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At least 1,513 records · Page 84Linked to original sources
PubMed1997

Rational design of selective ligands for trypanothione reductase from Trypanosoma cruzi. Structural effects on the inhibition by dibenzazepines based on imipramine.

Trypanothione reductase, the enzyme which in trypanosomal and leishmanial parasites catalyses the reduction of trypanothione disulphide to the redox-protective dithiol and has been identified as a potential target for rational antiparasite drug design, has been found to be strongly inhibited by tricyclic compounds containing the saturated dibenzazepine (imipramine) nucleus, with Ki values in the low micromolar range. This drug lead structure was designed by molecular graphics analysis of a three-dimensional homology model, focussing on the active-site. Inhibition studies were carried out to determine the effect of inhibitor structure on the inhibitory strength towards recombinant trypanothione reductase from Trypanosoma cruzi. Hansch analysis showed that inhibitory strength depended on terms in pi, pi 2 and sigma m indicating dependence on both lipophilicity and inductive effect for ring-substituted analogues of imipramine. The side-chain omega-aminoalkyl chain had to be longer than 2-carbon units for inhibition. The effect on inhibition strength of the substituent at the omega-amino position on the side-chain of the central ring nitrogen atom depended markedly on the detailed substitution pattern of the rest of the molecule. This provides kinetic evidence studies of multiple binding modes within a single, blanket binding site for the inhibitor with the tricyclic ring system in the general region of the hydrophobic pocket lined by Trp21, Tyr110, Met113 and Phe114. This aspect of the structural sensitivity of the precise active-site triangulation adopted by the inhibitor is probably a function of the use of hydrophobic interactions of low directional specificity in this pocket combined with an electrostatic anchoring by the omega-N+ HMe2 function of the inhibitor, presumably with a glutamate side-chain, such as Glu-18, Glu-466' and/or Glu-467'.

Animals↗
PubMed1998

Predictors of response to acute treatment of chronic and double depression with sertraline or imipramine.

BACKGROUND: The literature on predictors of response to treatment of nonchronic major depression has identified shorter duration of illness, acute onset, and less severity of illness as positive predictors. Unfortunately, there are almost no data on predictors of response to treatment for chronic depression. This study examined predictors of response to pharmacotherapy (sertraline or imipramine) in the treatment of outpatients who had DSM-III-R-defined chronic major or double depression. METHOD: The acute phase of the Chronic Major Depression and Double Depression Study is a double-blind, randomized, parallel-group 12-week comparison of sertraline and imipramine. Analyses are based on 623 patients who comprised the intent-to-treat sample, of whom 299 were nonresponders and 324 were responders, defined by a priori criteria as either remission or satisfactory therapeutic response. A stepwise logistic multiple regression analysis was performed on candidate clinical, psychosocial, and demographic variables previously identified as statistically significant in an attempt to develop a predictive model of positive antidepressant response. RESULTS: The sociodemographic variables that were predictive of positive response included living with spouse or partner or being at least a high school graduate. With regard to symptomatology and clinical history, responders had significantly lower baseline depression severity scores. In general, comorbid anxiety, substance abuse, and personality disorders did not influence rates of response. However, the presence of depressive personality traits was associated with a higher nonresponse rate. Among psychosocial variables, longer duration of personal relationships as well as higher baseline quality of life were associated with positive response. A stepwise logistic multiple regression identified 5 variables-living with spouse or partner, higher educational level, passive-aggressive personality, lower introverted-tense personality traits, and higher quality of life--that significantly and independently contributed to the predictive model. This model correctly classified 67% of patients. CONCLUSION: A higher baseline quality of life, living with spouse or partner, and having more education were the strongest predictors of response to acute pharmacotherapy among chronically depressed patients. Clinical variables and comorbidity were not identified as independent predictors, although personality traits did appear to influence treatment response. Overall, the predictive value of these baseline measures was modest, and therefore of limited clinical utility.

