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Two dosages of imipramine in hospitalized endogenous and neurotic depressives.

Fifty-one newly hospitalized depressed patients participated in a double-blind comparison of two dosage levels of imipramine hydrochloride (150 mg vs 300 mg daily). Although some patients were suffering from neurotic depressions, they, together with the endogenous depressives, were a severely depressed group who required hospitalization. Improvement occurred with both dosage regimens, although a greater and more consistent improvement was noted in the 300-mg group than in the 150-mg group. There were a few differences between the response of the endogenous and that of the neurotic depressives, as assessed by the physician and self=rating scales. However, endogenous depressives who received 150 mg were overrepresented in the treatment failure group. A comparison of the response of deluded and nondeluded depressives indicated that the deluded patients responded less well than the nondeluded depressives, although half of the delusional group did respond to the treatment.

Adjustment Disorders↗

Correlation between plasma and cerebrospinal levels of imipramine.

This study measured the levels of imipramine hydrochloride and desipramine hydrochloride (desmethylimipramine) in the plasma and cerebrospinal fluid (CSF) in 11 depressed patients. The oral doses correlated significantly with the plasma levels irrespective of different diagnostic categories. The CSF levels varied significantly. In the endogenous depressive group the CSF levels were significantly higher in responders as compared to nonresponders. The CSF levels of the nonresponders in the endogenous depressive group, and of both responders and nonresponders in the schizo-affective groups, were similar.

Depression↗

Cognitive dysfunction and imipramine in outpatient depressive.

A group of moderately depressed, nonpsychotic outpatients had impaired performance on a short-term item-recognition memory task (compared with a group of matched normal controls) without evidence of impaired speed or attention on two simpler tasks. Compared with placebo, treatment with imipramine hydrochloride in a multiple crossover design using three-week treatment periods led to improved performance on the memory task without either clinically apparent improvement in depression or significantly improved performance on the other task rather than a specific impairment of short-term memory, but the data do support the presence of cognitive dysfunction in depression, even in ambulatory patients without substantial impairments of attention or motor functioning. The results also indicate that antidepressant drugs can produce improvement in cognitive function, possibly as a forerunner of clinical improvement.

Adult↗

Platelet alpha 2-adrenergic receptor binding and plasma catecholamines. Before and during imipramine treatment in patients with panic anxiety.

Specific binding of tritiated clonidine, an alpha 2-adrenergic receptor agonist, and tritiated yohimbine, an alpha 2-adrenergic receptor antagonist, to platelet membranes was measured in persons with panic attacks or major depression and in normal subjects. Plasma catecholamine levels were measured in patients with panic attacks and in normal subjects. The number of binding sites in patients with panic attacks, as measured with tritiated clonidine, was lower than in depressed persons and was the same as in normal subjects. The number in patients with panic attacks, as measured with tritiated yohimbine, was lower than in either depressives or normal subjects. Catecholamine levels were somewhat higher in patients with panic attacks than in normal subjects. Treatment with imipramine hydrochloride decreased the number of sites, as measured with either ligand, in both patient groups and increased catecholamine levels in patients with panic attacks.

Adolescent↗

Effects of antidepressant treatments on platelet tritiated imipramine binding in major depressive disorder.

The effects of four antidepressant treatments on platelet tritiated imipramine binding have been studied in 51 hospitalized patients with severe major depressive disorder. There was an increase in maximum binding (Bmax) during the first week of treatment with antidepressants and electroconvulsive therapy, which was further magnified after three weeks' treatment with the serotonin uptake blockers alaproclate and zimeldine hydrochloride, but the Bmax values returned to baseline levels with nortriptyline hydrochloride and electroconvulsive therapy. The equilibrium dissociation affinity constant (Kd) did not change with any of the treatments. On reexamination one or two years after admission to the study, Bmax had not reached control values in clinically recovered, drug-free patients. Low pretreatment Bmax was associated with delusions during illness and with a poor long-term clinical outcome. There was no correlation between binding parameters and monoamine metabolite concentrations in the cerebrospinal fluid, either before or during treatment.

