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PubMed1982

Augmentation of central and peripheral morphine analgesia by desipramine.

Using the rat tail-flick method to assess analgetic efficacy, the effects of desipramine (DMI) on analgesia produced by either systemic or central (i.e., periaqueductal gray) administration of morphine sulfate (MS) were evaluated. Pretreatment of rats with DMI (30 mg/kg, s.c.) increased the duration of analgesia following systemic injection of MS (5.0 mg/kg, s.c.) from 50 min to 150 min, but did not significantly alter the peak analgetic response. A similar but less marked effect was observed following a 2.5 mg/kg dose of MS. Pretreatment with DMI likewise extended the duration of effective analgesia following microinjection of 2.5 micrograms and 5.0 micrograms MS into the ventrolateral periaqueductal gray region (VLPAG). In addition, the maximal analgetic response to the 5.0 microgram dose of MS was increased by DMI. These results suggest that potentiation of morphine-induced analgesia by DMI cannot be ascribed solely to a peripheral interaction (i.e. inhibition of hepatic biotransformation) but probably involves a central interaction as well.

Acetylcholine↗
PubMedDate not supplied

The effect of proadifen, a drug metabolism inhibitor, on action of imipramine and desipramine in mice.

Proadifen (SKF 524 A) inhibited the following effects of imipramine (IMI), without affecting those of desipramine (DMI) in mice: antagonism towards reserpine-induced hypothermia, ptosis and sedation, antagonism to apomorphine hypothermia and insignificant shortening of the immobility time in the behavioral despair test. Cerebral levels of DMI were very low after administration of IMI; pretreatment with proadifen did not affect the already low levels of DMI but significantly elevated these of IMI. This may indicate that some other than DMI metabolites (e.g., 2-hydroxy-derivatives) may be of importance for the action of IMI in mice in the tests employed in this study.

Animals↗
PubMed1981

Influence of proadifen, an inhibitor of the metabolism of drugs, on the action of imipramine and desipramine in rats.

The influence of proadifen (SKF-525-A), an agent inhibiting the metabolism of drugs, on the antidepressant action of imipramine (IMI) and desipramine (DMI) in rats was investigated. Proadifen antagonized the action of IMI when investigated in reserpine hypothermia and ptosis and in the behavioral despair test. The action of DMI in the same tests was not changed by proadifen. Proadifen lowered the level of DMI and increased the level of IMI in rat brains. The results permit to draw the conclusion that DMI plays an essential role in the action arising from IMI administration, that is, the noradrenergic--and not the serotonergic--mechanism is of essential importance.

Animals↗
PubMed1995

Effects of specific antibody Fab fragments on desipramine pharmacokinetics in the rat in vivo and in the isolated, perfused liver.

Drug-specific antibody fragments, which can reverse tricyclic antidepressant toxicity in rats, represent a potential clinical treatment for tricyclic antidepressant overdose in humans. To delineate the pharmacokinetic mechanisms, we studied the effects of a high-affinity, drug-specific Fab fragment on desipramine (DMI) disposition in rats and on DMI kinetics in the isolated, perfused rat liver. These studies were performed at high DMI and Fab doses, with Fab administered at the time of peak DMI toxicity, to simulate the treatment of overdose. Rats received 20 mg/kg DMI intravenously over 30 min followed in 10 min by DMI-specific ovine polyclonal Fab (DMI-Fab) or nonspecific human Fab (control-Fab) (1.1 g/kg; molar Fab-to-DMI ratio, 0.34) intravenously over 20 min. The serum DMI concentration increased by 50-fold 5 min after DMI-Fab administration. The mean area under the serum concentration-time curve increased by more than 3-fold. The steady-state volume of distribution was decreased by 90% and total body clearance was decreased by 70% after DMI-Fab administration compared with control-Fab. Renal clearance increased by 72% after DMI-Fab and total renal excretion of DMI increased by 7-fold due to the much higher serum DMI concentration. Ninety-four percent of DMI-Fab excretion and 87% of DMI excretion occurred in the first 12 h. The percent of DMI bound in urine was markedly increased by DMI-Fab (87.1 vs. 19.1%), as was the molar ratio of DMI to DMI-Fab in urine (0.75 vs. 0.08). Isolated rat livers were perfused with DMI alone, DMI and DMI-Fab or DMI and control-Fab.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

On mixtures of three normal populations caused by monogenic inheritance: application to desipramine metabolism.