Adult↗
PubMed1999

The pharmacotherapy of depressive illness in adolescents: an open-label comparison of fluoxetine with imipramine-treated historical controls.

BACKGROUND: This open-label, 6-week clinical trial investigated the response to fluoxetine in medication-naive adolescents hospitalized for treatment of major depression. METHOD: A total of 52 consecutively admitted patients (mean age = 15.7 years) fulfilling Research Diagnostic Criteria for unipolar, nonpsychotic major depression received fluoxetine monotherapy (mean dose = 33.2 mg/day) in conjunction with psychosocial therapies. Outcome was assessed weekly using the Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions Scale (CGI). Response in this cohort was compared with that observed in 28 historical controls treated with imipramine (mean dose = 217 mg/day) who were consecutively admitted patients to this same facility and assessed in an identical, standardized, open-label protocol. RESULTS: HAM-D scores decreased by a mean of 13.2 in the fluoxetine group compared with 10.2 in the group receiving imipramine (p<.002). The mean percentage decreases in HAM-D scores in the 2 groups were 54.3% and 41.4%, respectively (p<.003). The percentages of patients classified as responders based on a final CGI score of 2 or less were 48.1% and 17.9%, respectively (p = .009). Medications were generally well tolerated with only 5 patients failing to complete the full 6 weeks of their original treatment. CONCLUSION: In spite of the uncontrolled nature of these data, the findings add to recent evidence suggesting more favorable response to selective serotonin reuptake inhibitors than tricyclics in adolescents with depressive illness.

Adolescent↗
PubMed2003

Chronic depression and comorbid personality disorders: response to sertraline versus imipramine.

BACKGROUND: Chronic subtypes of depression appear to be associated with high rates of Axis II personality disorder comorbidity. Few studies, though, have systematically examined the clinical correlates of Axis II personality disorder comorbidity or its effect on treatment response or time to response. METHOD: 635 patients diagnosed with DSM-III-R chronic major depression or "double depression" (dysthymia with concurrent major depression) were randomized to 12 weeks of double-blind treatment with either sertraline or imipramine between February 1993 and December 1994. Axis II diagnoses were made using the personality disorders version of the DSM-III-R Structured Clinical Interview. The effect of study treatment was measured utilizing the Hamilton Rating Scale for Depression and the Clinical Global Impressions scale. RESULTS: Forty-six percent of patients met criteria for at least 1 comorbid Axis II personality disorder, with cluster C diagnoses being the most frequent at 39%; 21% met criteria for at least 2 Axis II personality disorders. A cluster C diagnosis was associated with significantly higher rates of early-onset depression (before age 21; 47% vs. 32% for no cluster C; p =.005) and comorbid anxiety disorder (34% vs. 18% for no cluster C; p <.001). Overall, the presence of Axis II personality disorder comorbidity had minimal-to-no effect on the ability to achieve either an antidepressant response or remission and had inconsistent effects on time to response. The presence of Axis II personality disorder comorbidity did not appear to reduce functional and quality-of-life improvements among patients responding to acute treatment with sertraline or imipramine. CONCLUSION: In this treatment sample, rates of Axis II personality disorder comorbidity were substantial in patients suffering from chronic forms of depression. Axis II personality disorder comorbidity did not appear to diminish symptomatic response to acute treatment or associated improvement in functioning and quality of life.

Adult↗
PubMed1999

Catalysis of drug oxidation during embryogenesis in human hepatic tissues using imipramine as a model substrate.

