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PubMed1997

Simultaneous determination of imipramine and its metabolite desipramine in human plasma by capillary gas chromatography with mass-selective detection.

An analytical method for the simultaneous determination of imipramine (IMI) and its N-desmethyl metabolite, desipramine (DIMI) in human plasma by capillary gas chromatography-mass selective detection (GC-MS), with D4-imipramine (D4-IMI) and D4-desipramine (D4-DIMI) as internal standards, was developed and validated. After addition of the internal standards, the compounds were extracted from plasma at basic pH into n-heptane-isoamyl alcohol (99:1, v/v), back-extracted into acidic aqueous solution and re-extracted at basic pH into toluene. Desipramine and D4-desipramine were converted into their pentafluoropropionyl derivatives. The compounds were determined by gas chromatography using a mass selective detector at m/z 234 for IMI, m/z 238 for D4-IMI, m/z 412 for DIMI and m/z 416 for D4-DIMI. The method was applied to clinical samples.

Administration, Oral↗
PubMed2000

Spectrophotometry assay of imipramine and desipramine using ammonium metavanadate and its application to pharmaceutical preparations.

Simple and sensitive method for determination of imipramine and desipramine is reported. The procedure is based on the oxidation of the drugs by ammonium metavanadate. Linear calibration graphs were obtained in the concentration range 0.6-40 microg ml(-1) of imipramine and 0.7-35 microg ml(-1) of desipramine with a relative standard deviation (RSD) less than 0.5%. The method was applied to the determination of the drugs in pharmaceutical preparations and compared favourably with independent official methods.

Antidepressive Agents, Tricyclic↗
PubMed2003

Rates of metabolism of chlorzoxazone, dextromethorphan, 7-ethoxycoumarin, imipramine, quinidine, testosterone and verapamil by fresh and cryopreserved rat liver slices, and some comparisons with microsomes.

In the present study we have investigated the disappearance of chlorzoxazone, dextromethorphan, 7-ethoxycoumarin, imipramine, quinidine, testosterone and verapamil from the medium in which fresh and cryopreserved rat liver slices were incubated. These compounds are all substrates of major isoforms of cytochrome P450 expressed in the liver. The metabolism of five of these compounds in microsomes from rat liver was also examined. Determinations of the concentrations of the compounds were performed employing LC/MS. Intrinsic clearance values (CL(ints)) were calculated on the basis of the concentration-vs.-time curves. No significant differences in the CL(int) values obtained with fresh and cryopreserved rat liver slices were observed for any of the compounds. The highest CL(int) value estimated with liver slices was observed for testosterone and the lowest values were with chlorzoxazone and 7-ethoxycoumarin. The total CL(int) values for 7-ethoxycoumarin and imipramine, calculated using scaling factors, were similar for liver slices and microsomes. In the case of testosterone, this total CL(int) was approximately 3.7-fold lower, whereas for dextromethorphan and quinidine it was 2.5- and 8.5-fold higher, respectively, with liver slices than with microromes. In conclusion, the rate of metabolism of the seven compounds tested with rat liver slices was not affected by cryopreservation. This finding adds further support to the general conclusion that the major activities involved in drug metabolism are not affected by cryopreservation of rat liver slices.

Animals↗
PubMed1999

Adrenergic receptor function in panic disorder. I. Platelet alpha 2 receptors: Gi protein coupling, effects of imipramine, and relationship to treatment outcome.

Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.

Adult↗
PubMed1999

The effect of arginine-428 mutation on modulation of activity of human liver flavin monooxygenase 3 (FMO3) by imipramine and chlorpromazine.

