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PubMed1992

Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine.

The hemodynamic, cardiographic, and initial pharmacokinetic characteristics of the de novo administration of the 2-hydroxymetabolite (2-OH-IMI) of imipramine (IMI), compared with its parent was studied in a swine preparation. Cardiac output, arterial pressure, and the continuous electrocardiogram were assessed after the intravenous administration of the drug or its metabolite. Plasma, sampled over 120 min and CSF sampled at 60 min were analyzed by reverse phase HPLC with spectroflurometric detection. Equilibrium dialyses were performed on plasma sampled at 60 min. 2-OH-IMI, in doses of 5-6 mg/kg, compared to dosages of IMI up to 8.5 mg/kg, produced a significantly greater incidence of life-threatening arrhythmias, and caused profound and significant decreases in blood pressure and cardiac output. 2-OH-IMI had a smaller volume of distribution (Vd) and shorter half-life. CNS penetration, as estimated by CSF/plasma ratios, was significantly greater for 2-OH-IMI. These phenomena were partly accounted for by significantly less protein binding for the hydroxymetabolite. It is concluded that 2-OH-IMI has increased penetrance into the CNS despite a smaller Vd and that it is significantly more cardiotoxic than its parent.

Animals↗

PubMed1995

Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine.

Chronic exposure to mild unpredictable stressors (CMS) has previously been found to reduce the consumption of palatable, sweet solutions in rats. In the present study, the utility of this procedure was assessed in mice. Male AP mice subjected to CMS showed reduced consumption of a 2% or 4% sucrose solution. This effect was reversed by chronic (3 weeks) treatment with the tricyclic antidepressant imipramine (20 mg/kg per day). These results extend previous reports of a generalized decrease in sensitivity to reward (anhedonia) in rats caused by CMS and the efficacy of antidepressant treatment in this paradigm. Chronic unpredictable mild stress in mice appears to provide a realistic animal model of depression.

Analysis of Variance↗

PubMed1990

Increased platelet 3H-imipramine binding and monoamine oxidase B activity in Alzheimer's disease.

Several biochemical abnormalities in peripheral tissues have been reported in Alzheimer's disease (AD). With this in mind we studied platelet monoamine oxidase B (MAO B) activity and 3H-imipramine (IMI) binding in both AD patients and healthy subjects and found a significantly higher level of platelet MAO B activity and 3H-IMI Bmax values in the AD patients. In view of the part that MAO B plays in metabolizing serotonin (5HT) and of the relationship which exists between 3H-IMI binding and 5HT uptake, our results would suggest that with AD there occurs a complex dysfunction in the 5HT system, at least at a peripheral level.

Aged↗

PubMed1992

Population pharmacokinetics of imipramine in children.

The population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6-13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method. The mean value of the elimination constant of the drug and metabolite were 0.0425 h-1 and 0.0359, h-1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg.kg-1.day-1. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.

Adolescent↗

PubMed1986

Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors.

The high-affinity binding sites for [3H]-imipramine (IMI) present in human platelets are associated with the neuronal uptake system for 5HT. It was recently demonstrated that previous antidepressant therapy with drugs which inhibit 5HT uptake could down-regulate [3H]-IMI binding and that this effect could persist up to 1 month after the end of treatment. We therefore re-examined the reported differences in Bmax of [3H]-IMI binding in platelets between control and depressed untreated patients, to evaluate the residual influence of previous antidepressant medication. The saturation characteristics of [3H]-IMI binding were compared in platelets from 17 depressed patients carefully selected according to previous antidepressant therapy and washout period, who were closely matched, for age and sex, with a group of control healthy volunteers. The results reveal a significant decrease by 47% in the Bmax of [3H]-IMI binding in platelets of untreated depressed patients when compared with controls. There was no significant modification of Kd values for platelet [3H]-IMI binding between the depressed and the control groups. Our results support the view that platelet [3H]-IMI binding is a useful tool as a biological marker in depression.

Adult↗

PubMed1979

Comparative distribution of two antidepressant drugs (imipramine and indalpine) in the rat as determined by analog computer simulation.

A ten-compartment analog computer model is presented to determine the precise distribution and excretion of two antidepressant drugs, LM 5008 AND Imipramine. Eight patterns were simulated using experimental data and drug distribution in the two undetermined compartments were obtained by the analog model. Close agreement with existing experimental data lends confidence in the model as a valuable tool for predictions in a variety of therapeutic situations.

