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At least 19 recordsLinked to original sources
PubMed1989

Neuroanatomically selective down-regulation of beta adrenergic receptors by chronic imipramine treatment: relationships to the topography of [3H]imipramine and [3H] desipramine binding sites.

The down-regulation of beta adrenergic receptors by chronic imipramine treatment was investigated with high resolution autoradiography of [125I]pindolol binding to brain sections. Neuroanatomically selective down-regulation of [125I]pindolol binding was found after chronic imipramine treatment. Subdivisions of the amygdala and hippocampus and discrete cortical regions were differentially affected. In the hippocampus, reduction of [125I]pindolol binding was observed in imipramine-treated rats in the CA-1 stratum radiatum and dentate molecular layer, but not in the CA-3 stratum radiatum. In the amygdala, the basolateral nucleus exhibited reduced [125I]pindolol binding after imipramine treatment but the central and medial nuclei were not affected. Chronic imipramine treatment was also associated with reduced [125I]pindolol binding in layer 1 of the cingulate cortex and layer 3 of the piriform cortex. In contrast, no effect on [125I]pindolol binding was apparent in the ventrolateral thalamic nucleus, caudate-putamen, lateral hypothalamus or layers 2 and 3 of the somatosensory cortex. In order to determine if regional variation in binding sites for imipramine, or its pharmacologically active metabolite desipramine, was responsible for the observed neuroanatomically selective reduction in [125I]pindolol binding, the binding of [3H]imipramine and [3H]desipramine was investigated. In some brain regions that exhibited high densities of [3H]imipramine and [3H]desipramine binding sites, [125I]pindolol binding was reduced after chronic treatment with imipramine. However, other regions that contained high densities of binding sites for antidepressant drugs did not show a reduction in [125I]pindolol binding after chronic imipramine treatment. Thus, regional binding of [3H]imipramine or [3H]desipramine cannot fully explain the neuroanatomical specificity of imipramine-induced beta adrenergic receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Comparison of imipramine-imipraminium in mice. To elucidate central or peripheral origin of effects of imipramine.

Imipramine hydrochloride shows effects in a battery of tests used for the screening of antidepressant drugs. The central origin of these pharmacological effects of imipramine has not been clearly established. Imipramine methiodide is a quaternary derivative of imipramine which does not cross the blood-brain barrier easily. The effects of the two forms of imipramine have been compared: on an effect known to have a central origin; on two effects known to have a peripheral origin; on a battery of tests used for the screening of antidepressant drugs. It has been demonstrated that imipramine methiodide is as active as imipramine hydrochloride on two effects of peripheral origin, less active than imipramine hydrochloride on an effect considered to have a central origin and less active than imipramine hydrochloride or inactive on the tests which are used for the screening of antidepressant drugs. Consequently, the tests used for the screening of antidepressant drugs represent, primarily or exclusively, effects of central origin.

Animals↗
PubMed1983

Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine.

The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.

Animals↗
PubMed1993

Imipramine is effective after unsuccessful cognitive therapy: sequential use of cognitive therapy and imipramine in depressed outpatients.

As a partial test of whether the same or different patients benefit from cognitive therapy and tricyclic antidepressant agents, depressed outpatients first received cognitive therapy, then nonresponders were treated with either imipramine or placebo. If the two treatments were effective for the same subgroup of patients, imipramine should not be more effective than placebo because potential responders should already have been removed by treatment with cognitive therapy. Alternatively, if cognitive therapy and imipramine are effective for different subtypes of depressive disorder, then imipramine ought to be more effective than placebo for patients failing to benefit from cognitive therapy because some potential imipramine failures would already have been removed. Thirty-six depressed outpatients were treated with weekly cognitive therapy for 16 weeks with 17 (47%) responding. Nonresponders were then randomly assigned to imipramine or placebo for 6 weeks to a maximum dose of 300 mg of imipramine per day. Of 12 patients completing the double-blind medication trial, all 5 assigned to imipramine had a clear-cut response, whereas none of the other seven benefited from placebo (chi 2 = 12.00; p = 0.001). Although the numbers are small, these results suggest rejection of the hypothesis that imipramine is effective for the same subpopulation of depressed patients as is cognitive therapy.

