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PubMed1999

Differential effect of a single high dose of the tricyclic antidepressant imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion following an in vivo lipopolysaccharide challenge in rats.

Tricyclic antidepressants (TCAs) of which imipramine is one, are commonly used in the treatment of depressive disorders and other forms of psychiatric illness. There have been many reports regarding the suppressive effects of TCAs on immune function. However, information is still limited regarding the effects of TCAs on the immune system, as many of the studies conducted to date have concentrated on in vitro exposure to such drugs, or ex vivo measures of immunity following drug administration. Thus in the present investigation, an in vivo challenge with bacterial lipopolysaccharide (LPS) (100 microg/kg; i.p.) was used to assess immunocompetence following administration of a single high dose of the TCA, imipramine (100 mg/kg, p.o.). The results demonstrated that imipramine pretreatment inhibits LPS-induced increases in serum concentrations of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha both 3 and 6 h, following administration. However, LPS-induced interleukin (IL)-1beta secretion was not significantly altered following imipramine treatment at either of the timepoints examined. In addition, serum concentrations of corticosterone and the antiinflammatory cytokine IL-10 were measured, and imipramine treatment failed to alter either basal, or LPS-induced increases in these immunosuppressive agents. In conclusion, although IL-1beta and TNF-alpha are both macrophage-derived proinflammatory cytokines, the present study demonstrates a differential sensitivity of these cytokines to the suppressive effects of the TCA imipramine. Furthermore, the suppressive effects of imipramine on LPS-induced TNF-alpha secretion could not be attributed to either increased glucocorticoid levels, or increased secretion of the antiinflammatory cytokine IL-10. The relevance of these findings to antidepressant-induced immunotoxicity are discussed.

Animals↗
PubMed2003

Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression: a double-blind, randomized trial.

Depression is a major health problem and is not only underrecognized and undertreated but is associated with significant morbidity and mortality. Lavandula angustifolia Mill. (Lamiacae) is used to treat depression. Many medicinal plant textbooks refer to this indication, whereas there is no evidence-based document. Our objective was to compare the efficacy of tincture of L. angustifolia with imipramine in the treatment of mild to moderate depression and to evaluate the possible adjuvant effect of this tincture in a 4 week double-blind, randomized trial. Forty-five adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive lavandula tincture (1:5 in 50% alcohol ) 60 drops/day plus placebo tablet (Group A), tablet imipramine 100 mg/day plus placebo drop (Group B) and tablet imipramine 100 mg/day plus lavandula tincture 60 drops/day (Group C) for a 4-week study. In this small preliminary double-blind and randomized trial, lavandula tincture at this concentration was found to be less effective than imipramine in the treatment of mild to moderate depression (F=13.16, df=1, P=.001). In the imipramine group, anticholinergic effects such as dry mouth and urinary retention were observed more often that was predictable, whereas headache was observed more in the lavandula tincture group. A combination of imipramine and lavandula tincture was more effective than imipramine alone (F=20.83, df=1, P<.0001). As this study indicates, one of the advantages of this combination is a better and earlier improvement. The main overall finding from this study is that lavandula tincture may be of therapeutic benefit in the management of mild to moderate depression as adjuvant therapy. A large-scale trial is justified.

Adult↗
PubMed2003

Sertraline is more effective than imipramine in the treatment of non-melancholic depression: results from a multicentre, randomized study.

The acute treatment efficacy, tolerability, and effects on health-related quality of life of sertraline (50-200 mg/day) versus imipramine (75-225 mg/day) were compared in outpatients with non-melancholic depression. The study employed an open-label, parallel-group design. One hundred and sixteen patients were randomized to receive sertraline and 123 to receive imipramine for 8 weeks. In the intent-to-treat (ITT), last-observation-carried-forward (LOCF) analysis, sertraline produced statistically significantly greater improvements in depressive (21-item Hamilton Depression Rating Scale [HAM-D(21)] scores of 24.9 and 24.4 were reduced to 10.3 and 13.1 at endpoint, P<.005) and anxiety symptoms (Hamilton Anxiety Rating Scale [HAM-A] scores of 21.8 and 21.9 were reduced to 9.5 and 13.9, P<.01), as well as in response (69.0% versus 53.7% at endpoint, P=.016) and remission rates (51.3% versus 38.0% at endpoint, P=.041) from week 4 onwards compared with imipramine. The proportion of patients who were 'very much improved' or 'much improved' (Clinical Global Impressions Scale of Improvement [CGI-I] score of 1 or 2) was significantly higher at endpoint in the sertraline group (76.1%) than in the imipramine group (62.8%) (P=.028). At week 8, patients in both treatment groups showed clear improvements in quality of life, although nonstatistically significant differences were evident in the quality of life of sertraline- versus imipramine-treated patients. Sertraline was significantly superior in tolerability with less discontinuations due to adverse events (10.3%) compared with the imipramine group (24.4%) (P=.004). It was concluded that sertraline is more effective than imipramine in the acute treatment of depressive and anxiety symptoms in patients with non-melancholic depression.