Animals↗

PubMed2001

Pharmacokinetic interaction between imipramine and carbamazepine in patients with major depression.

RATIONALE: Despite the fact that carbamazepine (CBZ) is frequently added to the existing tricyclic antidepressant (TCA) therapy, to date little is known about serum levels of pharmacologically active hydroxy metabolites of TCAs, as well as about possible changes in free (non-protein-bound) concentrations of these drugs and their metabolites during such combination treatment of depression. OBJECTIVE: The aim of this study was to evaluate the effect of CBZ on steady-state total and free serum concentrations of imipramine (IMI) and its metabolites, desipramine (DMI), 2-hydroxyimipramine and 2-hydroxydesipramnine, in depressed patients. In addition, the free and total serum concentrations of CBZ and 10,11-epoxycarbamazepine were measured. METHOD: Thirteen patients with DSM-III-R diagnosis of major depression were enrolled in the study. All patients hospitalised at the Department of Psychiatry, Collegium Medicum, Jagiellonian University were treated with IMI at a dose of 2 mg/kg per day for 3 weeks, after which CBZ at a dose of 400 mg/day was added. Steady-state serum concentrations of IMI, CBZ and their metabolites were assayed by HPLC. Free drug concentrations were measured by ultrafiltration. RESULTS: After 2 weeks of combination therapy a significant decrease in mean steady-state total serum concentrations of IMI (from 168.84 +/- 102.18 to 98.12 +/- 43.79 ng/ml) and DMI (from 293.89 +/- 171.93 to 221.85 +/- 153.21 ng/ml) was observed. Simultaneously, steady-state serum concentrations of total hydroxy metabolites and free IMI and its metabolites, measured just before and 2 weeks after CBZ were started, did not differ significantly. In consequence, a significant increase in free fraction of the parent drug was observed (3.36 +/- 3.24% vs 5.75 +/- 3.60%). Also free fraction of DMI tended to be higher after CBZ addition. CONCLUSION: CBZ affects not only the metabolism of IMI and its metabolites, but also their protein binding. Therefore, despite considerable reductions in total serum levels of IMI and DMI, but when the unchanged free fraction concentration of these compounds is maintained, a dosage elevation of IMI does not seem to be necessary after CBZ addition to TCA therapy.

Antidepressive Agents, Tricyclic↗

PubMed2001

Clinical options for imipramine in the management of urinary incontinence.

Urinary incontinence is a common disorder in both childhood and adulthood. Proper treatment depends on insight into the pathophysiology and pharmacology of the lower urinary tract. This article reviews the mechanism of action of an old but commonly used drug, the tricyclic antidepressant agent imipramine, in nocturnal enuresis and stress and urge incontinence with reference to neuropharmacology and the relevant pathophysiology.

Antidepressive Agents, Tricyclic↗

PubMed2003

Effect of imipramine on linear and nonlinear measures of heart rate variability in children.

We investigated the effects of treatment with the tricyclic antidepressant (TCA) imipramine in eight children in supine and standing postures. We used 256 seconds of real-time data for the analyses. Spectral analysis showed a significant decrease of high-frequency (HF) power (0.15-0.5 Hz), especially in the standing posture. Low frequency (LF) HF ratios were significantly higher in the standing posture after treatment, suggesting increased sympathovagal interaction. We also obtained the nonlinear measures of fractal dimension (FD), and approximate entropy (APEN). Although the FD of heart rate was significantly lower in the standing posture, APEN was significantly decreased after treatment in either posture and was the most sensitive measure in this study. These findings suggest a decreased cardiac vagal function with a relative increase in sympathetic responsiveness, which may in part be related to the cardiotoxicity of these drugs. These findings are discussed in relation to the cardiovascular side effects of TCAs.

Adolescent↗

PubMed2006

Increased hippocampal nitric oxide synthase activity and stress responsiveness after imipramine discontinuation: role of 5HT 2A/C-receptors.

