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The effects of amphetamine, imipramine and ICI 58,834 (Vivalan), a potential antidepressant, on unconditioned behaviour in rats.

The effects of amphetamine, imipramine and ICI 58,834 (Vivalan), on the unconditioned behaviour of rats were compared using a novelty preference test and the open field test. Overall, the effects of ICI 58,834 (Vivalan) showed a marked resemblance to those of imipramine but differed from those of amphetamine. It is suggested that an adequate explanation of these drugs' effects can be offered in terms of changes in emotional reactivity, in general activity, and in exploratory activity. A dissociation of drug effects on general and exploratory activity in the novelty preference test was demonstrated. The use of this test and the open field test in drug screening is briefly discussed.

Amphetamine↗

Platelet uptake of serotonin following repeated administration of 3-cyano-imipramine to healthy volunteers.

In a double blind, placebo-controlled study the effects of daily oral administration of 3-cyano-imipramine on the 3H-serotonin uptake capacity of platelets were investigated in healthy volunteers. The initial dose was 1 mg, rising to 3 mg daily for 7 days. A rapid and profound inhibition of 3H-serotonin uptake was observed in platelets isolated from the treated subjects. During repeated administration, uptake was reduced to less than 10% of pre-drug values. Five days after the final dose uptake had only partially recovered, to 53% of pre-drug values. A similar inhibition profile was observed when serum from the treated subjects was incubated with normal platelets and 3H-serotonin. The results establish 3-cyano-imipramine as a potent inhibitor of platelet serotonin uptake in humans.

Adolescent↗

Endogenous depression and imipramine levels in the blood.

Approximate determinations of imipramine plus desmethylimipramine levels in the blood made by a method available in routine clinical chemistry laboratories, in 20 nondelusional endogenous depressives after 3 weeks of treatment (mean dose 130 mg/day, SEM 18.05 mg/day) have shown levels ranging from 10 ng/ml to 494 ng/ml. A positive significant correlation between blood levels and percentage change in scores on the Hamilton scale was found (Spearman's O = 0.49 P < 0.05). Patients with levels above 85 ng/ml had a significantly better therapeutic response than patients with levels below 85 ng/ml. Among the 11 nonresponders, 8 had low levels, 2 had intermediate levels, and 1 had the highest level of the study. In a given nonresponder, approximate determination of imipramine plus desmethylimipramine in the blood may be useful.

Adult↗

Effects of water temperature and weight of wheel load on water wheel turning behavior of imipramine administered mice.

This experiment investigated the effect of imipramine on water wheel turning behavior in relation to the water temperature and the wheel load. It was shown that the higher the water temperature, the more the mice rotated the wheel, and the greater the wheel load, the less mice rotated it. However, these factors did not reduce the effect of imipramine, which increased the number of responses. It was suggested that the water wheel test shows promise as a screening test for antidepressants.

Animals↗

A statistical model for the classification of imipramine response in depressed inpatients.

We present a statistical model, recently developed for application in mathematical economics, that yields empirical evidence for the existence of two distinct subtypes of depression. We reanalyze previously reported data on 65 depressed patients treated with imipramine and repeatedly rated on the Hamilton Rating Scale (HRS). The estimated model parameters suggest two underlying response processes. Patients in the first subgroup were initially more severely depressed (as measured by the total HRS score), but exhibited a rapid rate of symptomatic response over time. In contrast, patients in the second subgroup were initially less severely depressed, yet showed a much slower rate of improvement. These findings recommend a refinement of the clinical definitions of endogenous depression. While this model suggests that there are two underlying response processes, it does not classify individual patients. Subject classification was made possible by fitting an item-response model to the data. This model relates the 17 individual symptom ratings, at baseline, to the total post-treatment HRS scores. The results of this analysis suggest that the previously described relationship between high initial severity of depression and more rapid improvement over time is characteristic of subjects who exhibit initial motor retardation and decreased sexual interest. Graphical analysis clearly indicates that subjects who exhibit both motor retardation and decreased sexual interest at baseline have higher total HRS scores at baseline and show more pronounced improvement in total HRS scores in response to treatment with imipramine. Patients not exhibiting motor retardation and decreased sexual interest were less severely depressed initially and show virtually no clinical response over time.

Depressive Disorder↗

Imipramine and EEG sleep in children with depressive symptoms.

Depression in children is currently an area of considerable controversy, as is the use of potent psychopharmacologic agents in children. Since EEG sleep techniques have proven to be useful in understanding the mechanisms of depression in adults and in predicting their response to antidepressants, a pilot study employing these techniques was undertaken in a population of hospitalized children. The EEG sleep of 12 children with significant depressive symptomatology was first examined after a two-week drug-free period and again approximately three weeks later when an optimum dose of imipramine had been maintained for at least 7 -- 10 days. Changes in sleep continuity, as reflected in increased wakefulness and a decreased sleep efficiency, as well as an increase in Stage 2 and a decrease in Stage 4 sleep, were observed throughout the entire sample. REM suppression was also noted, but tended to be most pronounced in those children who improved on imipramine.