Adolescent↗
PubMed2003

Influence of alpha-adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice.

Effects of adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10-40 mg x kg(-1)), alpha2-adrenoceptor agonist clonidine (0.05-0.1 mg x kg(-1)), alpha1-adrenoceptor agonist phenylephrine (6 mg x kg(-1)) and alpha1-adrenoceptor antagonist prazosin (1-4 mg x kg(-1)) but not alpha2-adrenoceptor antagonist yohimbine (1-4 mg x kg(-1)) induced significant hypothermia. The hypothermic response induced by imipramine (10-30 mg x kg(-1)) was not altered by clonidine (0.05-0.1 mg x kg(-1)) or phenylephrine (2-6 mg x kg(-1)). The response of imipramine (10-30 mg x kg(-1)) was reduced significantly by yohimbine (2 mg x kg(-1)) and was potentiated by prazosin (1 mg x kg(-1)). The hypothermic effect of clonidine (0.1 mg x kg(-1)) and imipramine (20 mg x kg(-1)) were also decreased significantly by different doses of yohimbine (1-4 mg x kg(-1)). The hypothermia induced by different doses of prazosin (1-4 mg x kg(-1)) was not altered by yohimbine (2 mg x kg(-1)) or by low dose of imipramine (10 mg x kg(-1)). It is concluded that alpha2-adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.

Adrenergic alpha-Agonists↗
PubMed1988

Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers.

Recently detoxified men with alcohol dependence (n = 15) and healthy volunteers (n = 14) were administered oral and intravenous imipramine and desipramine. Alcoholics had significantly greater total body clearance of imipramine (0.93 vs. 0.48 L/hr/kg; P less than 0.05) and desipramine (1.00 vs. 0.62 L/hr/kg; P less than 0.05) than did control subjects. Intrinsic clearance of unbound imipramine was greater in the alcoholic group (19.80 vs. 6.56 L/hr/kg; P less than 0.05), as was the intrinsic clearance of unbound desipramine (14.52 vs. 9.05 L/hr/kg; P less than 0.05). The mean elimination half-life for imipramine was significantly decreased in alcoholics (8.7 vs. 19.9 hours after intravenous infusion and 10.9 vs. 19.6 hours after oral administration; P less than 0.05). The mean elimination half-life for desipramine was decreased in alcoholics after intravenous infusion (16.5 vs. 22.4 hours; P less than 0.05). Unbound fractions of drug in plasma were decreased in the alcoholic group for both imipramine and desipramine after both routes of administration. alpha 1-Acid glycoprotein levels were elevated in the alcoholic group whereas total protein and albumin levels did not differ between groups. These findings suggest that recently detoxified alcoholics may require higher doses of imipramine than do nonalcoholic subjects. Desipramine clearance was affected to a lesser degree than imipramine, suggesting that from a pharmacokinetic standpoint it may be the preferred drug for the treatment of alcoholics with depression. Periodic monitoring of plasma levels may be required for recently abstinent alcoholics treated with antidepressants.

Administration, Oral↗
PubMed1997

Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.

AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.

1-Naphthylamine↗
PubMed2002

DNA damage in children treated with imipramine for primary nocturnal enuresis.

