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PubMed1987

Pharmacokinetic profiles and temporal changes in quantitative EEG after imipramine administrations.

A study of the relationship between pharmacokinetic profiles and temporal changes in quantitative EEG following imipramine administrations showed that a single dose of imipramine administered by different routes decreased the alpha-power spectra of healthy subjects. The EEG changes were time-related and their latent period and duration depended not on the plasma levels, but on the pharmacokinetic parameters. These effects were produced by imipramine without the influence of its desmethylated product, desipramine. Also, both single and multiple doses after oral or intramuscular imipramine administrations to depressive patients led to two types of EEG responses, with Type 1 patients exhibiting fast improvement of their symptoms. Therefore, chronologically-recorded quantitative EEG should be useful in judging the clinical prognosis of depressive patients after the imipramine treatment. At a steady state, however, neither the EEG recording nor the evaluation of the plasma level is adequate for the judgment.

Adult↗
PubMed1980

Intraneuronal site of action for imipramine in rat striatal slices.

The uptake of 3H-labeled imipramine ([3H]IMI) in rat carpus striatum slices was found to be strongly temperature-dependent. The accumulation was shown to be saturable and two apparent Km's were found: 2.2 x 10(-8) and 3.5 x 10(-7) M. Once incorporated, the labeled drug was released from superfused slices by K+ (55 mM) depolarization in the presence of calcium ions. Imipramine was also studied for its ability to induce the release of [3H]dopamine ([2H]DA) which had been previously accumulated by striatal slices. It was found that striatal slices superfused during 1 or 6 min with imipramine (10(-6) - 10(-4) M) release substantial amounts of radioactive dopamine, independently of the presence of Ca2+ in the medium. This release is completely abolished after reserpine pretreatment. It is proposed that imipramine enters the dopaminergic storage vesicles and displaces dopamine. An intraneuronal mechanism of action for imipramine is discussed.

Animals↗
PubMed1982

[3H]Imipramine is accumulated but not released from slices of the rabbit caudate and hypothalamus.

Slices of rabbit caudate and hypothalamus take up and accumulate [3H]imipramine. In superfused slices of both structures electrical stimulation or exposure to tyramine failed to release recently taken up [3H]imipramine. Depolarization by exposure to 30--60 mM-potassium caused only a small release of [3H]imipramine that was not concentration-dependent. The release of [3H]imipramine by high potassium was independent of the presence of calcium ions in the superfusion medium. These results contrasted with those obtained for the release of [3H]dopamine from the caudate and [3H]noradrenaline from the hypothalamus, where tyramine, electrical stimulation, and high potassium caused a significant release of the labeled neurotransmitters. The release of [3H]dopamine from the caudate and [3H]noradrenaline from the hypothalamus elicited by electrical stimulation or high potassium was entirely calcium-dependent. It is concluded that [3H]imipramine is taken up into the two brain regions and is accumulated in a nonvesicular site from which it is not released by calcium-dependent depolarizing stimuli.

Amphetamine↗
PubMed1984

Similarities and differences between high-affinity binding sites for cocaine and imipramine in mouse cerebral cortex.

Previously we found close similarities between high-affinity binding sites for [3H]cocaine and those for [3H]imipramine in the mouse cerebral cortex in regard to their association with neuronal uptake of serotonin. In the present study we investigated whether the two ligands bind to the same site. The two ligands had the following high-affinity binding properties in common: localization in both synaptosomal and microsomal fractions; vulnerability to treatment with N-ethylmaleimide, trypsin, and phospholipase A2; and resistance to exposure to dithiothreitol. In contrast, cocaine binding in the cerebral cortex was more sensitive to heat inactivation than imipramine binding. In addition, the mechanism by which cocaine inhibited [3H]imipramine binding differed from that by which imipramine inhibited [3H]cocaine binding. These data suggest that the high-affinity binding sites for [3H]cocaine and [3H]imipramine in the cerebral cortex are distinct entities.

Animals↗
PubMed1986

Binding of [3H]imipramine to mouse cerebrocortical membranes and to glass fiber filters.

