi=155, p<.001). The CFR from desipramine exceeded that of amitriptyline, doxepin, imipramine, and nortriptyline by 7- to 8-, 4-, 6- to 12-, and 7- to 10-fold, respectively. CONCLUSIONS: The excess CFR from desipramine in children and adolescents and the reports of sudden death in children treated with therapeutic doses call for caution in prescribing desipramine to children and adolescents.

Adolescent↗

PubMed1990

Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study.

1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl-clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.

Adult↗

PubMed1995

The contribution of lysosomal trapping in the uptake of desipramine and chloroquine by different tissues.

Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non-specific binding to membrane phospholipids, and ion-trapping within acidic cellular compartments. The aim of this study was to assess the individual contributions of these two mechanisms on the uptake in vitro of desipramine and chloroquine into tissue slices of control and desipramine-treated rats. Drug uptake into intact slices was compared with uptake into slices with destroyed or non-functional acidic compartments. The sequence of desipramine uptake by tissue slices of eight different organs was: lungs > brain > heart > diaphragm > kidneys > skeletal muscles > adipose tissue > liver. The low desipramine concentration in liver may be due to metabolism of the parent drug by cytochrome P-450. Uptake of chloroquine differed widely between slices of different organs with the sequence: lungs > kidneys = brain = liver > diaphragm = heart = skeletal muscles > adipose tissue. Destruction or inactivation of the acidic compartments by homogenization and freeze-thawing or by ammonium chloride, sodium fluoride, or monensin, reduced drug uptake to similar extents. The reduction was organ-specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affected than that of desipramine, suggesting that ion-trapping is the main factor for chloroquine accumulation, while binding to membrane phospholipids, is the main factor for desipramine uptake. Single or multiple-dose treatments of rats with desipramine hardly had any effect on consecutive desipramine uptake into lung and liver slices, while the accumulation of chloroquine was enhanced in these slices. In conclusion, the extent of uptake of cationic amphiphilic drugs into tissue slices was tissue-specific, and the contribution of the two uptake mechanisms was strongly drug-dependent.

Adipose Tissue↗

PubMed2003

Effect of the antidepressant desipramine on cytosolic Ca(2+) movement and proliferation in human osteosarcoma cells.

In human osteosarcoma MG63 cells, the effect of desipramine, an antidepressant, on intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured by using fura-2. Desipramine (>10 micromol/l) caused a rapid and sustained rise of [Ca(2+)](i) in a concentration-dependent manner (EC(50) = 200 micromol/l). Desipramine-induced [Ca(2+)](i) rise was prevented by 80% by removal of extracellular Ca(2+) but was not altered by voltage-gated Ca(2+) channel blockers. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum (ER) Ca(2+)-ATPase, caused a monophasic [Ca(2+)](i) rise, after which the increasing effect of desipramine on [Ca(2+)](i) was abolished; also, pretreatment with desipramine partly reduced thapsigargin-induced [Ca(2+)](i) increase. U73122, an inhibitor of phospholipase C, did not affect desipramine-induced [Ca(2+)](i) rise. Overnight incubation with 10 micromol/l desipramine did not alter cell proliferation, but killed 32 and 89% of cells at concentrations of 100 and 200 micromol/l, respectively. These findings suggest that desipramine rapidly increases [Ca(2+)](i) in osteoblasts by stimulating both extracellular Ca(2+) influx and intracellular Ca(2+) release, and is cytotoxic at high concentrations.

Antidepressive Agents↗

PubMed2006

Desipramine inhibits Na+/H+ exchanger in human submandibular cells.

A common and significant side-effect of the antidepressant desipramine is xerostomia (dry mouth). We investigated the effect of desipramine on Na(+)/H(+) exchanger, which is an important modulator of salivary secretion. In dissociated human submandibular acinar cells, desipramine inhibited intracellular pH recovery in a concentration-dependent manner. Likewise, 5-(N-ethyl-N-isopropyl)amiloride (EIPA), a Na(+)/H(+) exchanger inhibitor, had the same effect as desipramine, whereas the effect of 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), a Na(+)/HCO(3)(-) co-transporter inhibitor, was not dramatic. Although desipramine is known to inhibit catecholamine re-uptake, desipramine also inhibited pH recovery in the human submandibular gland cell line, HSG cells, which lack nerve inputs. Our results suggest that desipramine directly inhibits Na(+)/H(+) exchange in human submandibular glands without the involvement of catecholamine re-uptake, revealing the cellular mechanism of desipramine-evoked xerostomia.

Adult↗

PubMed2001

Involvement of GABAergic systems in manifestation of pharmacological activity of desipramine.