Adult↗
PubMed1984

Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination.

In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study.

Actuarial Analysis↗
PubMed1993

Simultaneous high-performance liquid chromatography-electrochemical detection determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine N-oxide in human plasma and urine: preliminary application to oxidation pharmacogenetics.

This assay method allows a simultaneous determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine-N-oxide in 0.5 ml of plasma or 0.1 ml of urine within 35 min by an ion-paired, reversed phase (C18) high-performance liquid chromatography (HPLC) with electrochemical detection. The analytes are extracted from alkalinized plasma or urine with 5 ml of a 90/10 mixture (by vol) of diethyl either/2-propanol, back-extracted into 0.5 ml of 0.1 mol/L phosphoric acid. Urine samples are enzymatically treated with beta-glucuronidase/arylsulfatase before extraction. The electrochemical detection is performed with a glassy carbon electrode set at +0.85 V against the Ag/AgCl reference electrode. Recoveries for the analytes and the internal standard (propericiazine) from plasma or urine ranged from 66.4 to 105.7% with coefficients of variation (CVs) of < 6.8%. The intra- and interassay CVs for the analytes were < 17.4% in plasma and < 14.2% in urine. The limits of determination (a signal-to-noise ratio of 3) for imipramine, desipramine, 2-hydroxyimipramine, 2-hydroxydesipramine, and imipramine-N-oxide were 0.5, 0.3, 0.02, 0.02, and 1.0 microgram/L, respectively. Only four of the 23 psychotropic drugs, which might be coadministered with imipramine or desipramine, were considered to be the possible sources to interfere with the assay. We evaluated clinical applicability of this method by determining plasma concentration- and urinary excretion-time courses of the respective analytes in an extensive and a poor metabolizer of the debrisoquine/sparteine-type oxidation after a single oral dose of imipramine HCl (25 mg). The present method appears to be suitable not only for the therapeutic drug monitoring of imipramine and its active metabolites but also for studying the pharmacogenetically related metabolism of imipramine or desipramine.

Arylsulfatases↗
PubMed1989

The influence of the route of administration of imipramine on imipramine and desipramine blood levels.

Imipramine was used to treat 18 depressed inpatients for 22 days. Imipramine 2 mg/kg/day was administered from day 0 to day 14 intramuscularly, and 4 mg/kg/day was administered orally from days 15-21. Two pharmacokinetic studies were performed, the first at the end of the intramuscular phase (day 14) and the second at the end of the oral phase (day 21). Imipramine and desipramine blood levels were measured every hour from 8 a.m. to 4 p.m. Between these two pharmacokinetic evaluations, blood levels of imipramine and desipramine were measured every morning at 8 a.m. During intramuscular administration, the parent drug imipramine predominated in the plasma and, conversely, the desmethylated metabolite predominated during oral administration. With the changeover in route of administration, the doubling of the dose kept the blood levels of imipramine equal, while desipramine increased; the sum of imipramine and desipramine also increased, and the ratio of imipramine and desipramine decreased sharply, the median ratio changing over 3 days from 1.50 (day 15) to 0.62 (day 18).

Administration, Oral↗
PubMed1990

Platelet imipramine binding in endogenous depressed patients and controls: relationship to platelet MAO and 5HT uptake during successful imipramine treatment.

Platelet imipramine binding was measured in 25 unmedicated depressed patients and 25 age- and sex-matched healthy controls. In the patients, the measurement was repeated after 3 weeks and 2 months of imipramine treatment leading to clinical recovery. No significant differences in imipramine binding were found between controls and unmedicated patients. In the latter, imipramine administration produced a progressive change in the binding characteristics, increasing the apparent Kd and decreasing the number of binding sites (Bmax). The results suggest that platelet imipramine binding is not altered in depression and that changes in this parameter are the consequence of the presence of imipramine in the blood stream. However, such changes accompany changes in other biological parameters, such as platelet monoamine oxidase and serotonin uptake, seen in the same patients throughout imipramine treatment, suggesting that the drug acts on a wide range of normal or altered serotonin-related cellular mechanisms while it accelerates the clinical recovery from depression.