It was suggested in a recent report by Phillips et al. [J. Neurochem. 43, 479-486 (1984)] that the low-affinity binding of [3H]imipramine in the mouse cerebral cortex could in fact represent binding of [3H]imipramine to the GF/B glass fiber filters used to terminate the assays. The present study demonstrates that this is not the case and advances two lines of evidence: (a) For saturation analysis, mouse cerebrocortical membranes were incubated with [3H]imipramine concentrations between 0.8 nM and 3.6 microM, and parallel incubations were carried out with buffer replacing the brain membranes. The same low-affinity component, in addition to the high-affinity component, was present in the binding of [3H]imipramine to brain membranes plus GF/B filters (uncorrected data), and in that to brain membranes alone (corrected data). (b) Dissociation experiments, in which filter binding is equal for all samples and dissociation time is the only variable, clearly indicated the nonhomogeneity of [3H]imipramine binding. Our results, however, do show that binding to recently purchased GF/B filters is not a negligible phenomenon in saturation experiments. Relatively lower binding was found to GF/C, GF/F, Gelman A/E, and Reeves Angel 934 AH filters; pretreatment of GF/B filters with polyethyleneimine (PEI) reduced binding to a greater extent in the single manifold than in the cell harvester.

Animals↗
PubMed1991

Different mechanisms of beta-adrenoceptor down-regulation by chronic imipramine and electroconvulsive treatment: possible role for protein kinase C.

The aim of this study was to find out how protein kinase C (PKC) is involved in down-regulation of the beta-adrenoceptor in cortical slices of rats subjected to antidepressant treatments. The responses of the cyclic AMP generating system to forskolin, isoproterenol, and noradrenaline were tested in the absence and presence of a PKC activator, 12-O-tetradecanoylphorbol 13-acetate (TPA). The antidepressive treatments applied were chronic administration of imipramine and electroconvulsive shock. The potentiating effect of the phorbol ester on cyclic AMP response to isoproterenol was retained in imipramine-treated animals and even accentuated in rats subjected to electroconvulsive treatment; the TPA effect on noradrenaline-induced cyclic AMP response was blunted in rats receiving imipramine, but augmented in those receiving electroconvulsive treatment. In imipramine-treated rats the beta-down-regulation was still evident in the presence of TPA; after electroconvulsive treatment the phorbol ester-induced potentiation was so high that no significant beta-down-regulation could be observed. No procedure affected the response to forskolin. The beta-down-regulation that develops during chronic imipramine treatment differs from that caused by chronic electroconvulsive treatment; in both cases it is not related to the direct effect on adenylate cyclase.

Adenylyl Cyclases↗
PubMed1985

Selective effects of thiol reagents on the binding sites for imipramine and neurotransmitter amines in the rat brain.

The action of the antithyroid drugs methimazole (MMI) and propylthiouracil (PTU) on the binding of [3H]-imipramine, [3H]-5-hydroxytryptamine [3H]-5-HT) (to 5-HT1-receptors) and [3H]-spiperone (to 5-HT2-, D2-receptors) of rat brain membranes has been examined. The synaptosomal uptake of [3H]-5-HT was also studied. Micromolar concentrations of the disulphide bond reducing agents MMI, PTU, dithiothreitol (DTT) and mercaptoethanol increased both the binding of [3H]-imipramine and the uptake of [3H]-5-HT. In contrast, they decreased the number of 5-HT1-receptors, and did not affect 5-HT2-and D2-sites. Reaction with membrane-bound sulphydryl (SH) groups by micromolar concentrations of N-ethylmaleimide (NEM), hydroxymercuribenzoic acid (PCMB), or Ellman's reagent (DTNB) decreased the binding of [3H]-imipramine, the number of 5-HT1-receptors, and the uptake of [3H]-5-HT. Millimolar concentrations of NEM were necessary in order to decrease partially 5-HT2- and D2-receptors. The effects of NEM on imipramine recognition sites and on the uptake of 5-HT could be prevented by DTT; protection was not obtained in other receptor systems. Three groups of receptors have been, thus, postulated, based upon their different sensitivity towards alterations in membrane [disulphide bridges in equilibrium SH] equilibrium: Group I, including imipramine recognition sites and the uptake system for 5-HT; Group II, including 5-HT1-receptors; Group III, including 5-HT2-and D2-receptors.

Animals↗
PubMed1977

Comparative clinical evaluation of lofepramine and imipramine. Psychiatric aspects.