This study was carried out to investigate the molecular basis for modulation of recombinant FMO3-catalyzed activity by the tricyclic antidepressants, imipramine and chlorpromazine. A mutant of human liver FMO3 (T428R) was formed by site-directed mutagenesis and characterized along with the native enzyme in order to elucidate a possible structure-function relationship. Functional properties of native and T428R human FMO3s were studied with methimazole as substrate. Both enzymes catalyzed the S-oxidation of methimazole with the same Km value. Imipramine modulated the activities of the native and T428R human FMO3s differently; the activity of the native FMO3 was increased at all concentrations, whereas the activity of the mutant enzyme was inhibited at concentrations above 300 microM. Chlorpromazine activated the native enzyme at all concentrations of methimazole but activated the mutant enzyme only at high substrate concentrations. The direction (activation or inhibition) and extend of modulation of FMO3 activity is not only dependent on the concentration of the modulator, it is also dependent on the substrate concentration. This study confirms our previous findings with FMO1 that position 428 is important in the interaction of the FMO with modulators.

Arginine↗
PubMed1992

Role of alpha 1 receptors in the behavioural supersensitivity to D2 agonists induced by chronic treatment with imipramine.

Chronic treatment with imipramine increased the locomotor response to quinpirole, a selective D2 receptor agonist. This effect was blocked by minute doses of prazosin (0.1-1 mg/kg), a selective alpha 1 receptor blocker, in a dose-dependent manner. Conversely, in control rats the locomotor response to quinpirole was enhanced by the stimulation of alpha 1 receptors with the selective agonist St 587. The results suggest that alpha 1 receptor stimulation plays a permissive role in the supersensitivity of D2 receptors following chronic treatment with imipramine.

Adrenergic alpha-Antagonists↗
PubMed1986

Binding of yohimbine and imipramine to platelets in depressive illness.

Radioligand binding to intact platelets was carried out in antidepressant-free patients and the 1 mg dexamethasone suppression test (DST) was performed. There were no differences in binding characteristics between patients and controls for either [3H]yohimbine or [3H]imipramine. There were no differences in binding between patients classified as endogenous using the Newcastle Scale, compared with non-endogenous patients, and no difference between DST suppressors and non-suppressors. The severity of depression did not affect binding values. After 4-6 weeks antidepressant treatment [3H]yohimbine binding was significantly reduced but [3H]imipramine binding was unaffected.

Adult↗
PubMed1982

Pre-treatment neurotransmitter metabolites and response to imipramine or amitriptyline treatment.

Preliminary data are presented from the NIMH Collaborative Study on the psychobiology of depression, biological studies, dealing with relationships between the pre-treatment levels of the neurotransmitter metabolites 3-methoxy-4-hydrophenethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and the subsequent therapeutic response of depressed patients to imipramine or amitriptyline. Eighty-seven depressed patients were studied during pre-treatment and treatment periods. It has been found that (1) both low pre-treatment urinary MHPG and low CSF 5-HIAA values are associated with a response to imipramine; these relationships were not artefacts due to sex or age; (2) there were no significant relationships between pre-treatment urinary MHPG, CSF MHPG, 5-HIAA, or HVA values and the subsequent response, or failure of response, to amitriptyline; (3) there was not a bimodal distribution for CSF 5-HIAA. For both males and females, there were positive and statistically significant correlations between CSF MHPG and urinary MHPG; for the females, there were positive and significant correlations between both urinary and CSF MHPG and CSF 5-HIAA. The theoretical and practical implications of these findings are discussed.

Amitriptyline↗
PubMed2004

Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram.

The effect of antidepressants is the culmination of a series of molecular actions occurring in the brain. These events are thought to lead to changes in the expression level of numerous, but as yet unknown genes that result in different cellular functions. In our present study we addressed this issue by establishing gene expression profiles of the rat brain after treatment with imipramine and citalopram at therapeutic doses. After 96 h and 4 wk, fronto-temporal cortices from controls and each treated strain were prepared and total RNA was isolated, and assessed using a cDNA microarray system containing 3200 clones. The expression of 6 genes was decreased and 8 were over-expressed by imipramine, whereas 27 were repressed and 7 were up-regulated by citalopram. Members of signal transduction (e.g. phosphatidylinositol transfer protein), structural elements (e.g. tubulin, fibronectin), factors related to protein metabolism in general (e.g. proteasomal subunits, ubiquitin-like proteins, polyadenylation sites), components involved in cell survival (e.g. midkine, stress-inducible protein), and determinants of membrane conductance and ion transport (e.g. vacuolar H+-ATPase), and basics of nuclear functions (e.g. translin, basal transcription factor 3), were some of the genes with altered expression. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signalling, survival and protein metabolism. Our results demonstrate for the first time that antidepressants specifically regulate neuronal plasticity through induction of a highly specific transcriptional programme in brain cells.

