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PubMed1996

Simultaneous inhibition of catecholamine-O-methylation by entacapone and neuronal uptake by imipramine: lack of interactions.

OBJECTIVE: We have evaluated the effects of simultaneous inhibition of catechol-O-methyltransferase (COMT) by entacapone and of neuronal monoamine reuptake by imipramine on haemodynamics and catecholamine metabolism, and the safety and tolerability of the drug combination in healthy women. METHODS: In a randomized, single-dose, single-blind, cross-over study, 12 healthy women were given placebo, entacapone (200 mg), imipramine (75 mg) or entacapone and imipramine in combination. Heart rate, blood pressure, systolic time intervals, and plasma concentrations of catecholamines and their metabolites were measured at rest and during exercise. RESULTS: The only drug-related effect on haemodynamics was an increase in heart rate during exercise after imipramine. The increase in heart rate after the combination of entacapone and imipramine was similar to that after imipramine alone. Entacapone alone had no effects on haemodynamics. Imipramine and entacapone had no significant effects on the plasma concentrations of noradrenaline and adrenaline. No interactions between entacapone and imipramine were detected.

Adrenergic Uptake Inhibitors↗
PubMed1984

Oxidant-mediated electronic excitation of imipramine.

The interaction of imipramine with both resting and zymosan-activated human polymorphonuclear leukocytes (PMNs) resulted in the generation of chemiluminescence (CL). This CL was not accompanied, however, by an enhanced release of superoxide anion. CL was also observed following the interaction of imipramine with either a xanthine oxidase or a horseradish peroxidase catalyzed system. Collectively, these observations support the concept that the CL elicited from these interactions is reflective of the electronic excitation of the imipramine molecule. In contrast to the response seen with PMNs, addition of imipramine to resting alveolar macrophages (AMs) failed to yield CL. However, CL from imipramine was observed with resting AMs upon supplementation with exogenous horseradish peroxidase. The lack of response with control AMs and the significant inhibition of the imipramine-PMN CL by the myeloperoxidase inhibitor azide suggests that a peroxidase-derived oxidant facilitated the oxidation of imipramine, yielding a product in an electronically excited state. In addition to PMNs, CL was elicited from imipramine by rat or rabbit liver microsomes, suggesting that PMNs may be a useful model system to predict a xenobiotic effect on the CL response elicited by other cellular oxidant-generating systems. Moreover, these observations underscore the possibility that the metabolic activation of drugs by PMNs may be of pharmacologic and toxicologic importance.

Animals↗
PubMed1984

The prevention by (+)-Cyanidanol-3 of hepatitis-induced changes in the disposition of imipramine in the rat.

The administration of (+)-Cyanidanol-3 [+)-catechin) to the rat using a subchronic dosing regime based on that currently used in the therapy of acute viral hepatitis in man, largely prevented the changes in the disposition of a single dose of [14C]imipramine hydrochloride induced by the hepatotoxin, D-(+)-galactosamine hydrochloride in rats. Complete return to normal pharmacokinetics was not attained due to interaction between (+)-Cyanidanol-3 and imipramine. Biliary excretion of imipramine metabolites was 79.3% of the dose in control rats. This was reduced to 69.3 and 39.8% by the separate administration of (+)-catechin and galactosamine respectively. Concurrent administration of (+)-Cyanidanol-3 and galactosamine resulted in 64.8% of the imipramine dose appearing in bile. These results were reflected in changes in faecal and renal excretion of imipramine metabolites in surgically unmodified rats in which galactosamine injection caused an elevation of urinary excretion from 31.0 to 69.8% of the imipramine dose. Concurrent Cyanidanol administration reduced the effect of galactosamine so that only 46.9% was excreted in urine. These changes were due to decreased biliary excretion and increased renal excretion of the glucuronide conjugates of 2-hydroxyimipramine, 2-hydroxydesmethylimipramine and 10-hydroxyimipramine. None of the treatments used impaired the overall ability of the rat to metabolize imipramine, although the plasma clearance of imipramine was reduced by 42% as a result of galactosamine administration and by 21% during treatment with (+)-catechin alone or combined catechin and galactosamine treatment.

Animals↗
PubMed1987

5-Hydroxytryptamine-sensitive [3H]imipramine binding of protein nature in the human brain. II. Effect of normal aging and dementia disorders.