For a mixture of three normal distributions, which represent genotypes AA, Aa and aa, a method of estimation of the seven unknown parameters is proposed which works well whenever the phenotype (aa) is sufficiently well separated from the phenotype (AA, Aa). It is based on p-values of Kolmogorov's test of goodness of fit to normality. Initial parameter values for this iterative algorithm can be found by visual check and/or by using the EM algorithm. In an example of a data set of size 59 from a study of the metabolic rate of desipramine, the usefulness of this method is demonstrated. Extensions to more complex situations are feasible and are indicated at the end.

Adolescent↗
PubMed1994

Reversal of desipramine toxicity in rats with polyclonal drug-specific antibody Fab fragments.

Drug-specific antibodies, or fragments containing their binding site(s), are a potential means of treating drug overdose. Affinity purified polyclonal ovine Fab (TFab) with a high average affinity constant (Ka = 1.4 x 10(10) M-1) for the common tricyclic antidepressants was evaluated as a possible treatment for tricyclic antidepressant toxicity. Groups of eight anesthetized rats received 30 mg/kg body weight of desipramine (DMI) intraperitoneally, followed after 15 minutes by a 10-minute intravenous injection of 3 ml normal saline solution, 2 gm/kg nonspecific Fab as a control (CFab), or 1 or 2 gm/kg TFab (representing a molar ratio of TFab to DMI of 0.11 and 0.22, respectively). The animals were observed for 3 hours. During the initial 15 minutes, serum DMI levels in the four groups reached 2.3 to 2.9 micrograms/ml, the QRS duration increased by 67.5% to 77.9%, and the systolic pressure fell to between 65% and 85% of its initial value. The group given saline solution showed a gradual return of all these parameters toward normal, whereas CFab caused a transient further QRS prolongation. CFab also caused an initial rise in blood pressure, which then fell progressively, and two of the rats died 2 to 3 hours later with hypotension and bradycardia. Serum DMI concentration did not change significantly in either the saline or CFab groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The influence of desipramine on thyroid hormone metabolism in rat brain.

The effect of the antidepressant desipramine (DMI) on the activities of the three iodothyronine deiodinase isoenzymes involved in the central metabolism of thyroid hormones were investigated in 11 brain regions and 3 peripheral tissues in the rat. The investigations were carried out at three different times during the light/dark cycle: 5 A.M., 1 P.M. and 11 P.M. Interest is focused on changes in the two enzymes that catalyze: i) the 5'deiodination of T4 to the biologically active T3, i.e., type II 5'deiodinase (5'D-II), and ii) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3,3'T2, i.e., type III 5 deiodinase (5D-III). Fourteen days' treatment with 20 mg/kg DMI, but not with 5 mg/kg DMI, induced significant increases in 5'D-II in eight different areas of the CNS. The regions affected were identical to those that receive noradrenergic input from the locus coeruleus. Even control animals showed a circadian rhythm of 5'D-II activity in some brain regions, and the effects of DMI also depended on the time of death within the 24-hr rhythm. 5D-III was not affected. Serum T4 were lower after administration of DMI, most probably because of enhanced tissue uptake of T4. This is in line with the corresponding finding in depressed patients, indicating that similar changes in both central and peripheral thyroid hormone metabolism may occur after antidepressant pharmacotherapy in both humans and rats. These data support the hypothesis that interactions with the CNS metabolism of the thyroid hormones may be involved in the mechanisms of action of DMI.

Animals↗
PubMed1993

Preliminary report: placebo-controlled, double-blind study of the clinical and metabolic effects of desipramine in panic disorder.

Fifty-six males and females with panic disorder with or without agoraphobia participated in a 12-week, placebo-controlled treatment study of the efficacy of desipramine (DMI). Twenty-six of 28 patients receiving DMI completed the study; 17 of 28 placebo (PBO) recipients completed 12 weeks. Patients receiving DMI responded significantly better than did PBO recipients as measured by Hamilton Anxiety Scale (HAM-A) and global phobia ratings, with a trend toward greater global improvement, but no between-group differences on panic attack frequency were discerned. By Week 12, 22 of 26 (85%) DMI patients were panic-free; 13 of 17 (76%) PBO patients were panic-free. Resting metabolic rate (RMR) was tested on a subset of the patients. Patients receiving DMI showed no effects on RMR or thyroid indices but lost a significant amount of weight; the PBO recipients exhibited no weight loss or RMR effects. In this study, the high PBO response rate obscured treatment group differences on some measures. This study underscores the need for placebo comparisons in treatment studies. In summary, DMI appears to be an effective treatment for panic disorder. DMI appears to have little effect on RMR; a slight but significant weight loss was observed in the DMI but not PBO group.

