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PubMed1995

Chronic imipramine, L-sulpiride and mianserin decrease corticotropin releasing factor levels in the rat brain.

Among clinically effective antidepressant drugs, the action mechanism of mianserin has recently been related to variations in corticotropin releasing factor (CRF) levels in the rat locus coeruleus. We describe a specific effect on CRF levels after chronic treatment with different antidepressants: mianserin (10 mg/kg), imipramine (20 mg/kg), both for 21 days, or L-sulpiride (1 mg/kg) for 15 days. While all antidepressants used greatly decreased CRF concentrations in the hypothalamus, only mianserin decreased CRF concentrations by 40% in extrahypothalamic sites. Acute treatments failed to modify CRF levels. Chronic treatment with mianserin did not affect CRF density either in the hypothalamus or the extrahypothalamic areas. This new finding may add another facet to the therapeutic action of certain antidepressants and in particular to the atypical profile of mianserin.

Animals↗
PubMed1989

[3H]imipramine binding in idiopathic pain syndromes. Basal values and changes after treatment with antidepressants.

The binding affinity (Bmax, Kd) of [3H]imipramine to platelet membranes was investigated in 43 patients with a diagnosis of idiopathic pain syndrome. Measurements were carried out prior to and after 6 weeks' treatment with the antidepressants clomipramine or maprotiline (randomized double-blind trial). Before treatment the Bmax was 11% lower (1109 +/- 237 fmol/mg protein) compared to historical control subjects (n = 21, 1240 +/- 390) and comparable to patients with psychogenic pain with affective symptoms (n = 62, 1110 +/- 360) previously measured at the same laboratory. The Kd was 0.5 +/- 0.3 nM comparable to the Kd of the controls (0.6 +/- 0.2). After 6 weeks of treatment the clomipramine group (n = 11) had significantly lower Bmax = 208.5 +/- 286 (P less than 0.001). In the maprotiline-treated patients (n = 18) the Bmax values (1221 +/- 258) tended to increase towards the values of the controls but without statistical significance. No significant statistical correlation was found between initial Bmax values and clinical outcome.

Antidepressive Agents↗
PubMed1992

Effects of atropine, pirenzepine, imipramine and phenothiazines on the mammalian neuromuscular junction.

1. Trifluoperazine (EC50 = 11.5 nM), chlorpromazine (13.8 microM), imipramine (15 microM), atropine (75.8 microM), and pirenzepine (316.2 microM), all produced neuromuscular facilitation and antagonized the blockade produced by oxotremorine (20 and 30 microM) in the rat isolated diaphragm. 2. These antagonists did not change the responses of curarized diaphragms to direct stimulation, or the twitch tension produced by retrograde injection of acetylcholine. 3. Trifluoperazine (2.5 ng, intra-arterially) reduced the tetanic fade produced by further intra-arterial injection of d-tubocurarine (10 micrograms/kg) in the in situ cat tibial muscle. 4. These results indicate that these antagonists may interact with muscarinic autoreceptors to increase acetylcholine output in the neuromuscular junction.

Acetylcholine↗
PubMedDate not supplied

A double-blind, placebo-controlled study of the effect of imipramine on TRH-induced urinary urgency in healthy men.

We studied the effect of imipramine (IMI) on thyroid releasing hormone (TRH)-induced urinary urgency as a way of investigating the mechanism of the beneficial effect of IMI on enuresis. In a double-blind study, 12 normal, healthy men between 21 and 39 yr of age ranked their urge to urinate at 30-sec intervals following IV injection of TRH (500 micrograms) or saline. The subjects then were randomly assigned to either IMI (1 mg/kg) or placebo groups for 10 days, and the procedure was repeated. Compared to saline, TRH produced a significant elevation in urinary urgency in all subjects. IMI did not significantly blunt TRH-induced urinary urgency. Thus, the mechanism by which IMI affects enuresis is likely not mediated at the level of the urinary urgency induced by TRH.

Adult↗
PubMed1993

Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability.