Administration, Oral↗
PubMed1988

Unaltered 5-HT- and desipramine-sensitive [3H]imipramine binding and [3H]5-HT uptake in rat brain after chronic imipramine and norzimeldine treatment.

Several reports have shown heterogeneity of [3H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [3H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [3H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [3H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [3H]imipramine binding or 5-HT uptake after the antidepressant treatment.

Animals↗
PubMed1989

Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine.

On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day. During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30-100 nmol.l-1) but not during quinidine. It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.

Adult↗
PubMed1983

3H-imipramine uptake into rat striatal slices and imipramine-induced 3H-dopamine efflux.

The effect of imipramine on spontaneous efflux of radiolabelled dopamine (DA) from slices of rat striatum was examined by a superfusion method. Imipramine at concentrations of 10 - 100 microM enhanced the efflux of DA accumulated in a high-affinity uptake system in a concentration-dependent manner. This efflux of 3H-DA was not affected by conditions (Ca2+-free medium, 100 microM bretylium and 30 microM tetrodotoxin) which inhibited the release of 3H-DA by electrical stimulation. Furthermore, this imipramine-induced 3H-DA efflux was temperature-dependent. The uptake of 3H-imipramine into striatal slices was determined. This uptake was concentration- and temperature-dependent and increased linearly. These results are discussed in relation to the hypothesis that 3H-DA efflux by imipramine is connected with uptake of imipramine.

Absorption↗
PubMed1984

3H-imipramine and 3H-cyano-imipramine binding in rat brain tissue: effect of long-term antidepressant administration.

3H-imipramine and 3H-cyano-imipramine binding was determined in brain homogenates of rats which had been treated for 21 days with imipramine or desimipramine. When compared to control animals, long-term administration of these antidepressants did not induce any alteration in the maximal number of 3H-imipramine or 3H-cyano-imipramine binding sites. However, a transient increase in the apparent dissociation constant was observed. Such findings are discussed in respect to previous studies, which have been highly contraversial.

Animals↗
PubMed1980

Down regulation of dihydroalprenolol and imipramine binding sites in brain of rats repeatedly treated with imipramine.

In rats receiving repeated injections of imipramine, there is a reduction in the number of high affinity binding sites for [3H]imipramine and [3H]dihydroalprenolol present in crude synaptic membrane preparations from various brain structures. The location of the sites that become subsensitive to the two ligands did not coincide; the binding sites to [3H]imipramine became subsensitive in the hippocampus but not in cortex or cerebellum. In contrast the binding sites to [3H]dihydroalprenolol became subsensitive in cortex and cerebellum but not in hippocampus. It can be suggested that in rats repeatedly treated with imipramine the down regulation of beta-adrenergic receptors may not coincide with the down regulation of the high affinity binding sites for imipramine. Such a dissociation is supported further by experiments with rats treated with iprinidol.

Alprenolol↗
PubMed1985

Imipramine treatment differentially affects platelet 3H-imipramine binding and serotonin uptake in depressed patients.

Uptake of serotonin and 3H-imipramine binding in platelets of depressed patients were investigated simultaneously with changes in clinical state. Both Vmax for serotonin uptake and Bmax for 3H-imipramine binding were significantly lower in unmedicated depressed patients with respect to normal subjects. Successful treatment with imipramine led to a significant increase in Bmax for 3H-imipramine binding, without significant change in Vmax for serotonin uptake. Bmax values increased to the normal range following complete, rather than partial clinical improvement. These data indicate that successful antidepressant treatment may increase the density of 3H-imipramine binding sites on platelets by a process which is independent of the uptake of serotonin.

Adolescent↗
PubMed1990

Two affinity states for [3H]imipramine binding to the human platelet 5-hydroxytryptamine carrier: an explanation for the allosteric interaction between 5-hydroxytryptamine and imipramine.