Adolescent↗

Phase I metabolism of imipramine by microsomes of small intestine in comparison with metabolism by liver microsomes.

The metabolism of imipramine was investigated by the incubation of C-14 labelled compound in Krebs-Ringer bicarbonate buffer with microsomes of small intestine and of liver from guinea pigs. Imipramine and its metabolites were extracted with chloroform, separated by TLC and determined quantitatively by direct scanning with a TLC Linear Analyzer. With intestinal microsomes, the following metabolites could be identified: DMI, 2-OH-IMP, IMP-N-oxide. DMI is the main metabolite. The same metabolites appeared after incubation with liver microsomes, but the proportions were different: the N-oxide formation was predominant, followed by N-demethylation and hydroxylation. The formation of DMI and 2-OH-IMP seems to follow Michaelis-Menten kinetics, both in assays with intestinal and with liver microsomes. The liver/intestine ratio of DMI and 2-OH-IMP formation is proportional to the cytochrome P-450 ratio in the microsomes, in contrast to N-oxide formation.

Animals↗

Hepatic sensitivity to imipramine.

A case of significant hepatic reaction related to imipramine is presented, documented by challenge with imipramine and liver biopsy. The mechanism, while not entirely clear, is presumed to involve hypersensitivity or induction of toxic metabolites.

Adult↗

In vitro and in vivo effect of chloropromazine, imipramine and lithium chloride on monoamine oxidase activity in rat brain mitochondria.

Chloropromazine (CPZ) and imipramine at a concentration of 1 x 10(-3) M inhibit rat brain mitochondrial monoamine oxidase activity in vitro by 70 and 55% respectively, while lithium, even at a concentration of 0.05 M, inhibits the activity of this enzyme very negligibly (4%). In vivo, these drugs at a dose level of 56 mg CPZ, 76 mg imipramine and 76 mg lithium chloride/Kg body wt., did not cause any observable variation from normal in brain mitochondrial monoamine oxidase activity.

Animals↗

Paraganglionic cell response to chronic imipramine and handling stress: an ultrastructural study.

The ultrastructure and connectivity of monoamine-storing paraganglionic cells in the rat superior cervical ganglion were investigated following chronic treatment with imipramine (Tofranil, Ciba-Geigy) and compared with uninjected unhandled controls and saline injected animals. The study reveals a significant decrease in the number of dense core vesicles in the drug-treated group (P less than 0.001) which is regarded as a specific effect due to receptor blocking actions of imipramine. A significant reduction in the maximum diameter of the external rim and internal cores of the vesicles (P less than 0.05) in the drug-treated group is mimicked to a certain extent by saline injections, indicating a mixed effect of stress handling and specific alteration. Although the paraganglionic cell morphology is unaltered in the group comparisons, the interrelationship of the paraganglionic cells to surrounding neural processes is significantly altered in both the control versus saline and the control versus drug group comparisons (P less than 0.05). The drug- and saline-induced alterations of neural connectivity may reflect stress-induced general changes demonstrating the plasticity of the paraganglionic cell population.

Animals↗

Is Ro 11-2465 (cyan-imipramine) an antagonist of postsynaptic serotonin receptors?

Ro 11-2465, a selective inhibitor of serotonin uptake of the imipramine group, was examined for its central and peripheral antiserotonin activity. Ro 11-2465 (10 mg/kg) antagonized the stimulation of the hind limb flexor reflex in the spinal rat evoked by serotonin agonists of direct mode of action (LSD, quipazine, m-chlorophenylpiperazine). However, in doses up to 20 mg/kg it did not inhibit the clonidine-induced stimulation of the flexor reflex. It also reduced the number of the quipazine-induced head twitches in rats (ID50 = 20.1 mg/kg) and, in doses 0.3--10.0 mg/kg, dose-dependently attenuated the pressor response to serotonin in the pithed rat. Like doxepine, amitriptyline, clomipramine and imipramine, Ro 11-2465 reduced the serotonin-induced contractions of the rat stomach fundus strip (its IC50 = 5 x 10(-5) M). The obtained results indicate that like other tricyclic inhibitors of serotonin uptake, Ro 11-2465 may also weakly block the postsynaptic serotonin receptors. Additional studies with fluoxetine and Org 6582 indicate that anti-serotonin properties of tricyclic compounds are not related to the serotonin uptake blocking properties.

Amitriptyline↗

Preliminary study of imipramine in profoundly retarded residents.