Animals↗
PubMed1979

Electrochemical oxidation of hydroxylated phenothiazine and imipramine derivatives.

The electrochemical oxidations of several hydroxylated derivatives of promazine, chlorpromazine, imipramine, and 3-chloroimipramine are examined and compared. Oxidation of the monohydroxyphenothiazine derivatives leads to both dihydroxy species and substituted benzoquinones, while oxidation of hydroxylated imipramines leads to only the corresponding benzoquinones. The oxidation potentials of 17 tricyclic psychoactive drugs and metabolites are tabulated and compared. The potential importance of these results to drug activity and side effects is discussed.

Electrochemistry↗
PubMed2000

Treatment of late-onset nonketotic hyperglycinaemia: effectiveness of imipramine and benzoate.

We report a patient with late-onset nonketotic hyperglycinaemia managed with a sequential approach to drug therapy in placebo-controlled therapeutic trials. Partial response to low-protein diet and sodium benzoate and dramatic response to imipramine are demonstrated, with parental scores on the Developmental Behavioural Checklist falling from the 86th centile before treatment to normal with combined benzoate and imipramine therapy.

Benzoates↗
PubMed2002

Effect of chronic administration of imipramine on 2A-serotonin receptor mRNA in brain cortex of rats predisposed and resistant to catalepsy.

Rats selected by predisposition to catalepsy showed decreased level of 2A-serotonin receptor mRNA in the frontal cortex in comparison with Wistar rats (p<0.05). Chronic administration of tricyclic antidepressant imipramine hydrochloride 2-fold increased the content of receptor mRNA in genetically cataleptic rats (p<0.001) and did not change this parameter in Wistar rats. These results prompted us to revise current notion on the mechanisms of chronic effect of imipramine on 2A-serotonin receptors.

Animals↗
PubMed2001

Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial.

OBJECTIVE: To determine the relative efficacy, tolerability and risk of precipitating mania of moclobemide and imipramine in the treatment of bipolar depression. METHOD: A randomized, double-blind, parallel group, multicentre study of moclobemide (MCB) (450-750 mg daily) and imipramine (IMI) (150-250 mg daily) in 21 centres in nine countries; 156 patients (65 males, 91 females) aged 18-65 with bipolar depression (17-item Hamilton Depression Rating Scale (HAMD) score chi16) participated. Clinical status was assessed using standardized rating scales before treatment and at 1,2,3,4,6 and 8 weeks. The data were analysed on an intention to treat basis with the last observation carried forward. RESULTS: In the MCB group, the mean HAMD fell from 23.0 to 13.1, in the IMI group it fell from 22.5 to 9.5; the mean score on the Montgomery-Asberg Depression Rating Scale (MADRS) fell from 29.5 to 16.3 on MCB and from 29.2 to 11.6 on IMI. There were no statistically significant differences between the two groups on any efficacy measures. Anticholinergic side-effects were three times more common with IMI than MCB and weight gain was also greater on IMI. Two patients (3.7%) on MCB and six patients (11%) on IMI were withdrawn because of manic symptoms, with manic symptoms occurring earlier on IMI, although these differences did not reach statistical significance. CONCLUSION: No differences in efficacy were detected between MCB and IMI in the treatment of bipolar depression. The data suggests that MCB is less likely than IMI to precipitate mania.

Adolescent↗
PubMed1983

Imipramine serum protein binding in healthy subjects.