A metabolism study of imipramine (IMI) has been conducted in vitro with commercially available human CYP2D6 isozyme expressed in a human AHH-1 TK +/- cell line. This enzyme system catalyzed the anticipated ring-oxidative biotransformation of IMI to 2-hydroxyimipramine (2-OH-IMI). In addition, however, the human CYP2D6 isozyme preparation was found to be unequivocally involved in the N-dealkylation of IMI to desmethylimipramine (DMI). 2-Hydroxydesipramine was also identified as a trace metabolite of IMI, but no 10-hydroxyimipramine was detected. The 2-OH-IMI metabolite was unstable and disappeared from metabolic solutions on standing. A procedure involving the O-acetylation of 2-OH-IMI was developed to minimize this decomposition. When an authentic sample of 10-OH-IMI was subjected to the same acetylation procedure, it was partially dehydrated to 10,11-dehydroimipramine, but also underwent unexpected degradations to two other products in which the dimethylaminopropyl side-chain was deaminated. Plausible structures for these two decomposition products are suggested from their gas chromatographic-mass spectrometric behaviour.

Acetylation↗
PubMed1993

High-performance liquid chromatography of imipramine and six metabolites in human plasma and urine.

A method for the simultaneous quantitation of imipramine and six metabolites (2- and 10-hydroxyimipramine, 2- and 10-hydroxydesipramine, didesmethylimipramine and desipramine) in human plasma and urine has been developed. The method is based on a three-step liquid-liquid extraction followed by isocratic, reversed-phase high-performance liquid chromatography with ultraviolet absorbance detection (detection wavelength: 220 nm). The chromatographic eluent consisted of 30% acetonitrile and 70% aqueous sodium perchlorate solution pH 2.5. Glucuronide conjugates in urine were deconjugated with beta-glucuronidase/arylsulphatase prior to extraction.

Arylsulfatases↗
PubMed1995

Rapid microsample analysis of imipramine and desipramine by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A rapid and highly sensitive HPLC assay method was developed to measure small amounts of imipramine and its major metabolite, desipramine. The assay involved simple extraction procedures using clomipramine as the internal standard. The mobile phase consisted of acetonitrile (60%) and 0.01 M triethylamine in distilled water (40%) with the pH adjusted to 3.0. Separations were achieved on a C18 column and the effluent measured for UV absorption at 260 nm. The chromatographic separation was excellent, with no interference from endogenous serum constituents. This assay was suitable for measuring drug concentrations in the range of 10-1000 ng/ml using a 0.1-ml serum sample. The method was applied to a drug disposition study in transgenic mice with increased plasma alpha 1-acid glycoprotein.

Animals↗
PubMed1995

High-performance liquid chromatographic method for the analysis of imipramine metabolism in vitro by liver and brain microsomes.

A new sensitive method for resolution and quantitation metabolites of in vitro imipramine metabolism has been developed for use in liver and brain microsomes. Separation of metabolites was done using a Supelcosil PCN column with a mobile phase of acetonitrile-methanol-potassium phosphate dibasic (40:35:25, v/v/v), pH 7. Resolution is achieved for 2- and 10-hydroxyimipramine, and desipramine. Varying levels of these metabolites formed during in vitro incubations of rat liver and brain microsomes following treatments.

Animals↗
PubMed1994

Imipramine-provoked paradoxical pheochromocytoma crisis: a case of cardiogenic shock.

The dramatic presentation of pheochromocytoma in crisis is uncommon and is classically associated with a state of hemodynamic and sympathetic hyperactivity. The case of a 35-year-old man with an occult pheochromocytoma presenting with hypotension and cardiogenic shock shortly after beginning imipramine therapy is presented. Retrospectively, there was a history of emergency department, inpatient, and outpatient evaluation of symptoms likely to be related to an occult pheochromocytoma. He presented with hypotension refractory to fluids and inotropes and in severe respiratory distress. The early differential diagnosis was extensive including acute myocardial infarction, pneumonia with sepsis, and toxic ingestion. Shortly after admission the patient's occult pheochromocytoma was discovered and subsequently specific therapy was initiated. The patient's symptoms resolved after surgical resection of the tumor, and he was ultimately discharged without signs of congestive heart failure. The clinical pathophysiology of cardiomyopathy secondary to pheochromocytoma, and possible mechanisms of pharmacological interactions with tricyclic antidepressants are discussed.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

Steady-state serum concentrations of imipramine, its main metabolites and clinical response in primary enuresis.

Thirty-seven children (6-13 years old), receiving a flexible dosage of imipramine (IMI) for nocturnal enuresis, were evaluated. After a mean time of 8.5 +/- 7.0 weeks of therapy, 40.5% no longer wet the bed; 32.4% had a mean benefit of 80%; 27.01% had a negligible response. The best relationship observed was between clinical effect and drug serum concentrations rather than with drug daily dose, the most satisfactory being that with IMI seric values (P = 0.019). Responders (effect higher than 50%) had higher IMI serum concentrations (P less than 0.05) than poor responders. At 3 and 6 months after stopping the drug, over 90% of the responders maintained the maximum response reached during treatment. The side-effects observed were irritability, reduction of appetite, headache, a mild increase of blood pressure.