BACKGROUND: Despite the fact that primary nocturnal enuresis (PNE) is self-limited and pathologically benign, the emotional stress and inconvenience that it produces, warrants treatment. Imipramine is one of the widely used drugs in PNE treatment. Although some mutagenic effects were suggested in imipramine administration, this toxicity has never been investigated in enuretic patients. The aim of this study was to evaluate the association of exposure to imipramine with DNA damage. METHODS: Thirty-five children treated with imipramine for at least 4.5 months who were in otherwise good health were accepted into the investigation. Twenty healthy sisters or brothers of the patients who did not use any long-term drugs were studied simultaneously as the control group. Comet assay was used to evaluate DNA damage. RESULTS: Damaged (limited and extensive migrated) cells of the enuretic children who were taking imipramine were statically higher than that of the control group (P < 0.05) indicating a detectable DNA damaging effect of imipramine in human lymphocytes. CONCLUSIONS: Our finding suggests that the difference in comet scores between two groups was induced by the imipramine treatment. The other possibility to be considered is the psychological stress of the children who were concerned by the symptoms and their parent's anxiety. As our preliminary data were based on a limited number of children, further research is needed considering the importance of this possible toxic effects which may be associated with mutagenicity.

Adolescent↗
PubMed1998

Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by the recombinant rat serotonin transporter SERT1.

Tricyclic and nontricyclic serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors are widely used for the treatment of depression. Here, we show that both the tricyclic antidepressant imipramine and the nontricyclic antidepressant citalopram competitively inhibit 5-HT transport mediated by the recombinant rat 5-HT transporter SERT1. For citalopram, the concentration producing half-maximal transport inhibition was in the same order of magnitude as its K(D) value determined by equilibrium binding. In contrast, the inhibitory potency of imipramine was more than one order of magnitude lower than its K(D) value. Our data are consistent with low-affinity imipramine binding occurring at or close to the substrate recognition site, which also binds citalopram. Occupation of the high-affinity imipramine binding site on SERT1 did not affect 5-HT transport but allosterically displaced citalopram from the substrate recognition site. Consequently, low concentrations of imipramine partially protected 5-HT transport from citalopram inhibition. This protection was only observed in the presence of Na+ because high-affinity imipramine binding is strictly sodium-dependent. Thus, depending on which of its binding sites on SERT1 is occupied, imipramine may exert distinct effects on 5-HT uptake mediated by the recombinant rat 5-HT transporter.

Allosteric Site↗
PubMed2004

Mechanism of block of hEag1 K+ channels by imipramine and astemizole.

Ether à go-go (Eag; KV10.1) voltage-gated K+ channels have been detected in cancer cell lines of diverse origin and shown to influence their rate of proliferation. The tricyclic antidepressant imipramine and the antihistamine astemizole inhibit the current through Eag1 channels and reduce the proliferation of cancer cells. Here we describe the mechanism by which both drugs block human Eag1 (hEag1) channels. Even if both drugs differ in their affinity for hEag1 channels (IC50s are approximately 2 microM for imipramine and approximately 200 nM for astemizole) and in their blocking kinetics, both drugs permeate the membrane and inhibit the hEag1 current by selectively binding to open channels. Furthermore, both drugs are weak bases and the IC50s depend on both internal an external pH, suggesting that both substances cross the membrane in their uncharged form and act from inside the cell in their charged forms. Accordingly, the block by imipramine is voltage dependent and antagonized by intracellular TEA, consistent with imipramine binding in its charged form to a site located close to the inner end of the selectivity filter. Using inside- and outside-out patch recordings, we found that a permanently charged, quaternary derivative of imipramine (N-methyl-imipramine) only blocks channels from the intracellular side of the membrane. In contrast, the block by astemizole is voltage independent. However, as astemizole competes with imipramine and intracellular TEA for binding to the channel, it is proposed to interact with an overlapping intracellular binding site. The significance of these findings, in the context of structure-function of channels of the eag family is discussed.

Astemizole↗
PubMed2000

Imipramine plus cognitive-behavioral therapy in the treatment of school refusal.