Chronic depressive illness may cause shrinkage of the hippocampus with stress-induced release of glutamate and nitric oxide possibly causally linked to this pathology. Poor antidepressant compliance may contribute to this pathology as well as to long term morbidity. However, antidepressant withdrawal-associated symptoms in depressed patients often reflect hyperserotonergia. The effect of chronic imipramine (IMI; 15 mg/kg/d ip x 3wks) treatment and withdrawal on swim stress responsiveness was studied in Sprague-Dawley rats together with assay of hippocampal NO synthase (NOS) activity. The dependence of any biobehavioral changes following IMI withdrawal on 5HT(2A/C) receptor-mediated events was studied using the 5HT(2A/C) receptor antagonist, ritanserin (RIT; 4 mg/kg/day ip x 7 days), administered alone or during IMI withdrawal. IMI significantly inhibited the situational stress response to forced swimming while also significantly decreasing NOS activity. IMI withdrawal was associated with a significant increase in swim immobility together with a significant increase in NOS activity compared to both control and IMI-treated groups. RIT re-established the anti-immobility effects and reversed NOS hyper-function during IMI withdrawal, although alone it increased NOS activity. Antidepressant discontinuation therefore increases stress responsiveness together with disinhibition of hippocampal NOS through a mechanism involving 5HT(2A/C) receptor activation. The resulting increased nitrergic activity may have significant implications for depressive illness and its treatment.

Animals↗

PubMed1982

Cardiac sensitivity to the inhibitory effects of chlorpromazine, imipramine and amitriptyline upon formation of flavins.

Chlorpromazine, imipramine and amitriptyline, drugs structurally related to riboflavin, each inhibited the formation in vivo of flavin adenine dinucleotide (FAD) from riboflavin in rat heart at 2-5 mg/kg body weight, doses comparable on a weight basis to those used clinically. All three drugs inhibited FAD formation in heart within 5 hr after a single dose of 25 mg/kg. Chlorpromazine under these conditions also inhibited FAD formation in liver, cerebrum and cerebellum. A series of psychoactive agents structurally unrelated to riboflavin did not inhibit flavin formation in the organs tested. These findings indicate that the inhibitory effects of the drugs studied have organ specificity with respect to FAD formation.

Amitriptyline↗

PubMed1988

On the mechanism of imipramine's influence in lowering p-hydroxyphenylglycol concentrations in the brain. The role of tyrosine.

Administration of imipramine (IMI) to rats was shown to lower after 4.5 hr the brain concentration of the octopamine metabolite p-hydroxyphenylglycol (pHPG) in a dose-dependent manner over the range of 10-40 mg/kg of IMI. Assay of plasma and brain levels of tyrosine revealed that IMI produced a reduction in both but with a shorter time-course than for the depletion in pHPG, with the maximal decreases occurring at 1.5 hr, before there was any loss of pHPG. The reductions in tyrosine and pHPG levels could not be explained by an effect of IMI on food intake, since the levels were diminished even in 24-hr fasted animals. When rats were injected with IMI 4.5 hr before 200 mg/kg of tyrosine and 5.5 hr before being killed, the elevation in brain pHPG levels were attenuated by about 50%, as compared to the animals that received tyrosine alone. These data suggest that the ability of IMI to lower brain pHPG probably involves two distinct mechanisms: (1) a lowering of brain and plasma tyrosine concentrations, and (2) an inhibition of the conversion of tyrosine to pHPG. It is unclear whether these effects are due to IMI itself or to one of its metabolites, such as desmethylimipramine or didesmethylimipramine, which were found in the plasma in amounts equal to or greater than IMI.

Animals↗

PubMed1993

The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of Wistar rats.

This study investigates the effect of imipramine (IMI) on the methylation of phosphatidylethanolamine (PE) in crude cortical membranes of rat brain in vitro and ex vivo. It was found that IMI enhanced the formation of phosphatidyl-N-monomethylethanolamine (PME) and phosphatidyl-N,N-dimethylethanolamine (PDE) and inhibited the formation of phosphatidylcholine (PC) in the cortical membranes of rats in vitro. The same effect i.e. increased incorporation of methyl groups in PE and PME and decreased formation of PC was found in the cortical membrane of rats killed 1 hr after intraperitoneal administration of IMI at a single dose of 10 mg/kg. Chronic treatment of rats with IMI for 14 days with a daily dose of 10 mg/kg i.p. led to further inhibition of PC formation but did not affect the formation of PME and PDE and abolished the stimulating effect of IMI on the formation of PME and PDE in vitro.