Adolescent↗
PubMed2005

Subchronic treatment with imipramine ameliorates the decreased number in neuropeptide Y-positive cells in the hippocampus of learned helplessness rats.

Learned helplessness, but not immobilization stress, decreased the numbers of neuropeptide Y (NPY)-positive cells (interneuron), but not calcitonin gene-related peptide (CGRP)-positive cells (mossy cell), in the hilus of the hippocampus. Subchronic treatment of learned helplessness rats, but not naive rats, with imipramine ameliorated the decrease in the number of NPY-positive cells. Therefore, NPY-positive cells in the hippocampus may contribute to depression.

Animals↗
PubMed2006

Chronic valproate fails to prevent imipramine-induced behavioural sensitization to the dopamine D2-like receptor agonist quinpirole.

Based on experimental evidence suggesting a relationship between dopamine and mania, we proposed the antidepressant-induced dopaminergic supersensitivity as a model of antidepressant-related mania. We have previously shown the ability of carbamazepine, but not lithium, to prevent this phenomenon. Here we show that sodium valproate (50 mg/kg/day for 3 weeks) fails to prevent imipramine (20 mg/kg/day for 3 weeks)-induced sensitization to the locomotor response to the dopamine D2-like receptor agonist quinpirole (0.15 mg/kg). Since lithium, carbamazepine and valproate are all considered poorly effective in the treatment of antidepressant-related mania, the validity of the proposed model should be disproved by the carbamazepine results, to which, however, a pharmacokinetic mechanism might have concurred.

Analysis of Variance↗
PubMed2004

Interaction of electrically neutral and cationic forms of imipramine with liposome and erythrocyte membranes.

Imipramine (IP) is an amphiphilic amine that is clinically useful as a tricyclic antidepressant. In the present work, we have investigated the pH effects on (a) the micellization properties of IP, (b) IP-induced release of aqueous contents from artificial vesicles (liposomes), and (c) IP-induced haemolysis, under hypotonic and isotonic conditions, in the pH range 5.0-10.0. Our data show that IP-membrane interaction caused important membrane destabilisation. However, changes in pH modified strongly the effects of IP. We suggest that the parameters of IP-induced model and cell membrane lysis are sensitive to the changes in the charge of this amphiphile. IP interacts more strongly with the membrane at basic pH (smaller net charge) than at neutral or acidic pH. A simple interpretation of these data is that increasing pH causes a decrease in IP net charge, thus a decrease in the critical micellar concentration of IP, and an increased partition into the lipid bilayer. Concomitantly, pH variations both above and below 7 tend to destabilise the cell membrane, so that the protective effect of IP against hypotonic haemolysis has a maximum at neutral pH.

Animals↗
PubMed2005

Application of two chemometric methods for the determination of imipramine, amitriptyline and perphenazine in content uniformity and drug dissolution studies.

Double-divisor spectra derivative and partial least squares methods were developed for content uniformity and dissolution tests in binary or ternary mixtures. The simultaneous determinations of perphenazine (PER) combined with amitriptyline hydrochloride (AMI) and/or imipramine hydrochloride (IMI) have been accomplished using the information of the absorption spectra of appropriate solutions. The double-divisor method is based on the use of the first derivative of the ratio spectrum obtained by dividing the absorption spectrum of the ternary mixture PER-AMI-IMI by a standard spectrum resulted from the addition of two of the three analytes in equal concentrations. The concentration of each component is then determined from their respective calibration graphs established by measuring the ratio derivative analytical signal at a specific wavelength. In this method, the linear determination ranges were of 3.65-18.24 microg/mL for PER, 4.32-21.60 microg/mL for AMI, and 4.83-24.19 microg/mL for IMI. The results were compared with those obtained by partial least squares multivariate calibration (PLS) method pre-treated by a wavelet compression-orthogonal signal correction (W-OSC) filter in zero-order derivative spectra. The calibration model was evaluated by internal validation (cross-validation) and by external validation over synthetic mixtures, content uniformity and dissolution tests. According to the dissolution profile test more than 95% of the three substances were dissolved within 10 min. The results from both techniques were statistically compared with each other and can be satisfactorily used for quantitative analysis and dissolution tests of multicomponent tablets.