Adolescent↗
PubMed1993

Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Comparison of high specific activity (-) and (+)-6-[18F]fluoronorepinephrine and 6-[18F]fluorodopamine in baboons: heart uptake, metabolism and the effect of desipramine.

(-)-Norepinephrine is the principal neurotransmitter of the mammalian sympathetic nervous system and a major CNS neurotransmitter. The simple ring fluorinated derivatives of (-)- and (+)-norepinephrine [(-)- and (+)6-fluoronorepinephrine] and dopamine (6-fluorodopamine) have been labeled with 18F in high specific activity (2-5 Ci/mumol) and evaluated as tracers for (-)-norepinephrine. Comparative PET studies of (-) and (+)-6-[18F]fluoronorepinephrine [(-)-6-[18F]FNE and (+)-6-[18F]FNE] and 6-[18F]fluorodopamine (6-[18F]FDA) in the same baboon showed strikingly different kinetics in the heart. Analysis of plasma showed more rapid metabolism of 6-[18F]FDA with only 1%-2% of 18F remaining as parent tracer at 10 min after injection of 6-[18F]FDA, in contrast to 28% and 17% remaining after injection of (-) and (+)-6-[18F]FNE. No changes in vital signs were observed at any time during the study. Pretreatment with desipramine (0.5 mg/kg), a tricyclic antidepressant drug which interacts with a binding site associated with norepinephrine reuptake, markedly decreased cardiac uptake of 6-[18F]FDA and (-)-6-[18F]FNE. However, a greater blocking effect was observed for (-)-6-[18F]FNE. These studies show that (-) and (+)-6-[18F]FNE are similar to (-)- and (+)-norepinephrine in their patterns of metabolism and clearance in the heart and that (-)-6-[18F]FNE is a promising tracer for endogenous (-)-norepinephrine.

Animals↗
PubMed1995

[Effects of desipramine and clomipramine on alpha 2-adrenergic receptor function in nucleus accumbens: studies with intracerebral dialysis in freely moving rats].

The effect of alpha 2-adrenoceptor agonist, clonidine (CLN) (100 micrograms/kg, i.p.), on the noradrenalin metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)-total in the rat nucleus accumbens after desipramine (DMI) (20 mg/kg, i.p.) and clomipramine (CMI) (20 mg/kg, i.p.) treatment was estimated in the freely moving rat by intracerebral dialysis. Locomotor activity was measured simultaneously by the Animex. Locomotor activity in the control decreased after CLN administration, in accordance with the decrease in MHPG. The difference of locomotor activity and MHPG between the single dose trial with DMI, CMI and the control did not reach statistical significance throughout the experiment. The results suggest that a single injection of DMI and CMI have not an inhibitory effect on presynaptic alpha 2-adrenergic receptor in the nucleus accumbens. Next, DMI (20 mg/kg, i.p.) and CMI (20 mg/kg, i.p.) were injected once daily for 14 days and experiments, the same method as used on the single dose trial. A difference in locomotor activity and MHPG between the chronic DMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-90 min period. A difference in locomotor activity and MHPG between the chronic CMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-120 min period. The results suggest that the chronic DMI treatment and the chronic CMI treatment may diminish the CLN-induced reduction of MHPG via the subsensitivity of presynaptic alpha 2-adrenergic receptor in the nucleus accumbens.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Antagonism of behavioral effects of electroconvulsive shock but not those of desipramine by the selective 5-HT-3 receptor antagonist, ondansetron.

The influence of ondansetron (ON) on desipramine (DMI) and electroconvulsive shock (ECS) effects in the open field (OFT) and forced swim test (FST) were studied in Wistar male rats. ON failed to influence the action of DMI but abolished stimulatory effect of ECS in the OFT and, in the lower dose (0.01 mg/kg) reduced ECS action in the FST. This result suggests that 5-HT-3 receptors are involved in behavioral effects of ECS but not DMI.

Animals↗
PubMed1995

Comparison of the effects of desipramine on noradrenaline- and methoxamine-evoked venoconstriction in man.