OBJECTIVE: To investigate the efficacy of 8 weeks of imipramine versus placebo in combination with cognitive-behavioral therapy (CBT) for the treatment of school-refusing adolescents with comorbid anxiety and major depressive disorders. METHOD: This was a randomized, double-blind trial with 63 subjects entering the study and 47 completing. Outcome measures were weekly school attendance rates based on percentage of hours attended and anxiety and depression rating scales. RESULTS: Over the course of treatment, school attendance improved significantly for the imipramine group (z = 4.36, p < .001) but not for the placebo group (z = 1.26, not significant). School attendance of the imipramine group improved at a significantly faster rate than did that of the placebo group (z = 2.39, p = .017). Over the 8 weeks of treatment, there was a significant difference between groups on attendance after controlling for baseline attendance; mean attendance rate in the final week was 70.1% +/- 30.6% for the imipramine group and 27.6% +/- 36.1% for the placebo group (p < .001). Defining remission as 75% school attendance, 54.2% of the imipramine group met this criterion after treatment compared with only 16.7% from the placebo group (p = .007). Anxiety and depression rating scales decreased significantly across treatment for both groups, with depression on the Children's Depression Rating Scale-Revised decreasing at a significantly faster rate in the imipramine group compared with the placebo group (z = 2.08, p = .037). CONCLUSIONS: Imipramine plus CBT is significantly more efficacious than placebo plus CBT in improving school attendance and decreasing symptoms of depression in school-refusing adolescents with comorbid anxiety and depression.

Adolescent↗
PubMed1993

Electrophysiological effects of the combination of imipramine and desipramine in guinea pig papillary muscles.

The electrophysiological effects of imipramine and its active metabolite desipramine, alone or in combination, were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) of the action potential was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, imipramine alone (5 x 10(-6) M), desipramine alone (5 x 10(-6) M), or their combination had no effect on action potential characteristics. However, in the presence of imipramine or desipramine, trains of stimuli at rates between 0.5 and 3 Hz led to a frequency-dependent Vmax block that was augmented at higher stimulation rates. At each driving rate, the Vmax block produced by desipramine was significantly greater than that produced by imipramine. The combination of imipramine and desipramine increased the onset rate of the frequency-dependent Vmax block, but the total amount of Vmax block was similar to that produced by desipramine alone. In the presence of imipramine alone, the recovery of Vmax was a monoexponential process, the time constant (tau re) being 2.3 +/- 0.4 s, whereas in the presence of desipramine, it was better defined by a biexponential function (tau re = 1.5 +/- 0.4 and 15.8 +/- 2.8 s). In the presence of the combination, the recovery process was also defined by a biexponential function and the tau re values were similar to those found in the presence of desipramine alone. Thus, according to their onset and offset kinetics of the frequency-dependent Vmax block, imipramine and desipramine can be classified as sodium channel blockers with intermediate and slow kinetics, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1997

Single dose imipramine reduces nocturnal urine output in patients with nocturnal enuresis and nocturnal polyuria.

PURPOSE: We investigated the effect of imipramine on nocturnal urine output in patients with nocturnal enuresis. MATERIALS AND METHODS: There were 15 monosymptomatic enuretic patients 15 to 37 years and 8 control subjects 25 to 32 years old. We measured nocturnal urine output, urine osmolality, creatinine clearance, osmolal clearance, free water clearance, excretion of solutes, fractional excretion of sodium, fractional excretion of potassium and plasma vasopressin with and without a single oral dose of imipramine (1 mg./kg. of body weight) taken at 8 p.m. RESULTS: Baseline studies showed significantly larger and less concentrated nocturnal urine among enuretics compared with controls. We observed a marked antidiuretic effect of imipramine in 6 enuretics with severe nocturnal polyuria. The imipramine induced decrease in urine output was accompanied by reduced osmolal clearance. Approximately a third of the observed decrease in solute excretion was attributed to lower excretion of sodium and potassium. The remaining two-thirds were most likely caused by an increased tubular reabsorption of urea, which may be secondary to a sympathomimetic effect of imipramine tubules, possibly because of altered adrenal medullary function with an increase in proximal tubular sodium and water reabsorption. The resultant lower tubular flow rate facilitates tubular reabsorption of urea in the distal part of the nephron. CONCLUSIONS: Imipramine has a vasopressin independent antidiuretic effect if nocturnal polyuria is present. The antidiuretic effect of imipramine can be attributed primarily to increased alpha-adrenergic stimulation in the proximal tubules with a secondary increased urea and water reabsorption more distally in the nephron.

Adolescent↗
PubMed1990

Nonlinear kinetics of imipramine in low and medium plasma level ranges.

