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PubMed1985

Plasma protein binding of imipramine in patients with rheumatoid arthritis.

In 23 patients with rheumatoid arthritis the plasma protein binding of 3H-imipramine and the plasma levels of 13 proteins were measured in order to examine the significance of the proteins for the binding of imipramine. The degree of 3H-imipramine binding did not differ significantly from that in healthy controls. It was positively correlated with the concentrations of fibrinogen, alpha 1-acid-glycoprotein, ceruloplasmin, complement C3c, haptoglobin and hemopexin. Erythrocyte sedimentation rate was also highly positively correlated with binding. The concentration of several of the proteins showed a significant covariation. The 3H-imipramine binding was negatively correlated with the concentration of albumin and the latter was negatively correlated with some of the proteins mentioned-above. No correlation with the levels of apolipoproteins A and B was found. There appears to be more a qualitative than a quantitative change in 3H-imipramine binding in patients with rheumatoid arthritis.

Aging↗
PubMed1985

Neuroleptics and beta-carbolines displace (3H)Imipramine from its binding sites in human and rat tissues.

Most investigations dealing with the pharmacological characterization of (3H)imipramine binding sites focus on tricyclic antidepressants (TCA). This approach seemed to be justified since imipramine belongs to that chemical group. Langer and coworkers, however, introduced a tetrahydro-beta-carboline (TH beta C) as a possible endogenous ligand. Thus, the high affinity of imipramine towards the binding sites might not be due to its special chemical structure but due to its tricyclic nature. In the present paper the structure-activity-relationships of neuroleptics and beta-carbolines were investigated and compared with that of tricyclic antidepressants. Among the tricyclic neuroleptics those with an electron attracting substituent (-Cl) exerted highest affinity. The effect was attenuated by a long, cyclic side chain. The affinity of tricyclic neuroleptics was only slightly weaker than that of 6-Meo-TH beta C the suggested endogenous ligand. The experiments with other TH beta Cs supported the observation that an electron attracting substituent increases the affinity of a compound to the (3H)imipramine binding sites. Comparison of the binding characteristics of (3H)imipramine to membranes of human brain and thrombocytes as well as those of rat brain and thrombocytes revealed no differences among both species. Furthermore, the displacing potencies of neuroleptics were very similar with only slightly more activity in human tissue. As a methodological aspect the applicability of the "Lowry" method to determine the protein concentration is discussed.

Aged↗
PubMed1989

Acceleration of rat brain beta-adrenoceptor subsensitivity following the coadministration of histamine receptor antagonists with imipramine.

Systemic administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively blocked by propranolol. This dipsogenic effect was significantly inhibited by the subacute (4 days) administration of imipramine (18.1 mg/kg/day) together with either the H1-histamine receptor antagonist, chlorpheniramine (0.1 or 1.32 mg/kg/day), or the H2-histamine antagonist, cimetidine (1.91 mg/kg/day) or ranitidine (0.60 or 1.51 mg/kg/day). The oral subacute administration of imipramine alone had no significant effect on this behavior. However, chronic ingestion of imipramine alone (21 days) caused a significant reduction in the isoprenaline-induced behavior. It is concluded that the desensitization of central beta-adrenoceptors, as evidenced by inhibition of isoprenaline-induced drinking, can be accelerated following the oral subacute co-administration of imipramine with either H1- or H2-histamine receptor antagonists. It is also seems the central histamine receptors may partially contribute towards the mechanism of antidepressant effect of imipramine.

Animals↗
PubMed1994

Imipramine reduces the local inflammatory response to carrageenin.

Imipramine was administered chronically to LEW/N, outbred and F344/N rats which were then exposed to the aseptic irritant carrageenin in order to determine whether the decreased hypothalamic expression of CRH m-RNA previously shown to be associated with imipramine affects peripheral immune processes. Both LEW/N and outbred but not F344/N rats had vigorous inflammatory responses to carrageenin, and imipramine was associated with significant decreases in the local cellular inflammatory response to carrageenin. Imipramine was also associated with changes in the expression of peripheral blood cell MHC class II expression in LEW/N and outbred rats. These results suggest that at doses comparable to those used clinically imipramine has significant effects on response to an inflammatory stimulus.

Animals↗
PubMed1990

Effect of imipramine in the "learned helplessness" model of depression in rats is not mimicked by combinations of specific reuptake inhibitors and scopolamine.