Adult↗

Dexamethasone suppression test identifies a subset of elderly depressed patients with reduced platelet serotonin transport and resistance to imipramine inhibition of transport.

Dysregulation of the hypothalamus-pituitary-adrenal axis (HPA) is more common in elderly patients with depression than in younger depressed patients, and glucocorticoids are known to influence serotonergic function. Elderly depressed patients are also reportedly more resistant to therapeutic effects of antidepressants. In the current study, we measured platelet serotonin transporter binding sites and transport function in young and elderly depressed patients and determined the relationship to HPA status as assessed with the dexamethasone suppression test (DST). The density and affinity of transporter molecules showed no differences between young and elderly depressed patients, regardless of DST results. Nevertheless, transporter function showed a substantial interaction of aging with DST: elderly DST suppressors showed a deficit in [3H]serotonin uptake capabilities and resistance to imipramine inhibition of uptake. No such defects were seen in the young depressed cohort, regardless of DST status, nor in elderly depressed DST non-suppressors. These results are consistent with the view that depression in the elderly exhibits basic biological differences from depression in earlier life, and that such distinctions may account in part for therapeutic ineffectiveness of antidepressants in specific subgroups, associated with the presence or absence of appropriate HPA regulation.

Adult↗

External ophthalmoplegia, alpha and spindle coma in imipramine overdose: case report and review of the literature.

A 13-year-old boy with imipramine overdose developed seizures, respiratory arrest, and coma. Abnormalities of oculovestibular reflexes, electroencephalograms, and brainstem auditory evoked potentials were monitored in relation to measurements of drug levels. An alpha-coma electroencephalographic pattern evolved into one evidencing spindle coma and eventually into a normal pattern. Prolonged brainstem auditory evoked potentials also normalized as coma and oculocephalic reflex abnormalities resolved. In spite of the history that suggested hypoxic damage, the absence of reflex eye movements in a comatose patient and the presence of alpha- and spindle-coma electroencephalographic patterns, even with prolonged brainstem auditory evoked potentials, are not reliable prognostic indicators in tricyclic drug overdose.

Adolescent↗

High-dose subchronic imipramine treatment: effects on anxiety-like (conflict) behavior in rats.

In the management of both anxiety and depression, agents such as imipramine (IMI) are noted for their 3-5 week delay to onset of clinical effect. A similar delay to onset has been reported for the anxiolytic-like (i.e., anticonflict) effect of chronic IMI treatment (2.5 mg/kg, BID for 5 weeks) in the Conditioned Suppression of Drinking (CSD) conflict paradigm; similar effects have been reported with other antidepressants and in other conflict procedures. In contrast, in the Forced Swim Test (FST) model of depression, antidepressant-like effects are reported immediately following subchronic treatment with relatively high doses of these agents (e.g., 30 mg/kg IMI, 3 times in 24 hr). The present study examined the effects of this high-dose, subchronic treatment with IMI on CSD conflict behavior. Conflict-trained female Sprague Dawley rats were divided into three groups with comparable pretreatment baselines for shocks received. Treatments (0, 15, and 30 mg/kg IMI) were administered intraperitoneally (IP) at 23, 5, and 1 hr prior to CSD conflict testing on day 1; CSD conflict behavior was then monitored daily (Mon-Fri) for 5 weeks following treatment. IMI treatment (30 and, to a lesser extent, 15 mg/kg) significantly reduced shocks received (punished responding) and water intake (unpunished responding) on day 1; although water intake was also slightly reduced in both IMI treatment groups for the remainder of test week 1, there was no difference in shocks received between the various treatments for this period. Subjects receiving 30 mg/kg IMI (but not those receiving 15 mg/kg IMI or vehicle) accepted significantly more shocks than controls on weeks 2-4 (maximal increase at week 3) and returned to pretreatment baseline levels by week 5. Thus, subchronic high-dose treatment with IMI (and perhaps other antidepressants) produces anxiolytic-like effects which are delayed in nature and persist for several weeks after treatment.