Lofepramine, an imipramine analogue, was compared with imipramine in a multicentre, double-blind clinical trial. The 62 patients (31 in each of two treatment groups) had a depressive syndrome that normally would have been treated with a tricyclic antidepressant. These patients had not received any adequate treatment for this present depressive episode. After a wash-out period and once a week during treatment (up to 5 weeks), routine laboratory tests and electrocardiograms was done. The dosage was 50 mg t.i.d. for imipramine and 70 mg t.i.d. for lofepramine. Depression ratings with the Cronholm-Ottosson depression rating scale were performed before treatment and once weekly for 3 weeks and then in the 5th week. The last four ratings were combined with rating of side-effects. In the 5th week of treatment 15 out of 31 in the lofepramine group and 18 out of 31 in the imipramine group had recovered. This difference was not significant, nor did the median values of individual symptoms differ between the groups. The side-effects were moderate and the two groups only differed significantly in the items "dry mouth" and accommodation disturbances in favour of lofepramine. The drug compliance was checked by plasma levels of desmethylimipramine in the imipramine group, parent compound, and "apparent" desmethylimipramine in the lofepramine group. The relationship between plasma drug levels, the effect on noradrenaline uptake in vitro and amelioration discussed in Siwers et al. (1977) in this issue. The clinical outcome in the two groups did not differ significantly; interpretation of this result is discussed in relation to the reliability and selection of patients.

Adult↗
PubMed1982

A double blind comparison of lofepramine, imipramine and placebo in patients with depression.

The results of double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group. In particular, for severe and/or moderate occurrences of dry mouth, the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 (8 lofepramine vs 21 imipramine patients).

Adolescent↗
PubMed1983

A multicentre double-blind comparative trial of zimeldine and imipramine in primary major depressive disorders.

Zimeldine, a new antidepressant with a selective inhibition of 5-HT reuptake, was compared with imipramine in a double-blind comparative study. The trial was conducted on 95 patients with primary major depressive disorder, of endogenous character. During the 4-week study period clinical efficacy was evaluated by using the Hamilton Depression (HAM-D) scale, Beck's Inventory and global ratings. Zimeldine (100 mg b.d.) was shown to have as good an antidepressive effect as imipramine (50 mg t.d.s.) when evaluated on the HAM-D scale. Assessment of the symptom improvement on this rating scale suggested that zimeldine was more effective in improving the patient's insight of the disease. There was no significant difference between zimeldine and imipramine as assessed by a final global improvement rating scale as well as by the patient's own impression. Exploratory data analysis revealed that zimeldine was significantly more effective than imipramine in the following groups; patients over 40 years of age; patients whose initial onset of illness occurred at over 40 years; patients with a history of at least three episodes of depressive illness; patients with mild to moderate depression; and patients who had previously failed to show an appreciable response to other antidepressant treatment. Analysis of global safety ratings revealed that zimeldine is significantly safer than imipramine, with a lower incidence of adverse symptoms involving the autonomic nervous system, especially anticholinergic reactions. No significant difference was observed between the two groups with respect to abnormal laboratory reports. One zimeldine patient developed symptoms suggesting a hypersensitivity reaction (fever, skin eruption and elevation of plasma levels of transaminases), which led to the patient's withdrawal from drug treatment.

Adolescent↗
PubMed1987

Comparison of the serum levels in primary non-agitated depressed out-patients treated with imipramine in combination with placebo, diazepam or dixyrazine.

Sixty-three non-agitated depressed out-patients were selected according to the Feighner-Robins-Guze criteria for primary depressions for a double-blind, between-patient randomized study for an 8 week duration. All the patients were treated with imipramine following a fixed dose schedule for the first 2 weeks and thereafter according to clinical response (100-200 mg/day). This treatment was combined with either placebo, diazepam (10 mg/day) or dixyrazine (50 mg/day). The serum concentration of imipramine both at 2 weeks and later was significantly higher (P less than 0.05) in the group treated with dixyrazine than in the other two groups. In the group treated with diazepam, the serum levels of imipramine and desipramine were significantly lower than in the placebo group. The serum concentrations of diazepam, desmethyldiazepam and dixyrazine were almost unchanged during the study. No significant correlation was found between the dosage and the serum concentration of imipramine or desipramine. The change in mean CPRS-score correlated neither with the imipramine nor with the desipramine serum levels, it did correlate but negatively with the degree of side effects. The degree of side effects correlated positively with the serum concentration of desipramine.