This was a double-blind, placebo-controlled crossover trial of imipramine (3 mg/kg/day) in 10 profoundly retarded residents. Two groups were formulated: one with depressivelike (or affective) symptoms and one with acting-out behaviors. Measures of drug response included ratings of ward behavior using the Aberrant Behavior Checklist, interval samples of behavior in the living units, and observations of behavior in a playroom situation. Results indicated that the drug caused behavioral deterioration in the Irritability, Lethargy/social withdrawal, and Hyperactivity dimensions of the rating scale, irrespective of subgroup. In addition, gross motor activity was significantly increased on the wards due to imipramine, and it was found that the affective group became less active and the acting-out group more active during free play. Physical side effects were uncommon. These unexpected adverse behavioral effects were discussed with respect to dosage and diagnostic considerations.

Acting Out↗

Synthesis and some pharmacological properties of a conformationally restricted imipramine analogue.

The synthesis of the semi-rigid imipramine analogue 2-(N,N-dimethylaminomethylene)-2,3,7,8-tetrahydro-1H-quino[1,8-ab] [I]-benzazepine is described. The compound was pharmacologically evaluated in a number of general in vivo screening tests for antidepressive activity. From these preliminary tests the compound appeared to show an imipramine-like activity. However, it did not have an effect on the noradrenaline depletion by 4, alpha-dimethyl-m-tyramine. These results are discussed on the basis of the conformational requirements determining the pharmacological profile of antidepressants.

Animals↗

Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT2 receptors, and hippocampal 5HT1A receptors were studied (using the ligands [3H]-dihydroalprenolol, [3H]-ketanserin and [3H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10 mg/kg per day). CMS increased Bmax for all three receptor systems. Imipramine decreased Bmax, reversing the effect of CMS, for beta-adrenergic and 5HT2 receptor binding, but increased Bmax for 5HT1A receptor binding. KDs were unaffected by either treatment. The beta-receptor and 5HT2 receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Chronic imipramine treatment normalizes levels of tyrosine hydroxylase in the locus coeruleus of chronically stressed rats.

Previous studies have demonstrated that chronic stress increases and antidepressant treatments decrease levels of tyrosine hydroxylase (TH) in locus coeruleus (LC). In the present study, the influence of chronic antidepressant treatment on the induction of TH immunoreactivity in response to cold stress is examined. It was found that chronic imipramine pretreatment (18 days) attenuated the induction of TH in response to cold stress, resulting in levels of TH immunoreactivity not different from control. In contrast, imipramine pretreatment for 1 or 7 days was not sufficient to normalize the stress-induced elevation of TH immunoreactivity. These findings raise the possibility that the therapeutic action of antidepressants may be derived, in part, from the ability of these treatments to normalize levels of TH and thereby the function of the NE neurotransmitter system under conditions of stress.

Animals↗

Effects of morphine, naloxone, buprenorphine, butorphanol, haloperidol and imipramine on morphine withdrawal signs in cynomolgus monkeys.

This study was conducted to characterize the opiate dependence potential of a number of opiate and non-opiate psychoactive drugs in morphine-dependent cynomolgus monkeys (Macaca fascicularis). In addition, the agonist/antagonist profiles of buprenorphine and butorphanol were directly compared. Six male cynomolgus monkeys were maintained on morphine (3.0 mg/kg, q.i.d.) for 6 months. On evaluation days, monkeys were scored for opiate withdrawal signs 18 h after the last dose of morphine. Single dose suppression studies were conducted by giving subcutaneous injections of morphine (3 or 6 mg/kg), naloxone (0.01, 0.05 or 0.1 mg/kg), buprenorphine (1, 3, 10, 30 or 100 micrograms/kg), butorphanol (0.01, 0.1, 1.0 or 3.2 mg/kg), haloperidol (0.01, 0.05 or 0.1 mg/kg), imipramine (2, 5 or 10 mg/kg) or saline and measuring the number and frequency of withdrawal signs that appeared over a 2-h period. In a separate precipitation experiment either saline or 0.01 or 0.1 mg/kg butorphanol was administered 2 h after the last maintenance dose of morphine. In the single dose suppression test, morphine completely suppressed most withdrawal signs while naloxone increased the severity of withdrawal. All doses of buprenorphine increased many withdrawal signs such as backward gait, rearing, chafing face, chain biting, vomiting, masturbation, and vocalizations after intimidation. Only a few signs were reduced, but the overall withdrawal scores were not significantly increased. Low doses of butorphanol suppressed some signs while the highest dose almost completely eliminated all withdrawal signs. Butorphanol also failed to precipitate opiate withdrawal, and actually reversed the signs present in the saline-treated monkeys. Imipramine and haloperidol had little effect on the morphine withdrawal syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Ineffectiveness of imipramine in children who fail to respond to methylphenidate.

Ten hyperactive children who had failed to respond to methylphenidate were treated with imipramine in a placebo-controlled, crossover design. No significant drug effects were obtained either on parent and teacher ratings of the child's behavior or on the child's performance in a laboratory measure of sustained attention. Findings suggest that imipramine has limited clinical usefulness in the treatment of hyperactive children who fail to respond to methylphenidate.

Aggression↗