We have conducted this study to elucidate the influence of GABAergic systems on manifestation of pharmacological activity of desipramine using both pharmacological and electrophysiological methods. Desipramine (20 mg/kg, i.p.) significantly blocked the adjuvant-induced thermal hyperalgesia, which was facilitated by treatment with the GABA(A) antagonist picrotoxin (2 mg/kg, i.p.) or the GABA(B) antagonist saclofen (2 mg/kg, i.p.). This analgesic effect of desipramine was antagonized by post-treatment with picrotoxin or saclofen. However, none of these compounds showed any effect in normal animals without adjuvant-induced inflammation. In a slice preparation of the hippocampus, treatment with GABA (10(-5)-5 x 10(-4) M), baclofen (10(-5)-10(-4) M) or muscimol (10(-5)-10(-4) M) inhibited the field potential evoked in pyramidal neurons by Schaffer collateral stimulation. The inhibitory effect of GABA was facilitated by concurrent application of desipramine, carbamazepine or diazepam at a concentration of 5 x 10(-5)-2 x 10(-4) M. The rank of order of facilitation is: desipramine > carbamazepine > diazepam. Desipramine also enhanced the inhibitory effect of baclofen and muscimol. These results suggest that desipramine causes GABAergic systems to activate still more, and this phenomenon appears to be involved in manifestation of the pharmacological activity of desipramine such as antinociception.

Animals↗

PubMed1982

Characterization of [3H]desipramine binding associated with neuronal norepinephrine uptake sites in rat brain membranes.

A variety of evidence indicates that [3H]desipramine can label neuronal norepinephrine uptake sites in brain membranes. Pretreatment of rat cerebral cortical membranes with 0.3 M KCl increases the ratio of high affinity to low affinity saturable [3H]desipramine binding. With this improved tissue preparation, we have confirmed our earlier observation that the high affinity [3H]desipramine binding component (KD = 2 to 4 nM) is associated with norepinephrine neuronal uptake sites. The potencies of various antidepressant drugs in reducing [3H]desipramine binding correlate with their inhibition of neuronal [3H]norepinephrine accumulation. Like the norepinephrine uptake system, high affinity [3H]desipramine binding is dependent both on sodium and chloride, with half-maximal stimulation by 10 mM chloride. Although bromide can substitute for chloride to stimulate binding, other anions, including iodide, fluoride, acetate, citrate, and phosphate, are inactive. Comparable sodium and anion regulation of [3H]imipramine binding to serotonin uptake recognition sites also is observed. The association of [3H]desipramine binding sites with neuronal norepinephrine uptake sites is supported further by the selective abolition of high affinity [3H]desipramine binding following the destruction of central norepinephrine neurons by intraperitoneal administration of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). In vitro incubation of cerebral cortical membranes with DSP-4 also selectively abolishes the high affinity [3H]desipramine binding, an effect which cannot be reversed by repeated washing of the membranes, suggesting that DSP-4 alkylates neuronal norepinephrine uptake sites.

Animals↗

PubMed1994

The pharmacodynamics of desipramine and desmethyldesipramine in rats.

The interrelationships between dose, drug and metabolite levels in the brain, cortex and blood and the magnitude of cortical beta adrenergic receptor downregulation were studied in rats after chronic i.p. administration of desipramine and its demethylated metabolite, desmethyldesipramine. Desipramine and desmethyldesipramine were distributed extensively into the brain and cortex with mean tissue to blood concentration ratios of approximately 10 to 1 and 14 to 1, respectively. Increasing doses of desipramine and desmethyldesipramine resulted in greater than linear increases in the corresponding steady-state trough concentrations of these drugs in brain, cortex and blood. Both drugs caused dose-dependent decreases in cortical beta adrenergic receptor density. The higher doses of desipramine and the highest dose of desmethyldesipramine used in this study caused maximal downregulation of beta adrenergic receptors. No changes were observed in the Kd of cortical beta adrenergic receptors after the administration of the two drugs. The ED50 for desipramine was determined to be 5.10 mg/kg, whereas the ED50 for desmethyldesipramine was 7.71 mg/kg. Nonlinear least-squares fitting of cortical concentration-effect data to the pharmacodynamic Emax model equation after the separate administration of desipramine and desmethyldesipramine generated Emax estimates for desipramine and desmethyldesipramine of approximately 36 and 29%, respectively, and EC50 estimates of 365 and 467 ng/g, respectively. Desmethyldesipramine is capable of maximally downregulating cortical beta adrenergic receptors and could account, in part, for the effect observed after desipramine administration.

Adrenergic beta-Antagonists↗

PubMed1994

Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine.

The pharmacokinetic interactions of sertraline and fluoxetine with the tricyclic antidepressant desipramine were studied in 18 healthy male volunteers phenotyped as extensive metabolizers of dextromethorphan. Concentrations in plasma were determined after 7 days of desipramine (50 mg/day) dosing alone, during the 21 days of desipramine and selective serotonin reuptake inhibitor (SSRI) coadministration (fluoxetine, 20 mg/day; sertraline, 50 mg/day), and for 21 days of continued desipramine administration after SSRI discontinuation. Desipramine Cmax was increased 4.0-fold versus 31% and AUC0-24 was increased 4.8-fold versus 23% for fluoxetine versus sertraline, respectively, relative to baseline after 3 weeks of coadministration. Desipramine trough concentrations approached baseline within 1 week of sertraline discontinuation but remained elevated for the 3-week follow-up period after fluoxetine discontinuation. Concentrations of SSRIs and their metabolites correlated significantly with desipramine concentration changes (for fluoxetine/norfluoxetine, r = 0.94 to 0.96; p < 0.001; for sertraline/desmethylsertraline, r = 0.63; p < 0.01). Thus, sertraline had less pharmacokinetic interaction with desipramine than did fluoxetine at their respective, minimum, usually effective doses.

1-Naphthylamine↗