Animals↗

Transdermal delivery of imipramine hydrochloride: development and evaluation (in vitro and in vivo) of reservoir gel formulation.

The in vitro permeation studies of imipramine hydrochloride (IMH) reported earlier from our laboratory showed that a combination of menthol (2.5% w/v) and oleic acid (2.5% w/v) worked well in terms of safety and efficacy. The main objective of this study was to evaluate the in vivo performance of this combination; in order to do that, penetration enhancers were incorporated in a hydro-alcoholic gel of hydroxypropylmethyl cellulose along with IMH and used as the drug matrix in a reservoir transdermal patch. A stability study of IMH gel was performed at 40 degrees C/75% RH for 2 months. The results of this study indicate that gels of IMH stored at 40 degrees C/75% RH turned yellow brown in 2 months and the small change in viscosity of gel at 40 degrees C/75% RH had an insignificant effect on the release rate of IMH from the gel (p>0.05). The in vivo performance of the gel was tested in rats using a reservoir transdermal patch, which consisted of a backing membrane, drug matrix and retaining membrane with an area of 12.5 cm2. Plasma concentrations of 3 microg/ml of IMH were achieved and in a histopathological study 24 h occlusion was found to be safe.

Administration, Cutaneous↗

Simultaneous measurement of imipramine and desipramine by selected ion recording with deuterated internal standards.

A gas chromatographic mass spectrometric method for the quantitative determination of imipramine and its N-demethylated metabolite desipramine in plasma samples at the nanogram level is reported. The method involves derivatization of the extracted drugs with trifluoroacetylimidazole, a mild derivatizing reagent. Specificity is provided by selected ion recording of the [M + H]+ ions, formed upon chemical ionization with methane as reagent gas. Quantitation is achieved by stable isotope dilution techniques, using deuterium labeled analogs, prepared by acid-catalyzed exchange, as internal standards. Data on patient samples are presented.

Chemical Phenomena↗

First-pass metabolism of imipramine in man.

The systemic availability of orally administered imipramine (IP) varied from 29 to 77% in 4 subjects. The decrease in availability was due to an excess in metabolism after oral administration. This first-pass metabolism did not correlate with plasma half-life, apparent clearance, or the rate of metabolite excretion in urine. There was close correlation with the excess in formation of demethylated metabolites after oral administration, which suggests that the first-pass metabolism is mediated by demethylation, but does not correlate to the total rate of demethylation.

Administration, Oral↗

Intestinal absorption, demethylation, and enterohepatic circulation of imipramine.

The intestinal absorption and metabolism of single oral doses of imipramine (ip) have been studied in man by portal catheterization. The concentration of ip and the formed desipramine (dmi) was followed in blood-plasma obtained from the portal and cubital veins. The absorption of ip seemed to be completed 80 min after the administration of the drug. There was no sign of demethylation of ip during the passage across the intestinal wall. Evidence was found of an enterohepatic circulation of both ip and dmi.

Dealkylation↗

Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose data.

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dise of desmethylimipramine (DMI) or imipramine (IMI) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady-state plasma levels. In patients receiving DMI there was a correlation (r = 0.97, n = 10) between 24-hr and steady-state DMI levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24-hr and steady-state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a "therapeutic" dosage regimen without delay.

Depression↗

Effect of imipramine on norepinephrine and blood pressure in enuretic boys.

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double-blind, placebo-controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationshhip between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug-induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.

Blood Pressure↗

Comparative biopharmaceutical performance of imipramine formulations in man.