Steady state plasma concentrations of imipramine and desipramine were studied at three to nine different imipramine dose levels in 17 extensive metabolizers of sparteine and at two dose levels in two poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. The imipramine doses were changed stepwise from doses yielding plasma concentrations of imipramine plus desipramine below 150 nM, up to doses yielding therapeutic drug levels of at least 300-500 nM. The imipramine doses required to achieve therapeutic drug levels was 20 or 25 mg/day in the two poor metabolizers and 50-350 mg/day in the extensive metabolizers. In the extensive metabolizers, the concentration/dose ratio increased for imipramine and desipramine with increasing dose. Dose adjustments based on a simple linear prediction from drug levels at initial dose (50 or 75 mg imipramine/day) thus would result in 0-130% (median, 20%) overestimates, most pronounced in patients with initial low steady state levels. The nonlinear kinetics of imipramine thus may be a significant clinical problem in patients treated for diabetic neuropathy symptoms.

Adult↗
PubMed1996

Imipramine metabolism in relation to the sparteine oxidation polymorphism--a family study.

The relationship between genetic polymorphism and imipramine metabolism has never been studied in a family study. A sparteine/mephenytoin test was carried out in 31 parents and 20 siblings of 18 Danish poor metabolizers of sparteine (PMs). One week later, each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by HPLC. There were 10 PMs (20%; 9.8-33%, 95% confidence interval) and 41 extensive metabolizers of sparteine (EMs) among parents and siblings. In 26 of the 28 PMs among probands and relatives, there were concordance between phenotype and genotype: D6-A/D6-D (n = 2), D6-A/D6-B (n = 5), D6-B/(n = 15) or D6-B/D6-D (n = 4). Two PMs were apparently heterozygous (EMs), D6-wt/D6-B. Accordingly, based on the present sample of 28 PMs the specificity of the genotype test was 100% and the sensitivity was 92.9%. Two EMs were homozygous dominant D6-wt/and 39 were heterozygous EMs; D6-wt/D6-D (n = 5), D6-wt/D6-B (n = 27), D6-wt/D6-A (n = 6), D6-wt/D6-wt* (unknown mutation) (n = 1). As previously reported in a population study the hydroxylation ratios (i.e. 2-hydroxymetabolite over parent compound) of imipramine were much lower in PMs than in EMs. This and the pedigrees confirmed the co-segregation of sparteine oxidation, imipramine 2-hydroxylation and the CYP2D6 genotype. None of the hydroxylation ratios could separate EMs and PMs completely, mainly because the 2-hydroxylation of imipramine also depends on P450s other than CYP2D6.

Adolescent↗
PubMed2005

Chronic imipramine treatment sensitizes 5-HT1A and 5-HT 2 A receptors in the dorsal periaqueductal gray matter: evidence from the elevated T-maze test of anxiety.

The dorsal periaqueductal gray matter (DPAG) has been implicated in the mediation of escape, a defensive behavior associated with panic disorder (PD). Chronic treatment with the anti-panic agent imipramine enhances the inhibitory effect on escape evoked by DPAG electrical stimulation of intra-DPAG administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the preferential 5-HT 2 A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). In the present study we further explore the hypothesis that sensitization of 5-HT1A and 5-HT 2 A receptors in the DPAG is involved in the anti-panic effect of imipramine. To this end, Wistar rats, subchronically or chronically treated with imipramine, were intra-DPAG injected with 8-OH-DPAT (0.4 or 3.2 nmoles) or DOI (16 nmoles), and tested in the elevated T-maze. In addition to its possible relevance to panic disorder, this test also measures inhibitory avoidance, a behavior that has been associated with generalized anxiety disorder (GAD). The effects of these 5-HT agonists in the DPAG were also investigated in animals chronically injected with buspirone, a drug clinically effective in treating GAD, but not PD. The results showed that intra-DPAG administration of the highest dose of 8-OH-DPAT and of DOI inhibited escape, and this panicolytic-like effect was significantly higher in animals previously treated chronically, but not subchronically, with imipramine. 8-OH-DPAT (0.4 nmole), although not affecting escape in animals systemically treated with saline, had a panicolytic-like effect in those receiving long-term treatment with imipramine. Microinjection of 8-OH-DPAT (3.2 nmoles), but not of DOI, impaired inhibitory avoidance, and this anxiolytic effect did not differ between animals treated with saline or imipramine. Chronic buspirone did not change the effect of 8-OH-DPAT and DOI on inhibitory avoidance and escape. Therefore, chronic imipramine seems to sensitize both 5-HT1A and 5-HT 2 A receptors in the DPAG, strengthening the view that these receptors are involved in the mode of action of anti-panic drugs.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

A double-blind placebo-controlled study of fluvoxamine and imipramine in out-patients with primary depression.