1. The dorsal hand vein compliance technique was used to investigate the dual effect of tricyclic antidepressants at the noradrenergic synapse (i.e. noradrenaline uptake blockade leading to potentiation and alpha 1-adrenoceptor blockade leading to antagonism of the effect of noradrenaline). The effects of a single oral dose (100 mg) of desipramine (DMI) on venoconstrictor responses to locally infused noradrenaline and methoxamine, a selective alpha 1-adrenoceptor agonist with little affinity for the uptake mechanism, were examined. 2. Eight healthy male volunteers participated in four weekly experimental sessions. Each session was associated with one of the following treatment conditions: noradrenaline/DMI, noradrenaline/placebo, methoxamine/DMI, methoxamine/placebo. Subjects were allocated randomly to treatments and sessions according to a double-blind balanced design. Noradrenaline acid tartrate (0.33-33 ng min-1) and methoxamine hydrochloride (0.0135-135 micrograms min-1) were infused into the superficial dorsal hand vein; each dose was infused for 5-7 min with 5 min intervening washout periods. Systolic and diastolic blood pressure and pulse rate were recorded before the infusion and immediately after the infusion of the highest dose. Salivation, an index of anticholinergic activity of the antidepressant, was measured by the dental roll technique. 3. Both noradrenaline and methoxamine produced dose-dependent venoconstriction: the geometric mean ED50 for noradrenaline was 4.41 ng min-1 and for methoxamine was 2558 ng min-1; the potency ratio (noradrenaline/methoxamine) was 2884. DMI shifted the dose-response curve for noradrenaline to the left (ANOVA: P < 0.025), resulting in a dose-ratio of 0.26. DMI did not affect the dose-response curve for methoxamine significantly; the dose ratio was 1.24. 4. None of the local infusions and/or systemic treatments had any significant effects on supine systolic and diastolic blood pressure and pulse rate. 5. DMI caused a substantial (47.6%) reduction in salivary output that significantly differed from the slight statistically insignificant increase (5.8%) of salivary output recorded after placebo. 6. These results show that a single oral dose (100 mg) of DMI causes significant potentiation of the response to noradrenaline without significantly affecting the response to methoxamine. The potentiation is likely to be due to uptake blockade since the response to methoxamine was not affected. Furthermore, the lack of significant antagonism of the response to methoxamine indicates that a single oral dose (100 mg) of DMI does not cause sufficient alpha 1-adrenoceptor blockade to be detected as a pharmacodynamic change in our test system.

Adolescent↗
PubMed1996

Effect of desipramine on spontaneous activity of hippocampal CA1 neuron after transient cerebral ischemia in rats.

AIM: To study the spontaneous firing of CA1 neurons in rat hippocampus after transient cerebral ischemia and the effect of desipramine (Des) on the post-ischemic electric activity of CA1 neurons. METHODS: Single-unit extracellular recordings were performed in rats on d 3 after 10 min of cerebral ischemia by occlusion of 4 arteries. Des and saline were injected into a tail vein. The histological changes of CA1 neurons was assessed by the neuronal density of the CA1 sector. RESULTS: The spontaneous firing rate of CA1 neurons on d 3 after ischemia was enhanced in comparison with the control value. Des (0.2 and 0.4 mg.kg-1, i.v., n = 5 & 6, respectively) reduced dose-dependently the increase of firing rate with maximal inhibition by 6 min (58% & 85%) to 9 min (69% & 94%) (vs vehicle group, P < 0.01). About 50% cells in CA1 region showed necrotic changes. CONCLUSION: Des antagonized the hyperexcitability of CA1 neurons after cerebral ischemia.

Animals↗
PubMed1996

Exposure to threshold doses of nicotine in utero: III. Augmentation of the prolactin and ACTH response to 8-OH DPAT by desipramine treatment is compromised in adult male offspring.

Gravid female rats were injected subcutaneously with saline (SAL) or nicotine (3.0 mg/kg and 0.05 mg/kg, bid) from days 14-21 of gestation. Adult 105-day old male offspring from each of the three groups were treated daily with saline or desipramine (DMI) (10 mg/kg, sc) for 14 days. Twenty-four hours after the last injection, animals were challenged with saline or 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH DPAT) (0.1 mg/kg, sc), a serotonin IA(5-HT(IA)) agonist, and plasma prolactin and ACTH concentrations were measured 15 minutes later. DMI treatment augmented both the prolactin and ACTH responses to 8-OH DPAT in the SAL controls. Neither the prolactin nor the ACTH response was augmented significantly in the animals exposed prenatally to either nicotine dosage regimen, although there was a strong trend for the augmentation to occur in the low-dose nicotine exposed animals. The results indicate the capacity of 5-HT systems to adapt normally to DMI administration, as manifested by neuroendocrine responsivity to 8-OH DPAT, was compromised in adult animals exposed to nicotine in utero.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Down-regulation of rat beta-adrenoceptors by clenbuterol or desipramine does not require chronic treatment: [3H] CGP-12177 binding reveals rapid (24 hour) modulation.