The systemic availability of an investigational liquid formulation of imipramine was compared to that of a commercially available tablet (Tofranil) whose therapeutic efficacy has been established by usage. The experiment was conducted under controlled conditions and a balanced 2-by-2 crossover design was used to dissociate the significance of formulation effects from subject, group, and experimental period sources of variation. Pharmacokinetic interpretation and statistical analysis of plasma concentrations as a function of time and of systemic availability indicators reveal a nearly identical biopharmaceutical behavior for the two preparations. Significant differences (P less than 0.05) were found in the cumulative area under the plasma concentration--time curve (AUC) up to 4 hours after administration and the availability lag time, but not in the maximum plasma concentration, the time at which this concentration is reached, the first-order availability rate constant, and the AUC to infinity. These results collectively indicate a very similar biopharmaceutical performance, where the differences in the early AUC values are partly attributable to a longer availability lag time for the tablet formulation.

Adult↗

Mechanisms and surface chemical prediction of imipramine-induced hemolysis suppressed by modified cyclodextrins.

The suppression of imipramine hydrochloride (IMP)- induced hemolysis by native cyclodextrins (alpha-, beta-, and gamma-CDs) and beta-CD derivatives is measured as a function of CD concentration and is quantitatively correlated with the surface tension of the solution determined at 37.0 degrees C. The modified beta-CDs are more or less adsorbed onto the air-water interface and occupy larger areas than the wider rim of beta-CD. The surface tension data at low CD concentrations in the presence of 3 mM IMP allow us to estimate the 1:1 binding constants of IMP with CDs. Both the capabilities of hemolysis suppression and surface tension elevation for 3 mM IMP are strong in the order carboxymethyl-beta-CD (CM) > beta-CD approximately equal to 6-O-glucosyl-beta-CD (G(1)) > gamma-CD > 2-hydroxypropyl-beta-CD (HP) > alpha-CD > or = 2,6-di-O-methyl-beta-CD (DM). The suppression of IMP-induced hemolysis is ascribed to the decrease in the concentration of free IMP molecules. This concentration can be quantitatively estimated from the surface tension data determined at 37 degrees C. Therefore, the suppression of IMP-induced hemolysis by most of the CDs can be quantitatively predicted from these surface tension data, regardless of the kind and concentration of CD. However, alpha-CD, HP, and DM are outliers of this prediction. This failure for alpha-CD and HP is ascribed to their weaker competitive binding to IMP than to membrane phospholipid. Because DM has a strong hemolytic activity, it does not almost suppress the IMP-induced hemolysis.

Antidepressive Agents, Tricyclic↗

Simultaneous determination of imipramine, desipramine, and their 2-hydroxy metabolites in plasma by ion-pair reversed-phase high-performance liquid chromatography with amperometric detection.

An ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method, using an electrochemical detector, is presented for the simultaneous and rapid quantitation of imipramine desipramine, and their 2-hydroxylated metabolites in plasma. The drugs are extracted from 1 ml of plasma at pH 9.7 with ether, back-extracted into 0. M HCl, and reextracted into ether following alkalinization. An efficient electrochemical oxidation reaction at the detector electrode affords a low detection level of approximately 5 ng/ml in a mobile phase of acetonitrile--acetate buffer (40:60) containing 0.005 M heptanesulfonate. Patient data are presented as correlations between the plasma level of each hydroxy metabolite and its respective parent compound. The method is applicable to the laboratory experienced in HPLC.

Chromatography, High Pressure Liquid↗

Study of the metabolic conversion of imipramine and desipramine to N-nitrosodesipramine by bacteria using a nitrogen-selective GC analysis.

A GC method using dual nitrogen selective and flame ionization detectors was developed for the determination of N-nitrosodesipramine using N-butyryldesipramine as the internal standard. The precision of the method was found to be +/- 5.0% and the accuracy was +/- 4.9%. The method could be used to detect 10 ng/ml of N-nitrosodesipramine in bacterial cultures. When desipramine and sodium nitrite were incubated with aerobic or anaerobic bacteria, the nitrosamine level was found to be 10-300 times higher than the controls. When imipramine and potassium nitrate were incubated with a mixed anaerobic culture, the level of N-nitrosodesipramine was found to be 4.5 times higher than the control.

Aerobiosis↗