Animals↗

PubMed1985

Effect of membrane protein concentration on binding of 3H-imipramine in human platelets.

Binding of 3H-imipramine to platelet membranes has been implicated as a marker for depression. Comparing 3H-IMI binding between depressed patients and normal subjects we observed an increase in the dissociation constant Kd with increasing membrane protein. This phenomenon was studied more rigorously in five normal subjects. Platelet membranes were prepared and adjusted to four concentrations of protein ranging from 100 to 800 micrograms/ml. The 3H-IMI binding parameters of maximum binding sites number (Bmax) and Kd were obtained by Scatchard analysis at each membrane concentration. A positive linear relationship was found between Kd values and the concentration of membrane protein in the assay, but no change was observed in Bmax. The variability in Kd values reported in the literature may be accounted for in part by the different concentrations of membrane protein used in various studies.

Adult↗

PubMed1985

Opposite effects of chronic imipramine treatment on brain and urine MHPG levels in the rat.

Acute imipramine (IMI; 20 mg/kg, ip) in rats decreased the brain concentration of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), a metabolite of norepinephrine (NE), to 85% of control 24 hr after injection. In contrast, chronic IMI (20 mg/kg, ip, daily for 14 days) significantly raised brain MHPG levels to 123% of control, while reducing brain NE levels. Urinary MHPG levels were reduced by both acute and chronic IMI treatments, to 52% and 51%, respectively. These data suggest that the brain turnover of NE is reduced after acute IMI, but is elevated after chronic treatment. Although urinary levels of MHPG changed in parallel with brain levels following an acute administration of IMI, such was not the case after chronic administration. We conclude that caution must be used in extrapolating drug-induced changes in urinary metabolite levels to brain amine function.

Animals↗

PubMed1986

Lack of seasonal variation in platelet [3H]imipramine binding in humans.

The Bmax of [3H]imipramine (IMI) binding has been reported to be reduced in platelets of depressed untreated patients as compared with normal controls. However, it has also been suggested that this difference could be related to the failure to take into account seasonal variations in the binding parameters for [3H]IMI recognition sites in platelets. For this reason, [3H]IMI binding was studied throughout 1 year in platelet membranes from 11 control volunteers, with blood samples collected once a month. The Bmax and Kd values of [3H]IMI binding showed no significant variation throughout the 12-month period of the study. These results indicate that in the control population, the platelet [3H]IMI binding parameters remain stable, and that the decrease in Bmax observed in depressed untreated patients reflects a genuine difference, which may be considered to be a biological marker in depression.

Adult↗

PubMed1986

Modification of ligand binding to membranes by a soluble acceptor. Alpha-1-acid glycoprotein attenuates 3H-imipramine binding to cerebral membranes.

The effect of individual plasma proteins on the binding of 3H-imipramine (3H-IMI) was investigated, using rat cerebral membranes as the binding site source. Addition of alpha-1-acid glycoprotein (aAGLP) to an incubation medium containing 4 nm 3H-IMI resulted in a concentration-dependent inhibition of 3H-IMI binding, with an IC50 value of 0.53 microM. Albumin (0.7 mM) and gamma globulin (3 microM) had no apparent effect. Scatchard analyses of 3H-IMI binding in the presence and absence of 0.5 microM aAGLP revealed that the inhibition of 3H-IMI binding was associated with an increased Kd, with no appreciable change in Bmax. The inhibitory action of platelet-free plasma (PFP) on 3H-IMI binding to cerebral membranes was eliminated after treatment of PFP with specific antibodies to aAGLP. It is suggested that the inhibition of 3H-IMI binding to cerebral membranes by PFP is due, at least partially, to the presence of aAGLP in the plasma. The observed inhibitory effect is consistent with a competition for the ligand between the membrane binding site and the soluble protein acceptor. These findings may explain the serum effect confounding radioreceptor assays of various drugs.

Animals↗

PubMed1987

Platelet [3H]imipramine binding in patients with panic disorder.

[3H]imipramine binding to platelets was measured in 17 drug-free panic disorder patients and 14 healthy controls. No difference in Bmax or Kd values was found between the two groups. Patients with a past history of major melancholic depression or severe agoraphobia had similar binding parameters as panic disorder patients without a history of depression or severe agoraphobia.

Adult↗