1 A double-blind placebo-controlled study of fluvoxamine and imipramine was performed in a group of depressed patients. Twenty-two patients received fluvoxamine (mean dose 101 mg/day), 25 received imipramine (mean dose 127 mg/day) and 22 received placebo. 2 Apart from an increase in the SGOT and SGPT values of four imipramine patients, no statistically significant changes in haematology or urinalysis were judged to be medically relevant. Fluvoxamine exhibited fewer anticholinergic side effects than imipramine. 3 Both fluvoxamine treated patients and imipramine-treated patients exhibited a statistically significant improvement at the end of the 28-day treatment period with respect to the placebo patients, as measured using the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Evaluations of the results of the Beck Depression Inventory and the Profile of Mood States revealed a statistically significant improvement for imipramine patients with respect to placebo at week 4, but not for fluvoxamine patients. It is postulated on the basis of quantitative pharmaco-EEG findings, that the slight superiority of imipramine over fluvoxamine was due to underdosing of the latter.

Adult↗
PubMed1985

5-Hydroxytryptamine uptake and imipramine binding sites in neurotumor NCB-20 cells.

NCB-20 cells (neuroblastoma X fetal Chinese hamster brain hybrids) are equipped with a [3H]5-hydroxytryptamine [( 3H]5-HT) uptake system and [3H]imipramine recognition sites. Approximately 80% of the radioactivity taken up by cells incubated with [3H]5-HT was identified with 5-HT. [3H]5-HT uptake was temperature-dependent, partially sodium-dependent, saturable (Km = 7.3 +/- 0.6 microM; Vmax = 2.0 +/- 0.6 pmol/min/mg), and inhibited by clomipramine, imipramine, fluoxetine, and desipramine, but not by iprindole, mianserin, or opipramol. Lineweaver-Burk plots showed a competitive type of inhibition by imipramine and fluoxetine. [3H]5-HT uptake was not inhibited by nisoxetine or benztropine. [3H]Imipramine binding sites had a KD of 12 +/- 2 nM and a Bmax of 22 +/- 7 pmol/mg protein. The binding was sodium-sensitive although to a lesser extent than that found with brain membranes. Imipramine binding was displaced by tricyclic antidepressants with the following order of potency: clomipramine greater than imipramine greater than fluoxetine greater than desipramine much greater than iprindole = mianserin greater than opipramol. These results suggest that imipramine binding sites are present together with the 5-HT uptake sites in NCB-20 cells and that these sites interact functionally but are different biochemically.

Animals↗
PubMed1985

Tryptamine, a substrate for the serotonin transporter in human platelets, modifies the dissociation kinetics of [3H]imipramine binding: possible allosteric interaction.

Tricyclic antidepressants and nontricyclic serotonin (5-hydroxytryptamine) uptake blockers monophasically inhibit [3H]imipramine binding in human platelets. Similarly, serotonin and tryptamine inhibit the binding of [3H]imipramine in the low micromolar range and with a pseudo-Hill coefficient near unity. Dissociation of the [3H]imipramine receptor complex in the presence of uptake inhibitors follows first-order kinetics with a half-life of approximately 60 min. Although serotonin and tryptamine do not decrease [3H]imipramine binding when added under equilibrium conditions, simultaneous addition of serotonin or tryptamine with serotonin uptake inhibitors decreases the rate of ligand-receptor dissociation in a concentration-dependent manner. These data suggest a common site of action for serotonin, which is the substrate of the transporter system, and of tryptamine, its nonhydroxylated analog. This hypothesis is supported by the identification of a high-affinity (Km = 0.55 microM), saturable, and temperature-dependent uptake of [3H]tryptamine in human platelets. Uptake of [3H]tryptamine was inhibited potently by imipramine and nontricyclic serotonin uptake inhibitors with a potency similar to that observed for [3H]serotonin uptake. These data support the hypothesis that in platelets, [3H]imipramine, tricyclic, and nontricyclic serotonin uptake inhibitors bind to a common recognition site that is associated with the serotonin transporter but that differs from the substrate recognition site of the carrier through which serotonin and tryptamine exert a heterotropic allosteric modulation on [3H]imipramine binding.

Allosteric Regulation↗