Recently, a high-affinity [3H]imipramine binding site of protein nature that appeared related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated in the rat brain. In a preceding paper a similar [3H]imipramine binding site of protein nature and displaceable by 5-HT was demonstrated in the human brain. Most previous [3H]imipramine binding studies of the human brain have used desipramine-sensitive binding, which appears to contain a significant amount of additional binding not related to 5-HT neurons. Therefore this study of the human brain in the normal aging, in Alzheimer's disease/senile dementia of Alzheimer type (AD/SDAT) and in multiinfarction dementia (MID) presents data on 5-HT-sensitive [3H]imipramine binding. The influence of normal aging (17-100 years) was studied in the frontal and cingulate cortices, in the putamen, caudate nucleus, amygdala and in the hippocampus. An age-related change in 5-HT-sensitive [3H]imipramine binding was only noted in the cingulate cortex with a 50% loss in Bmax over the adult age range. In contrast, desipramine-sensitive [3H]imipramine binding studied in the frontal cortex and in the putamen showed marked increases in Bmax with age which correlated with increases in Kd. It is suggested that these increases are related to an increased binding to lipophilic membrane components not related to 5-HT neurons. The 5-HT-sensitive [3H]imipramine binding (Bmax) was reduced to 60% of control in the cingulate cortex and to 50% in the putamen in AD/SDAT. In MID there was a 50% loss of [3H]imipramine binding sites (Bmax) in the putamen, but a 30% loss in the cingulate cortex did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Imipramine inhibits intrathecal substance P-induced behavior and blocks spinal cord substance P receptors in mice.

The mechanism of the antinociceptive effect of the tricyclic antidepressant imipramine was investigated in mice. Intrathecal (i.t.) administration of imipramine produced dose-dependent antinociception in the tail-pinch and tail-flick tests with ED50 values (95% confidence limit) of 27.5 (17.0-43.9) and 20.2 (12.6-32.2) nmol, respectively. In substance P (SP)-induced nociceptive behavior, imipramine (i.t.) also produced dose-dependent antinociception with ED50 value of 20.2 (16.1-25.2) nmol. Tissue concentration of imipramine was between 55.2 and 104.4 nmol/g tissue when these ED50 values of imipramine were i.t. administered. In the SP-induced behavior, the antinociceptive effect of 31.6 nmol of imipramine was not antagonized by the alpha-adrenergic receptor antagonist phentolamine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In vitro study, imipramine dose-dependently inhibited specific [3H]SP binding in the spinal cord homogenate with IC50 value of 2.37 x 10(-4) M and this value corresponds to 8.6 mumol/g tissue concentration. These data indicate that imipramine produces antinociceptive effect at about 100 times lower dose than SP receptor blockade.

Animals↗
PubMed1989

Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain.

Rats were given chronically i.p. imipramine (20 mg/kg), LiCl (1 mg/kg) or both drugs to examine the effects of lithium (Li) on the alterations of imipramine pharmacokinetics in the whole brain and on the imipramine-related changes of norepinephrine (NE) and serotonin (5-HT) levels in the brain. When rats were given Li for 3 days, followed by a single injection of imipramine, the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat, although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats. In rats receiving both drugs for 10 days, the steady state levels of imipramine and desipramine in the brain were the same as those in the vehicle-treated rats but the steady state level of desipramine was reached earlier with Li treatments presumably because of the enhanced demethylation of imipramine. Consequently, the desipramine-dependent alterations of NE and 3-methoxy-4-hydroxyphenylglycol levels in the brain appeared to be induced earlier and more markedly when Li was given simultaneously. As the 5-hydroxyindole acetic acid (5-HIAA) levels were elevated in the brains of Li-treated rats and reduced in brains of imipramine-treated rats as compared with the level in vehicle-treated rats, the 5-HIAA level in rats receiving both drugs was equivalent to that in vehicle-treated rats.

Animals↗
PubMed1989

Effects of imipramine and serotonin-2 agonists and antagonists on serotonin-2 and beta-adrenergic receptors following noradrenergic or serotonergic denervation.