Desipramine (DMI, 15 mg/kg, s.c.) decreased [3H]CGP-12177-labelled cortical beta-adrenoceptor density (Bmax) by 30% upon chronic (14 day) treatment. However, even a single dose (in mg/kg) of DMI (15) or the beta-adrenoceptor agonist, clenbuterol (20), induced a rapid (24 hour) and significant reduction of beta-adrenoceptor Bmax (-15%; p < 0.01). Acute treatment with amitryptiline (10), clorgyline (1), fluoxetine (10), nomifensine (10) or maprotiline (20) had no significant effect on [3H]CGP-12177-labelled beta-adrenoceptors, suggesting that rapid down-regulation may not be a general property of antidepressant drugs. None of the antidepressants altered the Bmax of [3H]ketanserin-labelled 5-HT2A receptors on acute treatment. These results show that beta-adrenoceptor down-regulation by clenbuterol and DMI is not dependent on chronic treatment and may, therefore, be a poor correlate of the gradual onset of therapeutic efficacy seen clinically with antidepressant drugs.

Adrenergic Uptake Inhibitors↗
PubMed1997

Neurotrophin-3- and norepinephrine-mediated adrenergic differentiation and the inhibitory action of desipramine and cocaine.

In the presence of neurotrophin-3 (NT-3), high-affinity norepinephrine (NE) uptake by quail neural crest cells was significantly increased as judged by in vitro colony assay of adrenergic differentiation. In the presence of the related neurotrophins nerve growth factor (NGF) or brain-derived neurotrophic (BDNF) factor, or of basic fibroblast growth factor (bFGF), there were no significant changes. When NE was added to the culture medium in addition to NT-3, more colonies contained dopamine-beta-hydroxylase (DBH)-immunoreactive cells, an enzyme that is characteristic for adrenergic cells. The NE-mediated increase in the portion of colonies that contained DBH-immunoreactive cells was prevented by the tricyclic antidepressant desipramine (DMI) and by cocaine, two types of drug that block cellular transport of NE. To further examine whether NE acts via uptake, colony assays were performed in the presence and absence of adrenergic antagonists and agonists. These would be expected to mimic the DMI and NE effects, respectively, if the mechanism of action involved activation of adrenergic autoreceptors. Neither class of drug showed a detectable effect within a wide range of concentrations. Immunocytochemistry using antibodies against beta 1 and beta 2 adrenergic receptors further supported the notion that DMI action and beta-receptor expression are not causally related. Ratio imaging was subsequently used in an attempt to elucidate the mechanism of NE action. Within a few minutes of addition of NE to the culture medium, there was an increase in intracellular free calcium in a subset of neural crest cells. Taken together, our data indicate that NT-3 is involved in the appearance of the NE transporter (NET) during embryonic development; internalized NE directly or indirectly increases adrenergic differentiation as measured by immunoreactivity of the adrenergic biosynthetic enzyme DBH; and norepinephrine uptake inhibitors have treatogenic potential.

Adrenergic Uptake Inhibitors↗
PubMed1976

Effects of desipramine treatment on the biliary, fecal and urinary excretion of methadone in the rat.

The effects of desipramine (DMI) given i.p. 1 hour before administration of 14C-methadone (5 mg/kg s.c.) on the excretion of methadone in bile, feces and urine were studied. Rats with cannulated bile ducts excreted 52% of administered 14C into bile within 4 hours, 60% of the excretion as 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 30% as water-soluble metabolite (WSM). The percentages of 14C excreted within 48 hours into the feces and urine of rats without biliary fistula were 60.6 and 17.4%, respectively. The excretion of 14C in feces consisted mostly of EDDP. Urinary excretion consisted of unchanged methadone, EDDP and WSM in the first 12 hours and consisted mostly of WSM thereafter. DMI treatment increased biliary flow but decreased the biliary excretion of 14C, mainly by a decrease in WSM. The fecal output was greatly decreased by DMI, thus decreasing fecal excretion of 14C in the first 12 hours. DMI treatment markedly decreased urinary volume but did not change the urine pH. The decreased urinary excretion of WSM in DMI-treated rats during the first 12-hour urine sample accounted for most of the decreased elimination of 14C. It is suggested that DMI-induced inhibition of methadone metabolism in the liver is a major factor responsible for the observed decreases in the biliary and urinary excretion of WSM...

Animals↗