Adult↗
PubMed1988

Imipramine: a model substance in pharmacokinetic research.

The pharmacokinetics of imipramine have been studied over a period of 20 years. Imipramine is rapidly and almost completely metabolized with the formation of desipramine (desmethylation), 2-hydroxy metabolites and subsequent glucoronide coupling. Imipramine has a high clearance (0.8-1.5 l/min) and a corresponding high first pass elimination (30-70%). Volume of distribution is high (650-1100 1) and half-lives accordingly of medium length (6-12 h). The 2-hydroxylation which is the most important step of elimination is mediated via microsomal cytochrome P450 isozyme that exhibit monogenetic polymorphism such that 5-10% of the population have a severely reduced clearance. Co-administration of neuroleptics may also considerably impair the 2-hydroxylation. Steady-state levels of imipramine and desipramine varies considerably among individuals mainly due to variations in metabolism, but also to a smaller extent due to variations in binding to plasma proteins. The variations in steady-state concentrations appear to have clear implication for the clinical effects of imipramine.

Depressive Disorder↗
PubMed1983

The influence of orphenadrine or imipramine on the hypertensive response of physostigmine in the rat.

UNLABELLED: An intravenous infusion of orphenadrine or imipramine to artificially ventilated, urethane anaesthetized rats, completely blocked the physostigmine induced increase in blood pressure and the blood pressure increase induced by electrical stimulation of the posterior hypothalamus; effects mediated via the sympathetic nerve. The noradrenaline induced blood pressure increase was not changed during an infusion with orphenadrine but was markedly depressed during an infusion with imipramine. During an infusion with both orphenadrine or imipramine the pressor response induced by stimulation of the spinal cord were completely blocked in pithed rats. The pattern of the blockade was comparable with the blockade of the pressor response after hypothalamic stimulation. These results show that at least in rats both orphenadrine and imipramine prevents the central stimulatory sympathetic effects on the cardiovascular system by interfering with the sympathetic nervous system. The site of action is discussed. IN CONCLUSION: the present results show that although physostigmine may be helpful in the treatment of central anticholinergic effects caused by overdoses of orphenadrine and imipramine it is of no use for combating the direct toxic effects of both drugs on the cardiovascular system.

Animals↗
PubMed1992

Failure of addition of lithium to imipramine to enhance activity in rats or mood in normal volunteers.

Lithium powerfully augments the effects of imipramine in resistant depression. We treated four groups of rats for five weeks with (1) saline alone, (2) saline followed by lithium, (3) imipramine alone, and (4) imipramine followed by lithium. There was no augmentation of activity by lithium. Normal human volunteers took imipramine 75 mg daily for three weeks, followed by imipramine 75 mg daily together with lithium 900 mg daily for another ten days. There was no elevation of mood after the addition of lithium. Lithium augmentation of antidepressants apparently requires a pre-existing neurochemical-behavioral disturbance.

Affect↗
PubMed1997

Modelling of non-linear pharmacokinetics in sheep after short-term infusion of cardiotoxic doses of imipramine.

Imipramine was administered to sheep (n = 10) by intravenous infusion in high doses (450 mg-900 mg) to elicit cardiovascular shock. A cardiac assist device was then employed to manage the acute overdose situation. The concentration-time course of imipramine and its metabolite desmethylimipramine in plasma was measured by HPLC. As an indicator of imipramine's cardiotoxic effect, cardiac output was monitored. The aim of the study was to evaluate the pharmacokinetics under these conditions and to assess the efficiency of a cardiac assist device with (n = 5) and without (n = 5) an integrated haemoperfusion unit in removing drug from the circulation. The kinetics of imipramine could be described by a three compartment body model with concentration-dependent clearance resulting in non-linear kinetics. The changes in cardiac output with time could be linked to the pharmacokinetic model by a linear relationship. The cardiac assist device was found to contribute to the overall elimination of imipramine whereas the haemoperfusion unit had no clinically relevant impact.

Animals↗
PubMed1986

The effect of antidepressants on ethylmorphine and imipramine N-demethylation in rat liver microsomes.