The effects of chronic (14 day) administration of the tricyclic antidepressant imipramine, the serotonin-2 (5-HT2) antagonist ketanserin, and the serotonin agonist quipazine on 5-HT2 receptor binding parameters and 5-HT2-mediated behavior were examined in rats with or without prior serotonergic denervation [via 5,7-dihydroxytryptamine (5,7-DHT)] or noradrenergic denervation [via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)]. Chronic administration of imipramine, ketanserin, or quipazine produced a marked reduction in the number of 5-HT2 binding sites which was accompanied by reductions in the 5-HT2-mediated quipazine-induced head shake response. In animals receiving DSP4 or 5,7-DHT lesions and continuous vehicle treatment, beta-adrenergic receptor binding sites were significantly up-regulated while 5-HT2 receptor binding sites did not change. Imipramine normalized the lesion-induced increases in beta-adrenergic binding observed in DSP4 and 5,7-DHT-lesioned rats but failed to down-regulate beta-adrenergic binding sites below non-lesioned control levels. Chronic imipramine, ketanserin, and quipazine reduced quipazine-induced head shakes and down-regulated 5-HT2 binding sites in rats with noradrenergic denervation. While imipramine, ketanserin, and quipazine all down-regulated 5-HT2 binding sites in animals with serotonergic denervation, only imipramine's ability to reduce quipazine-induced head shakes was attenuated in 5,7-DHT-lesioned rats. The present results suggest that imipramine-induced down-regulation of 5-HT2 receptors may not involve presynaptic 5-HT mechanisms, and imipramine-induced alterations in 5-HT2 sensitivity as reflected in the quipazine-induced head shake may, in part, be influenced by beta-adrenergic receptors.

5,7-Dihydroxytryptamine↗
PubMed1983

The effect of estradiol on the alterations in monoamine-mediated behavioural responses induced by administration of electroconvulsive shocks or imipramine to female rats.

Female rats were treated daily with electroconvulsive shocks (ECS) or imipramine (10 mg/kg) for 10 days. Both types of treatment enhanced behavioural responses mediated by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). A behavioural response mediated by dopamine (DA) was enhanced by electroconvulsive shock-treatment alone. On the other hand, rats treated only once with imipramine exhibited reduced DA-mediated behaviour. Priming the rats with estradiol valerate before starting electroconvulsive shock- or imipramine- treatment did not produce any significant effect on the enhancement in the behavioural response mediated by 5-HT. The enhancement in behaviour mediated by NA caused by electroconvulsive shock was also not altered, but that caused by treatment with imipramine was abolished. Enhancement of behaviour mediated by DA following electroconvulsive shock-treatment was also attenuated, while there was a positive reduction in behaviour mediated by DA in imipramine-treated rats. The two therapeutic approaches to depression, viz., electroconvulsive shock and imipramine, thus produced somewhat different effects on the central functions mediated by monoamines. Furthermore, an estrogen given prior to the treatments differentially altered the influence exerted by electroconvulsive shock and imipramine on monoamine functions in brain. The results may be pertinent to the clinical impression that estrogens produce a partial resistance to the antidepressant efficacy of imipramine-like drugs.

Animals↗
PubMed1987

Examination of the relationship between the uptake site for 5-hydroxytryptamine and the high affinity binding site for [3H]imipramine. II. The role of sodium ions.

Exogenous sodium ions stimulated both the high affinity binding of [3H]5-imipramine to membranes from the cortex of the rat and the high affinity accumulation of [3H]5-hydroxytryptamine (5-HT) into synaptosomes from the cortex of the rat with similar potencies. Imipramine and zimelidine inhibited synaptosomal uptake of [3H]5-HT potently in standard Tris-Krebs medium, but in a low-sodium medium their inhibitory potencies were significantly attenuated. The inhibitory potencies of panuramine and exogenous 5-HT on the uptake of [3H]5-HT were not significantly affected whether the uptake was measured in a normal or low-sodium Tris-Krebs. Imipramine and zimelidine were potent blockers of high affinity binding of [3H]imipramine whereas panuramine and 5-HT only inhibited the binding of [3H]imipramine at concentrations in excess of those required to inhibit the uptake of [3H]5-HT. It is suggested that imipramine inhibits the uptake of 5-HT by a sodium-dependent action probably at the high affinity binding site for [3H]imipramine, whereas panuramine and 5-HT inhibit the uptake of 5-HT by a sodium-independent mechanism at a site other than the binding site for [3H]imipramine.

Animals↗
PubMed1993

Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors.