Administration of imipramine, which blocks noradrenergic, serotonergic and cholinergic reuptake, to rats for 4 days counteracts the shuttlebox escape failures otherwise seen in rats which have been exposed to inescapable shock (the "learned helplessness" model of depression). The effects of the more selective reuptake inhibitors talsupram (noradrenergic), citalopram (serotonergic) and the anticholinergic compound scopolamine were assessed alone and in combination after acute or 4 days' administration on escape behavior. Their possible synergistic effects when combined with imipramine were also assessed. Talsupram and citalopram were ineffective, whereas scopolamine counteracted the escape failures. Combinations of talsupram, citalopram and a subeffective dose of scopolamine were ineffective. A synergistic effect was only seen when scopolamine was combined with a suboptimal dose of imipramine. Thus, the effect of imipramine on "learned helplessness" might rely partly on its anticholinergic component. However, as an acute high dose of imipramine (25 mg/kg) was ineffective [unlike the acute administration of scopolamine (0.12 mg/kg)], this drug retains a pharmacological effect which is not mimicked by scopolamine alone or by combining the specific reuptake inhibitors with scopolamine.

Animals↗
PubMed1991

Effects of long-term administration of imipramine on reticular-elicited hippocampal rhythmical slow activity.

All anxiolytics so far tested show a common reduction in the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether imipramine, an antidepressant drug which has also been used to treat generalized anxiety disorders, shares the common characteristics of anxiolytics on hippocampal RSA. Rats implanted with reticular stimulating electrodes and subicular recording electrodes received both acute and chronic injection of different doses of imipramine. Only relatively high doses (20 and 30 mg/kg, IP) of imipramine produced a reduction in RSA frequency after a single administration. Long-term administration of 20 mg/kg (but not 10 mg/kg, IP) imipramine induced an increase in baseline RSA frequency but there was no change in the acute frequency-reducing effect of the drug. These results suggest that changes in hippocampal RSA reflect different mechanisms of action for chronic versus acute treatment with antidepressant. It is possible that, at high doses, apparently anxiolytic effects of imipramine may be mediated by similar mechanisms to conventional anxiolytic drugs.

Animals↗
PubMed1993

Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine.

The anxiety/defense test battery has been developed to assess defensive reactions in rats to situations associated with a natural predator, the domestic cat. This comprises three paradigms designed to study the effects of cat exposure on general activity and location with respect to the cat (proxemic avoidance), the effects of cat exposure on non-defensive consummatory behavior, and the behavioral response to cat odor. In the present study subjects were exposed to 21 days pretreatment with imipramine (0, 5, and 15 mg/kg), before being assessed in the three experimental paradigms (carried out over a total period of 7 days). Imipramine treatment was maintained on a daily basis during the 7 days taken to complete the series of tests. The data indicated a behaviorally specific profile consistent with anxiety/fear reduction, but not with sedation, in three different paradigms, following treatment with 15 mg/kg imipramine. These behavioral changes included a reduction in freezing, proxemic avoidance and a disinhibition of suppressed feeding in response to cat presentation. Similarly, imipramine treatment (15 mg/kg) significantly reduced behaviors associated with risk assessment (e.g. flat back approach, stretch attend) during presentation of a cat odor stimulus. This behavioral profile suggests that chronic pretreatment with imipramine produces an attenuation of antipredator defensive behavior.

Aggression↗
PubMed1986

High affinity binding of 3H-paroxetine and 3H-imipramine to rat neuronal membranes.

Paroxetine is the most potent and one of the most specific serotonin uptake inhibitors. High-affinity 3H-paroxetine and 3H-imipramine binding was compared in rat neuronal membranes. The KD value for 3H-paroxetine binding to neuronal membranes was 0.08 nM, which is exactly the same value as with platelet membranes. The KD value for 3H-imipramine binding to neuronal membranes was about 4 nM, which is higher than the KD value for 3H-imipramine binding to platelet membranes (0.5 nM). The results indicated that the 3H-paroxetine binding site is identical in neuronal membranes and in platelet membranes; this binding site is probably located on the serotonin transport mechanism. In addition, part of the high-affinity 3H-imipramine binding to neuronal membranes is probably located on the serotonin transport mechanism, but another part is located elsewhere. Furthermore the polypeptides containing the 3H-imipramine binding sites may not be identical in neuronal and platelet membranes.