5-Hydroxytryptamine (5-HT) showed a biphasic effect on the dissociation rate of [3H]imipramine from human platelet membranes: At low concentrations (EC50, approximately 2.5 microM), 5-HT stimulated the rate, as expected for mutually exclusive binding of 5-HT and imipramine; at higher concentrations (EC50, approximately 40 microM), 5-HT reduced this stimulated rate, a result consistent with 5-HT binding at a site that is physically distinct from both the imipramine binding site and the 5-HT transport recognition site of the 5-HT carrier. This modulatory effect could be mimicked by tryptamine, was saturable and independent of Na+ concentration, and could also be demonstrated for detergent-solubilized carriers. Monophasic association kinetics for [3H]imipramine binding were found. Heat stability experiments showed biphasic thermal inactivation curves. These results are consistent with [3H]imipramine binding to two classes of binding sites at the 5-HT carrier on human platelet membranes, with affinities three- to fivefold different. 5-HT can convert the lower-affinity state into the higher-affinity state.

Binding Sites↗
PubMedDate not supplied

[Antenatal effect of imipramine on the ontogeny of the imipramine receptors in the cerebral cortex of rats].

Ontogenetic study of imipramine binding sites in the rat brain cortex employing autoradiographic and radioreceptor methods revealed that they can be detected at the 19th day of gestation and that by the 14 day of postnatal development their amount reaches the adult levels. The affinity constants of imipramine binding sites did not change significantly throughout the ontogenetic development. Exposure to the therapeutic doses of imipramine on days 17-19 of gestation resulted in a significant increase in the amount of binding sites (24% of the control level) on day 3 of postnatal development, which returned to normal by the end of the second week of postnatal development. The distribution of imipramine binding sites in the cortical layers did not change either in normal rats or in those antenatally treated with imipramine.

Animals↗
PubMedDate not supplied

A controlled double blind comparative study of single dose administration of imipramine pamoate and divided dose of imipramine hydrochloride in depressive illness.

A double blind therapeutic comparison of single dose administration of imipramine pamoate and divided dose of imipramine hydrochloride was made in 40 indoor patients suffering from depressive illness. A fixed dose of 150 mg was used for both drugs for four weeks, employing randomized methodology with placebo capsules and tablets to balance dosage schedules. Four patients two from each group were dropped, leaving 36 patients for final analysis. The criteria of assessment were Hamilton Rating Scale and global evaluation by both the psychiatrist and the patients. Both the dosage forms were found to be highly effective as anti-depressants. Imipramine pamoate seemed to provide more consistent improvement but statistically the differences were not significant at the end of four weeks treatment. The major conclusion drawn from the study was the confirmation of therapeutic equivalence between a single daily dose of 150 mg of imipramine pamoate and divided dose of 150 mg of imipramine hydrochloride. Generally mild side-effects occurred with equal frequency in both the groups and no adverse effects on haemopoietic, renal or hepatic function were seen with either dosage form.

Adolescent↗
PubMed1984

Imipramine binding site. Temperature dependence of the binding of 3H-labeled imipramine and 3H-labeled paroxetine to human platelet membrane.

The characteristics of 3H-labeled imipramine and 3H-labeled paroxetine binding to human platelet membranes were determined at various temperatures between 0 and 37 degrees C. Both paroxetine and imipramine probably bind to the same molecular complex in the platelet membrane, but the binding characteristics are different for the two molecules. The dissociation constant (Kd) for imipramine increases from 0.3 nM to 7.0 nM with increasing incubation temperature in a continuous way, whereas Kd for paroxetine is almost constant, about 0.05 nM, between 0 and 19 degrees C, and first begins to increase from 0.06 nM to 0.16 nM between 20 and 37 degrees C. This suggests that the binding of paroxetine to the binding site induces a conformational change in the molecular complex of the binding site, whereas the binding of imipramine takes place without conformational changes in the binding site.

Binding Sites↗