Imipramine serum protein binding was measured by equilibrium dialysis in healthy subjects (88 women and 57 men; age 21 to 79 yr) who were relatively evenly distributed according to age, sex, smoking habits, and oral contraceptive use. Average free fraction was 10.9 +/- 1.4%. Interindividual variation in degree of binding was less than 100%, the free fraction varying from 8% to 14.7%. Women age 30 to 39 yr had significantly lower binding than all other female age groups and lower binding than men age 30 to 39 yr. Oral contraceptive use and smoking habits did not correlate to degree of binding. Serum concentrations of 12 proteins were measured in subjects with the highest binding (n = 17) and lower binding (n = 18). The concentration of orosomucoid, complement C3c, and apolipoprotein B was higher in the high-binding group than in the low-binding group. Since covariation among concentrations of these three proteins was modest, the data indicate a separate significance of the three proteins. The binding of 3H-imipramine did not correlate with the albumin concentration.

Adult↗
PubMed1984

Cimetidine interaction with imipramine and nortriptyline.

The interaction between cimetidine and two tricyclic antidepressants was examined in healthy subjects. One tricyclic, imipramine, is primarily metabolized to a demethylated active metabolite, desipramine. The other, nortriptyline, is largely metabolized to a 10-hydroxylated metabolite. It was assumed that pretreatment with cimetidine, because of its inhibition of metabolic pathways of both demethylation and hydroxylation as well as its ability to reduce hepatic extraction of these drugs, would increase bioavailability and decrease clearance of both drugs. Such was the case with imipramine, but the bioavailability of nortriptyline was not increased. Further, the bioavailability of the 10-hydroxy metabolite of nortriptyline was increased rather than decreased. The degree of change in these kinetic variables varied widely between individuals. Thus it is not possible to predict which subjects might develop evidence of toxicity to tricyclics when cimetidine is added to the treatment program. The monitoring of tricyclic plasma concentrations is probably desirable in such circumstances.

Adult↗
PubMed1986

Increased urinary antidiuretic hormone excretion by imipramine.

Seven normal healthy individuals and ten depressive patients treated with imipramine (75 mg orally) were evaluated for their urinary ADH profile. It was observed that imipramine treated patients excreted higher amounts of urinary ADH (10.6 +/- 0.83 mU/hr) as compared to the control subjects (2.6 +/- 0.35 mU/hr) (P less than 0.01). Blood pressure in both groups was within the normal range.

Adult↗
PubMed1994

Efficacy of new generation antidepressants: meta-analysis of imipramine-controlled studies.

When assessing the efficacy of a new antidepressant in comparison with a standard treatment, most clinical trials have come to the conclusion that the nullhypothesis (equal efficacy) cannot be rejected, and have not been reformulated with respect to (at least) equivalent studies. However, it cannot be concluded from this that the compared treatments have the same (or similar) efficacy, because in many of the studies the statistical power is not sufficient. Using the effect-size formula described by Glass et al. (1981), a meta-analysis were performed combining the results of comparative trials of maprotiline, mianserin, viloxazine, trazodone, nomifensine, fluvoxamine, and fluoxetine, performed according to similar objectives and designs (similar patient selection, double-blind, randomized, etc.) and with imipramine as reference compound. Together with the results of a former meta-analysis of amitriptyline-controlled studies (Möller and Haug, 1988) the present investigation indicates differences in efficacy, which in the case of most of the new generation antidepressants is similar to the reference compounds imipramine and amitriptyline.

Adolescent↗
PubMed1988

Platelet 3H-imipramine binding and response to minaprine in patients with major depression.

Platelet 3H-imipramine binding was studied in 37 patients fulfilling Research Diagnostic Criteria for major depressive disorder, examined before and after four weeks of treatment with minaprine 200 mg/day, and in 19 healthy controls. Mean baseline Bmax values of depressed patients were found to be significantly lower than those of controls, while no significant difference between the two groups was observed with respect to mean Kd. Treatment with minaprine did not significantly affect Bmax or Kd in depressed patients. When patients who responded to treatment (n = 18) were compared with nonresponders (n = 19), mean baseline Bmax values were found to be significantly lower in the former group, whereas mean Kd values did not differ. It is hypothesized that reduced 3H-imipramine binding may represent a predictor of a favorable response to antidepressant drugs which potentiate serotonergic transmission.

Adult↗