Animals↗
PubMed1991

Protective effects of felodipine and verapamil against imipramine-induced lethal cardiac conduction disturbances in the anaesthetized rat.

The effect of verapamil and felodipine on imipramine-induced cardiac toxicity was assessed in anaesthetized rats. Rats received either infusion of saline (n = 13), or non-hypotensive doses of felodipine (n = 36) or verapamil (n = 36) over 40 minutes. In saline-pretreated rats IV bolus injection of imipramine (10 mg/kg) resulted in severe hypotension, bradycardia, electromechanical dissociation, and death within 3 minutes. Rats pretreated with nonhypotensive doses of felodipine (1, 3, 6, and 10 micrograms/kg/min) or verapamil (10, 30, 100, and 300 micrograms/kg/min) survived throughout the experiment, despite an initial fall in blood pressure within the first 5 minutes after imipramine administration. Blood pressure returned to baseline levels within 15 minutes. Intermittent ECG monitoring showed significant prolongation of QRS duration after imipramine in both saline (by 138%) and verapamil-pretreated rats (by 63%), whereas in the rats pretreated with felodipine no prolongation was observed (+3%). We conclude that, in our experimental model, felodipine, more than verapamil, protects against the cardiac effects of imipramine intoxication.

Animals↗
PubMed1998

Effects of phenelzine and imipramine on the steady-state levels of mRNAs that encode glutamic acid decarboxylase (GAD67 and GAD65), the GABA transporter GAT-1 and GABA transaminase in rat cortex.

There is an increasing body of evidence suggesting that GABA plays an important role in the therapeutic effects of antidepressant/antipanic drugs. Phenelzine and imipramine are efficacious in the treatment of depression and panic disorder and phenelzine has been reported to elevate GABA levels while imipramine enhances GABA release in rat brains. In the present study, using a multiprobe quantitative solution hybridization assay, we measured the steady-state levels of mRNAs that encode glutamic acid decarboxylase (GAD67 and GAD65), the GABA transporter GAT-1 and GABA transaminase (GABA-T) in rat cortex after treatment with constant infusion (via osmotic minipumps) of phenelzine or imipramine for a short-term (3 days) or long-term (21 days) period. We found that none of the treatments gave rise to significant changes in the steady-state levels of mRNAs encoding GAD67, GAD65 or GABA-T at any time point. The steady-state levels of GAT-1 mRNA were increased significantly (23%) after long-term, but not by short-term, treatment with phenelzine. Imipramine treatment, short- or long-term, did not alter the steady-state levels of GAT-1 mRNA. These results suggest that the GABA enhancing effects of phenelzine or imipramine in rat cortex do not affect the steady-state levels of mRNAs that encode GAD67, GAD65 and GABA-T. Further, the previously observed increases in GABA levels or GABA release induced by these drugs are probably not a consequence of changes in the expression of these genes.

4-Aminobutyrate Transaminase↗
PubMed2001

The use of short-form quality of life questionnaires to measure the impact of imipramine on women with urge incontinence.

Short-form questionnaires were used to measure the change in quality of life (QOL) of women with urge-predominant urinary incontinence treated with imipramine hydrochloride. Short forms of the Incontinence Impact Questionnaire (IIQ-7) and the Urogenital Distress Index (UDI-6) were integrated into a patient questionnaire, which was given to 25 patients with urge-predominant urinary incontinence before and after treatment with imipramine. Demographic data and self-reports of the number of incontinent episodes were also recorded. Total and subscale QOL scores and number of incontinent episodes were recorded and compared with Wilcoxson's signed ranks test, as well as correlated to the change in number of incontinent episodes with Pearson's correlation coefficient. Treatment with imipramine resulted in a clinical improvement or cure in 16/22 patients (72.7%), with an average reduction in incontinent episodes of 78.7% (P<0.001). The average per cent improvement in QOL scores for total IIQ-7 was 42.1% (P<0.01) and total UDI-6 score was 44.1% (P<0.001). All subscale QOL differences were also significant (P<0.01). The incidence of side effects to imipramine was 41%, which resulted in dose changes. Fourteen per cent eventually discontinued therapy. Neither total nor subscale QOL improvement scores were correlated with improvement in number of incontinent episodes. The short form IIQ-7 and UDI-6 are effective tools to determine change in QOL, as evidenced by the effectiveness of imipramine for the treatment of urge-predominant urinary incontinence. Significant reductions in incontinent episodes and improvements in IIQ-7 and UDI-6 QOL scores were both seen, but were not correlated. Short-form QOL measures can easily be integrated into a patient questionnaire to objectively measure a very subjective topic.