The effects of acute and chronic treatment of rats with the tricyclic antidepressant imipramine, the 5-HT1A receptor partial agonist tandospirone, or its metabolite 1-PP were compared on behavioral responses produced by the activation of 5-HT receptors and on brain monoamine receptors. The behaviors examined were the 5-HT behavioral syndrome elicited by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake response produced by the 5-HT2 receptor agonist DOB. Drug treatments were administered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were assessed when the drug was present and absent at the time of testing. The infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug present) and 24 hr after the drug was withdrawn (drug absent). When administered by injection, tandospirone blocked the production of the 5-HT syndrome 1 hr (drug present), but not 24 hr (drug absent), following either 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections of imipramine blocked the 5-HT syndrome when tested 1 hr but not 24 hr, after the final injection. Treatment with 1-PP did not alter the 5-HT syndrome. The head shake response was attenuated by acute and chronic injection of tandospirone either 1 or 24 hr after treatment, although chronic infusion of tandospirone did not alter this behavior. Head shaking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chronic injection of 1-PP also inhibited the head shake response 24 hr after injection, although 1-PP was ineffective at all other times and when given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in frontal cortex was reduced by the chronic infusion of either tandospirone, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced following chronic imipramine injections or infusion. The results suggest that both tandospirone and imipramine may regulate 5-HT-mediated responses and 5-HT2 receptor density, which may contribute to their efficacy as antidepressants, although their effects were dependent upon the method of administration and may involve different neuropharmacological mechanisms.

Analysis of Variance↗
PubMed1992

Cardiac beta-adrenergic mediated chrono- and inotropic effects of imipramine in vitro.

Clinical and experimental studies show that tricyclic antidepressants in "therapeutic plasma concentrations" can increase heart rate, myocardial contractility and blood pressure. Our study was undertaken to analyze the role of beta-adrenergic stimulation in the chronotropic and inotropic effects of imipramine. Strips of rat right atrium including the sinus node, which were beating spontaneously, were used to study chronotropism. Strips of the left atrium, electrically stimulated to beat at 1 Hz, were used to study inotropism. The preparations were superfused in vitro with Tyrode's solution at 37 degrees C and exposed to imipramine while recording membrane potentials or force of contraction. Imipramine exerted dose-dependent biphasic actions. Imipramine 0.8 microM produced positive chronotropic and inotropic actions which were blocked by propranolol. Imipramine 1.6 microM depressed the sinus node automaticity, but it did not modify the force of contraction. Imipramine 3.2 microM depressed both the sinus node automaticity and the myocardial contractility. In conclusion, imipramine in "therapeutic plasma concentrations" produces beta-adrenergic mediated cardiac positive chronotropic and inotropic actions. The possible mechanisms of the depressant effects of imipramine itself on automaticity and contractility are still not clear. The results presented can explain stimulatory and depressant cardiac effects of therapeutic doses and overdoses of tricyclic antidepressants.

Animals↗
PubMed2005

Exacerbation of harmaline-induced tremor by imipramine.

Imipramine is a well-established tricyclic antidepressant which was first approved for the treatment of depression in the late fifties. Antidepressant effect of imipramine is attributed to inhibition of serotonin (5HT) and noradrenaline (NA) reuptake in brain. These monoamines have been implicated in a variety of neurological disorders including tremor. In the present investigation attempt was made to study the effect of imipramine on harmaline-induced tremor in rats. Male Sprague Dawley rats weighing 115+/-2.5 g were given harmaline (10 mg/kg, i.p.) alone or along with imipramine (30 min before harmaline) in doses of 60 and 90 mg/kg respectively. The latency of onset, intensity and duration of tremor and EMG were recorded. To substantiate the role of 5HT in aetiopathology of tremor the above experiment was repeated in the rats pretreated with P-chlorophenylalanine (PCPA), a potent 5HT depleter. The levels of 5HT and 5-hydroxyindole acetic acid (5HIAA) in the brain stem were measured using high performance liquid chromatography. Imipramine dose-dependently exacerbated the duration, intensity and amplitude of EMG following harmaline-induced tremor. Imipramine treatment further decreased harmaline-induced 5HT turnover in the brain stem. However, this was statistically insignificant. Depletion of 5HT produced a significant reduction in the intensity and duration of harmaline-induced tremor. In conclusion, this study suggests that imipramine exacerbates harmaline-induced tremor. Clinical use of imipramine for the treatment of depression in patients who also suffer from tremors may require a close monitoring.

Animals↗
PubMed1999

Reboxetine versus imipramine in the treatment of elderly patients with depressive disorders: a double-blind randomised trial.