The effects of single and multiple doses of desipramine, amitriptyline or citalopram on the rat liver microsomal cytochrome P-450 level and on the rate of ethylmorphine and imipramine demethylation in-vitro have been investigated. Desipramine, amitriptyline or citalopram when given to rats as a single dose, did not affect the level of cytochrome P-450 in the liver microsomes, however, there was a tendency towards acceleration of imipramine, and particularly ethylmorphine, demethylation. Prolonged administration of desipramine and citalopram, but not amitriptyline, elevated the microsomal level of cytochrome P-450 and accelerated the rate of ethylmorphine demethylation. All the drugs investigated, when given chronically, inhibited the rate of imipramine demethylation. Since demethylation of ethylmorphine and imipramine in a CO atmosphere was inhibited by ca 90% for the former and only by 58% for the latter, it can be assumed that prolonged administration of the drugs investigated has two different effects on the oxygenase systems in rat liver microsomes: on the one hand they stimulate the cytochrome P450 oxygenase system involved in ethylmorphine demethylation and, on the other, they inhibit the other microsomal oxygenase system involved in demethylation of imipramine.

Animals↗
PubMed1992

The effect of dinoprost on transport of water and imipramine through rat small intestinal membranes.

The relation between transmucosal fluid movement and its effect on absorption and exsorption of imipramine was studied with the in-situ single-pass perfusion technique in rats. Dinoprost (prostaglandin F2 alpha, PGF2 alpha) caused a dose-related inhibition of both absorption and secretion of water across the intestinal membrane. When PGF2 alpha was infused at a rate of 5 mumols kg-1 h-1, the absorption rate of water decreased from 51.7 to 21.5 mL h-1 and the secretion rate decreased from 48.9 to 26.8 mL h-1. Net water flux changed from net water absorption (0.9 mL h-1) to net water secretion (5.33 mL h-1) by infusion of PGF2 alpha. However, absorption and exsorption of imipramine were little affected by infusion of PGF2 alpha. The absorption rates of imipramine were 3.03 and 2.36 mg h-1 in the absence and presence of PGF2 alpha, respectively. Furthermore, the average amounts of imipramine exsorbed into the intestinal lumen in 2 h were 7.82 and 8.10% in the absence and presence of PGF2 alpha, respectively. Infusion of PGF2 alpha also enhanced motility of the small intestine compared with the control. From these results, it appears that PGF2 alpha has no effect on the absorption and exsorption of imipramine across the intestinal membrane although it is reasonable to use PGF2 alpha in the case of patients with overdoses of drugs which decrease gastrointestinal motility.

Animals↗
PubMed1999

Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks.

OBJECTIVES: To assess the efficacy and safety of hypericum extract (STEI 300, Steiner Arzneimittel, Berlin) compared with imipramine and placebo in patients in primary care with a current episode of moderate depression. DESIGN: Randomised, double blind, multicentre, parallel group trial for 8 weeks. SETTING: Trained panel of 18 general practitioners from four German states: Bavaria, Berlin, Rhineland Palatinate, and Saxony. PARTICIPANTS: 263 patients (66 men, 197 women) with moderate depression according to ICD-10 (international classification of diseases, 10th revision) codes F32. 1 and F33.1. INTERVENTIONS: 1050 mg hypericum extract (350 mg three times daily), 100 mg imipramine (50 mg, 25 mg, and 25 mg daily), or placebo three times daily. MAIN OUTCOME MEASURES: Change from baseline score on the 17 item version of the Hamilton depression scale, the Hamilton anxiety scale, the clinical global impressions scale, Zung's self rating depression scale, and SF-36, and adverse events profile. RESULTS: Hypericum extract was more effective at reducing Hamilton depression scores than placebo and as effective as imipramine (mean -15.4 (SD 8.1), -12.1 (7.4), and -14.2 (7.3) respectively). Comparable results were found for Hamilton anxiety and clinical global impressions scales and were most pronounced for the Zung self rating depression scale. Quality of life was more improved in the standardised mental component scale of the SF-36 with both active treatments than with placebo but in the physical component scale was improved only by hypericum extract compared with placebo. The rate of adverse events with hypericum extract was in the range of the placebo group but lower than that of the imipramine group (0.5, 0.6, and 1.2 events per patient respectively). CONCLUSIONS: At an average dose of 350 mg three times daily hypericum extract was more effective than placebo and at least as effective as 100 mg imipramine daily in the treatment of moderate depression. Treatment with hypericum extract is safe and improves quality of life.

Adult↗