Adult↗
PubMedDate not supplied

Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes.

The antidepressants, imipramine and mianserin, have been reported to cause liver damage. We investigated a role of cytochrome P450 (CYP)-mediated formation of a reactive metabolite in antidepressant-induced acute cell injury using hepatocytes isolated from male and female Wistar rats, and male Dark Agouti rats, which have different relative abundance of CYP enzymes. Culture of the hepatocytes with imipramine and mianserin caused a marked decrease in glutathione followed by protein thiol, which preceded lactate dehydrogenase leakage. The decreases in glutathione and protein thiol contents by imipramine were significantly slower in hepatocytes from male Dark Agouti rats than those from male Wistar rats, whereas no significant sex difference in Wistar rats was observed. The decrease in thiol by mianserin was significantly slower in hepatocytes from female Wistar than those from male Wistar rats, whereas no significant differences were found between Wistar and Dark Agouti males. Results consistent with alteration of the thiols were obtained for lactate dehydrogenase leakage induced by imipramine and mianserin. These findings indicated that CYP-mediated metabolic activation was involved in acute cell injury induced by the antidepressants; namely a CYP2D enzyme(s), which is deficient in Dark Agouti rats, and a male specific CYP enzyme(s) were suggested to be responsible for the cytotoxicity of imipramine and mianserin, respectively.

Animals↗
PubMed2002

Imipramine restores the long-term impairment of appetitive behavior in socially stressed rats.

RATIONALE: Previous observations revealed that defeated and subsequently individually housed rats do not display behavioral anticipatory responses to the conditioned presentation of a bell/light stimulus associated with free access to a 5% sucrose solution reward. The absence of the appetitive responses suggests a decreased sensitivity to reward. This might be homologous to anhedonia, a symptom of human depression. OBJECTIVES: To further validate the inability to anticipate as indicative for a depressionlike state we investigated whether antidepressant treatment restores the impaired anticipatory responses in defeated and subsequently individually housed animals. METHODS: Male rats were defeated and subsequently individually housed or subjected to a control treatment. In the 19-20th weeks after the exposure to defeat rats were either injected daily with imipramine (20 mg/kg per os, dissolved in water) or water. Anticipatory behavior was measured both before and after 3-5 weeks of chronic treatment with imipramine. RESULTS: The long-term impairment of anticipatory behavior in defeated and subsequently individually housed rats was restored by chronic imipramine treatment. Impaired appetitive behavior in socially stressed rats was not accompanied by a decreased consumption of the 5% sucrose solution in the anticipatory tests. The recovery of the appetitive responses was independent of open field activity, body weight, and 5% sucrose preference in the home cage. CONCLUSIONS: Chronic imipramine administration restores the anhedonialike absence of anticipatory behavior in socially stressed rats. Predictive validity of the social stress model of human depression is suggested by the similar action of imipramine on the modeled behavior and on the anhedonia symptoms in depressive human patients.

Animals↗
PubMed2002

Imipramine, but not lithium, induces the serine/threonine phosphatase activity of calcineurin without affecting its mRNA expression in the rat brain.

The influence of imipramine and lithium on the expression of calcineurin (CaN) and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus was examined. Northern blot analysis demonstrated that single or repeated (14 day) administration of imipramine did not affect the levels of CaN A (catalytic subunit) mRNA in rat brain. Similarly, the administration of lithium for 1 or 14 days had no effect on the expression of CaN A mRNA. In contrast, the acute administration of imipramine significantly increased CaN activity in the cortex and hippocampus. In addition, the chronic (14 day) administration also significantly increased CaN activity. However, administration of lithium for either 1 or 14 days did not influence CaN activity. These findings indicate that imipramine, but not lithium, increases the phosphatase activity of CaN, suggesting that the changes in neuronal functions induced by CaN may be involved in the molecular activity of imipramine.

Adrenergic Uptake Inhibitors↗
PubMed2004

A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients.