BACKGROUND: Depression in older people is often unrecognised and untreated or under-treated. Antidepressant treatment may itself exacerbate a pre-existing illness, interact with concomitant medications or produce undesirable cognitive and sedative side effects. Newer antidepressants may offer advantages in terms of a lesser burden of adverse effects. METHODS: The comparative tolerability of the unique selective noradrenaline reuptake inhibitor (selective NRI) reboxetine (4-6 mg/day; n = 176) and that of imipramine (50-100 mg/day; n = 171) was assessed in an elderly ( > 65 years) cohort of depressed or dysthymic patients in an 8-week, double-blind, multicentre trial. Comparative efficacy was also assessed. RESULTS: Overall, 68% of patients in the reboxetine group experienced adverse events compared with 71% in the imipramine group. Reboxetine-treated patients were less likely to develop hypotension and related symptoms (7% vs. imipramine 16%) or cardiovascular disorders (12.5% vs. imipramine 21.1%), while those treated with imipramine were less likely to experience insomnia (6.3% vs. 2.9%). Adverse events were more often assessed as related to treatment (43%) and moderate to severe in intensity (73%) with imipramine than with reboxetine (33% and 65%, respectively). Furthermore, there were fewer serious adverse events in the reboxetine-treated group (P = 0.019). The reduction in the Hamilton Rating Scale for Depression (HAM-D) was comparable between the treatment groups in the total population. At the last assessment, the majority of patients in both treatment groups were assessed as normal to borderline or mildly ill using the Clinical Global Impression (CGI) scale. In a subanalysis of the dysthymic patients a modest but significant difference in favour of imipramine was observed for both HAM-D and CGI assessments. This may have been a reflection of a trend towards more severe depressive symptoms at baseline in the reboxetine group. CONCLUSIONS: Reboxetine is as effective as imipramine in the treatment of depression in elderly patients but is at least as well tolerated with a lower risk of hypotension and related symptoms, fewer serious adverse events, adverse event-related withdrawals and treatment-related adverse events.

Aged↗
PubMed2004

Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders.

There is evidence of gender differences in depressive disorders in terms of epidemiology and clinical manifestations. However, few studies have addressed the gender differences in terms of antidepressant treatment response in clinical practice. The aim of this study was to examine gender differences in the acute antidepressant response to sertraline and imipramine in nonmelancholic depressive disorders. A total of 239 patients with nonmelancholic major depression or dysthymia (DSM-III-R) and a score of >/=18 at baseline on the Hamilton Depression Rating Scale (HAM-D) were randomised in a 1:1 ratio treatment with flexible doses of sertraline (50-200 mg/day) or imipramine (75-225 mg/day) for 8 weeks in a multicenter, randomised, open-labeled, parallel group comparative trial. Depressive and anxiety symptoms were assessed using the HAM-D and the Hamilton Anxiety Rating Scale (HAM-A). Using HAM-D criteria, women were significantly more likely to respond to sertraline than to imipramine (72.2% vs. 52.1%, P=.008), whilst men respond similarly to sertraline and to imipramine (56.5% vs. 59.3%, P>.05). Response analysis based on HAM-A shows similar results (women: 68.9% vs. 43.6%, P=.001; men: 56.5% vs. 51.9%, P>.05). Women taking sertraline show statistically significant higher reductions in HAM-D, HAM-A, and in CGI-S than women taking imipramine. The proportion of women who dropped out due to adverse events was much lower in sertraline than in imipramine (10.9% vs. 27.8%, P=.006), with no differences between treatments in men (8.3% vs. 11.5%, P>.05). It was concluded that sertraline is more effective and better tolerated than imipramine in the acute treatment of nonmelancholic depressive disorders in women, whereas men responded similarly to sertraline and to imipramine.

Antidepressive Agents, Second-Generation↗
PubMed2005

Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test.

The activation of cell-mediated immunity and the hypothalamic-pituitary-adrenal axis may play a role in the pathophysiology of depression, especially a treatment-resistant one, and antidepressant treatments may exert their effect by suppressing this activation. In our previous studies we described synergistic, antidepressant-like effects of a combination of amantadine (10 mg/kg) and imipramine (5 mg/kg) - drugs otherwise ineffective when given separately in such doses - in the forced swimming test (FST), an animal model of depression. Moreover, preliminary clinical data show that the above-described combination has beneficial effects on treatment-resistant patients. However, it is still unknown whether these positive effects of combined treatment with amantadine and imipramine on behavioural depressive changes are accompanied with normalization of immunoendocrine parameters. Therefore, the present study was aimed at ascertaining whether the antidepressive effect of a combination of amantadine and imipramine was accompanied with a decrease in some immunoendocrine parameters. The antidepressant activity was accompanied with a reversal of the stress-induced increase in the proliferation of splenocytes in response to concanavalin A (ConA). Imipramine, amantadine and a combination of amantadine and imipramine enhanced the production of the negative immunoregulator IL-10 in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with imipramine or amantadine (a combination of imipramine and amantadine causes reduction within the margin of error). In summary, the antidepressive efficacy of a combination of amantadine and imipramine given in suboptimal doses may be related to their negative immunoendocrine effects.