Amitriptyline↗
PubMed2003

Interactions of acute morphine with chronic imipramine and fluvoxamine treatment on the antinociceptive effect in arthritic rats.

This study was undertaken to investigate the effects induced by chronic systemic administration of two different antidepressants: imipramine (IMI), a dual serotonin-noradrenaline reuptake inhibitor, and fluvoxamine (FVX), a selective serotonin reuptake inhibitor, on the antinociceptive effect of morphine (MOR) in a paw pressure test in adjuvant-induced arthritic rats. For 30 days rats were administered with IMI, FVX or saline (SAL). On days 15 and 30, animals were tested in the paw pressure test 20 min after MOR or SAL administration. MOR induced a significant antinociceptive effect in IMI, FVX and SAL treated rats. But, at 30 days, this increase in pain threshold was significatively higher in IMI than SAL rats. This increase was not seen in FVX rats. These results suggest that a combination of opioid and mixed monoaminergic activities is effective in enhancing the antinociceptive effect of MOR in arthritic rats while only opioid and serotonergic activities have no enhancer effect.

Analgesics↗
PubMed2005

Enhancement of antidepressant-like activity by joint administration of imipramine and magnesium in the forced swim test: Behavioral and pharmacokinetic studies in mice.

The effect of joint administration of imipramine (IMI) and magnesium (Mg) on antidepressant-like activity was studied in mice using forced swim test (FST). Mg doses ineffective per se (5 and 10 mg/kg) given jointly with IMI also at ineffective doses (10 and 15 mg/kg) resulted in a potent reduction in the immobility time. Since these combined treatments did not influence locomotor activity, the antidepressant-like activity was not due to non-specific behavioral activation. Moreover, we estimated the effect of joint administration of magnesium and IMI in FST on serum and brain magnesium, IMI and its active metabolite desipramine (DMI) concentrations in mice. Swim stress (mice subjected to FST) increased the magnesium concentration in serum and decreased it in the brain compared to naive animals. Moreover administration of IMI increased (normalized) magnesium brain concentration, without influence on the serum level. Joint administration of IMI and magnesium did not influence magnesium (compared with FST) or IMI and DMI (compared with IMI treatment alone) concentrations in both examined tissues. The present data demonstrated an enhancement of the antidepressant-like effect by joint administration of IMI and magnesium in the FST, and further indicate the particular role of magnesium in the antidepressant action. Since there was no increase in IMI, DMI or magnesium concentration after joint administration of magnesium and IMI, the data suggest that pharmacodynamic rather than pharmacokinetic interaction between magnesium and IMI is accountable for behavioral effect in the FST.

Animals↗
PubMed2005

Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s.

The drug-toxicant interaction between the antidepressant imipramine (IMI) and three organophosphorothionate pesticides (OPTs), to which humans may be chronically and simultaneously exposed, has been investigated in vitro. Concentrations of IMI (2-400 microM) and OPTs (< or =10 microM) representative of actual human exposure have been tested with recombinant human CYPs and human liver microsomes (HLM). The different CYPs involved in IMI demethylation to the pharmacologically active metabolite desipramine (DES) were CYP2C19 > CYP1A2 > CYP3A4. The OPTs significantly inhibited (up to >80%) IMI bioactivation catalyzed by the recombinant CYPs tested, except CYP2D6, and by HLM; the inhibition was dose-dependent and started at low pesticide concentrations (0.25-2.5 microM). The OPTs, having lower K(m) values, efficiently competed with IMI for the enzyme active site, as in the case of CYP2C19. However, with CYP1A2 and CYP3A4, a time- and NADPH-dependent mechanism-based inactivation also occurred, consistently with irreversible inhibition due to the release of the sulfur atom, binding to the active CYP during OPT desulfuration. At low IMI and OPT concentrations, lower IC50 values have been obtained with recombinant CYP1A2 (0.7-1.1 microM) or with HLM rich in 1A2-related activity (2-10.8 microM). The K(i) values (2-14 microM), independent on substrate concentrations, were quite low and similar for the three pesticides. Exposure to OPTs during IMI therapeutic treatments may lead to decreased DES formation, resulting in high plasma levels of the parent drug, eventual impairment of its pharmacological action and possible onset of adverse drug reactions (ADRs).

Biotransformation↗