OBJECTIVE: To compare the efficacy of imipramine and fluvoxamine in inpatients from two centers suffering from a depressive disorder according to DSM IV criteria. METHODS: The study included 141 patients with a depressive disorder according to DSM IV criteria. After a drug-free and placebo run-in period of 1 week, patients were randomized to imipramine or fluvoxamine; doses of both drugs were adjusted to a predefined target blood level. Efficacy was evaluated 4 weeks after attaining predefined adequate plasma level. RESULTS: The mean age of the study group (47 males, 94 females) was 51.8 (range 19-65) years. Of these 141 patients, 56 had episode duration longer than 1 year, 48 had mood congruent psychotic features, and 138 patients received medication. Seven patients did not complete the medication trial. The total number of patients using concurrent medication was 12/138 (8.6%). On the primary outcome criteria patients on imipramine improved significantly better on the change of illness severity score of the CGI (chi2 exact trend test=4.089, df=1, P=-0.048). There was no significant difference in 50% or more reduction on the HRSD, the other primary outcome criterion. On the secondary outcome criteria the mean reduction of the HRSD scores was significantly larger in the imipramine group than in the fluvoxamine group (mean difference=3.1, standard error (SE)=1.4, t=2.15, df=136, P=0.033). There was no significant difference in the number of patients with an HRSD < or =7 at the final evaluation. CONCLUSIONS: In depressed inpatients imipramine is more efficacious than fluvoxamine. Both drugs were well tolerated by all patients.

Adult↗
PubMed1982

Antiarrhythmic effect of imipramine hydrochloride in patients with ventricular premature complexes without psychological depression.

A study was performed in cardiac patients without psychological depression to determine (1) the antiarrhythmic efficacy of imipramine, (2) its half-life of elimination and duration of action, and (3) the frequency of adverse effects. Twenty-two patients with 30 or more ventricular premature complexes/hour entered the protocol. A drug-free and a placebo day were followed by dosing with imipramine, 1 mg/kg per day, given in two divided doses. The dose was increased by 1 mg/kg per day every other day until ventricular premature complexes were suppressed by at least 80 percent, adverse drug effects were encountered or a total daily dose of 5 mg/kg per day was given. Each day a 24 hour continuous electrocardiogram was recorded to determine the frequency of ventricular premature complexes and heart rate. During the acute dose-ranging period, 18 patients (82 percent) had an antiarrhythmic effect from imipramine. Two patients received 5 mg/kg per day without any decrease in the frequency of ventricular premature complexes. The half-life of elimination of imipramine (parent compound) was 8.8 +/- 3.72 hours but its duration of action was much longer. Four patients (18 percent) had treatment discontinued because of troublesome adverse effects during a follow-up period of 19 +/- 8.8 months. It is concluded that imipramine is a potent antiarrhythmic drug with a long duration of action and relatively few major adverse effects.

Adult↗
PubMed1983

Effect of deuteration of imipramine on its pharmacokinetic properties in the rat.

Imipramine was specifically deuterated in either both aromatic rings or in the N-methyl group, or in both positions, and the pharmacokinetic properties of the products were determined in the rat and compared with those of the non-deuterated analogue. Deuteration of imipramine resulted in a small but significant isotope effect on N-demethylation while aromatic hydroxylation was unaffected. This isotope effect led to a slower rate of systemic clearance, a longer half-life and, when orally administered, enhanced bioavailability. Urinary excretion of didesmethylimipramine-d4, following oral administration of imipramine-d7, was significantly lower than the excretion of didesmethylimipramine following administration of unlabelled imipramine, indicating inhibited demethylation. Similarly, the urinary excretion of desmethylimipramine-d4, didesmethylimipramine-d4 and 2-hydroxydesmethylimipramine-d4 were lower than for the corresponding unlabelled or d7-analogues, indicating the stability of the N-CD3 group. Deuteration had no effect on the pharmacological properties of imipramine as determined in this study.

Animals↗
PubMed1983

Imipramine does not act as a false transmitter in the rat hypothalamus.

[3H]Imipramine was accumulated by rat hypothalamic slices mostly by a passive low-affinity process. Accumulated [3H]imipramine was released by 60 mM potassium, but the release was small and was not Ca2+-dependent. Imipramine induced some release of [3H]norepinephrine. None of these events were abolished by pretreatment of the rats with reserpine. These results do not favor the view that imipramine acts as a false transmitter in the rat hypothalamus. Rather, imipramine appears to be accumulated in an extragranular pool from which it releases extragranular norepinephrine.

Animals↗