Amantadine↗
PubMed1998

Identification of amino acid residues associated with modulation of flavin-containing monooxygenase (FMO) activity by imipramine: structure/function studies with FMO1 from pig and rabbit.

The activity of the flavin-containing monooxygenase (FMO) can be modulated by a number of nitrogen-containing compounds in a manner that is both isoform and modulator-dependent. We now show that the direction (activation or inhibition) and extent of modulation can also be dependent on substrate concentration. Imipramine activates methimazole metabolism catalyzed by rabbit FMO1 or FMO2 at methimazole concentrations greater than 50 or 100 microM, respectively, and inhibits at lower methimazole concentrations. The extent of the activation increases as the substrate concentration increases, and the extent of inhibition increases as the substrate concentration decreases. With either inhibition or activation, the magnitude of the effect shows a similar, direct dependency on imipramine concentration. In contrast, imipramine inhibits the metabolism of methimazole catalyzed by pig FMO1 at all substrate concentrations. The structural basis for this unique ortholog difference between the responses of rabbit and pig FMO1 to imipramine was studied by random chimeragenesis and site-directed mutagenesis. Results with chimeras indicated that modulation of FMO1 activity by imipramine is controlled to a great extent by two areas of the FMO primary structure (residues 381-432 and 433-465). Four amino acids in these regions (positions 381, 400, 420 and 433) and one additional residue (position 186) were identified by site-directed mutagenesis as primary determinants of the imipramine response. When the residues at these positions in rabbit FMO1 are exchanged for the corresponding residues of pig FMO1, a mutant with the functional properties of pig FMO1 is produced. Our results suggest that the response of FMO1 to imipramine involves a distribution between two sites that is regulated by structural features that do not alter the overall binding. The inhibition observed, although it appears to be competitive, likely does not involve competition for a binding site since alteration of imipramine metabolism has no effect on the parameters of methimazole metabolism.

Amino Acid Substitution↗
PubMed2003

Involvement of 5-HT(2) receptor in imipramine-induced hyperglycemia in mice.

Effects of imipramine on plasma glucose levels were investigated in mice. Imipramine i. p. induced dose-dependent hyperglycemia, which was enhanced by pretreatment with 5-HT (1/2/5/7) receptor antagonist methysergide and 5-HT (2A/2B/2C) receptor antagonist LY 53857. 5-HT (2C/2B) receptor antagonist SB 206553 also augmented imipramine-induced hyperglycemia although 5-HT (1A) and 5-HT (1B) receptor antagonist (-)-propranolol,5-HT (2A) receptor antagonist ketanserin and 5-HT (3/4) receptor antagonist tropisetron each had no effect. Imipramine i. p.-induced hyperglycemia was antagonized by the 5-HT (2C/2B) receptor agonist 1-(3-chlorophenyl)piperazine (mCPP), while the 5-HT (2B) receptor agonist BW 723C86 had no effect. Intracerebroventricular injection of imipramine also elevated plasma glucose levels, which is enhanced by SB 206553. Hyperglycemia elicited by central injection of imipramine was abolished by adrenalectomy. These results suggest that imipramine-induced hyperglycemia in mice is related to its inhibition of the central 5-HT (2C) receptor. Moreover, our results indicate that adrenaline release is related to imipramine-induced hyperglycemia.

Adrenalectomy↗
PubMed1992

Combined treatment with imipramine and mianserin. A controlled pilot study.

The effect of imipramine plus mianserin and imipramine plus a placebo was compared in 40 depressed patients with a median age of 60 years. The imipramine dosage was flexible to give a plasma concentration around 200 nmol/l and mianserin was given at a fixed dosage of 30 mg daily. After six weeks of treatment the results showed that the scores on the Hamilton Depression Scale as well as on the Melancholia Scale were significantly more improved in the imipramine-plus-minaserin group than in the group of patients receiving imipramine alone (P less than 0.01). In terms of percentage of improvement (a reduction of baseline rating scores of 50% or more) 77% of the imipramine-plus-mianserin group had improved, compared with 27% of the imipramine group. The combination of imipramine and mianserin was well tolerated both as regards clinical side-effects and laboratory tests.

Adult↗