We investigated the catalysis of drug monooxygenation by human embryonic hepatic tissues at a very early stage of gestation (days 52-59). Imipramine was used as a model substrate and the metabolites generated were identified and quantified by electrospray mass spectroscopy and HPLC. The primary metabolite generated was desipramine. It was reported previously from this and other laboratories that cytochrome P-450 monooxygenase (CYP) 1A1, 1B1, 2E1, and 3A7 are each expressed in human embryonic hepatic tissues, and selective inhibitors were therefore used to elucidate their respective roles. Furafylline did not inhibit the reaction, supporting that CYP1A2 was not expressed in human embryonic hepatic tissues. Diethyldithiocarbamate also failed to inhibit the same reaction, suggesting that CYP2E1 did not play a significant role in catalyzing the reaction. Triacetyloleandomycin inhibited the reaction by approximately 90%, suggesting that CYP3A7 was primarily responsible for catalyzing the reaction. However, alpha-naphthoflavone inhibited the same reaction by approximately 70%, suggesting that CYP1A1 and/or CYP1B1 may also catalyze the reaction substantially. To explore this issue more, a cDNA-expressed human CYP3A7 (CYP3A7 SUPERSOMES) was incubated with alpha-naphthoflavone (1 microM). Generation of desipramine was inhibited by approximately 40 to 50%. The addition of the CYP3A subfamily selective inhibitor triacetyloleandomycin (1 microM) produced no statistically significant inhibition in reactions catalyzed by CYP1A1 or 1B1 SUPERSOMES. Taken together, the results indicated that CYP3A7 was the major if not sole isoform responsible for catalysis of the N-demethylation of imipramine in human hepatic tissues during embryogenesis.

Catalysis↗
PubMed1999

Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in shock-induced depression.

In the past few years, literature has accumulated describing manifestation of seizures following administration of certain antidepressants. Such reports are of particular importance because depression is a frequent psychiatric problem associated with epilepsy. Therefore, in the view of the fact that NMDA receptor antagonists have been reported to reduce behavioural deficits and have been shown to be anticonvulsant, it was considered imperative to study their antidepressant effect using shock-induced depression model in mice. Presentation of inescapable foot shock significantly reduced ambulation and rearing in the open field arena and increased immobility duration in the FST. Pretreatment with imipramine, MK 801 and ketamine significantly prevented the effect of shock. Also, the combination of imipramine with either of the NMDA antagonists antagonised the effect of shock. Haloperidol, prazosin and ketanserin pretreatment modified the effect of these agents. These findings suggest an antidepressant effect of the NMDA receptor antagonists, and a complexity of neurotransmitter mechanisms, which are responsible for the occurrence of behavioural effects in shock-induced depression model.

Animals↗
PubMed2000

Combined treatment with venlafaxine and tricyclic antidepressants in depressed patients who had partial response to clomipramine or imipramine: initial findings.

BACKGROUND: We report, after 3 years of work, a case series showing our initial results (efficacy, tolerability, and safety) with the addition of venlafaxine immediate release (IR) to either clomipramine or imipramine in depressed patients who had shown only partial response to maximal doses of one of those tricyclic antidepressants (TCAs) and no further improvement after addition of usual augmentation drugs. METHOD: Eleven patients were treated, 10 of them having a recurrent depressive disorder (DSM-IV) and all of them having current major depression (DSM-IV) that in 9 patients was moderate or severe despite intense TCA treatment as well as usual augmentations. Under open and outpatient conditions, we maintained TCA doses, discontinued previous augmentations, and then added venlafaxine IR to a maximum dosage, if necessary, of 150 mg every 12 hours. There was no control group. Response was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D), DSM-IV criteria, the Clinical Global Impressions-Severity of Illness scale, and persistence of improvements after 6 months. We measured clinical tolerance (using the UKU Side Effect Rating Scale), blood pressure and heart rate, electrocardiogram (ECG), and blood TCA levels after adding venlafaxine IR. RESULTS: A sustained improvement (> 50% decrease in HAM-D score plus decrease in DSM-IV severity level) appeared in 9 patients, and sustained full remission (DSM-IV criteria plus HAM-D score < 5) in 7. Panic-agoraphobic symptoms improved in the 2 patients suffering from them. There were no dropouts, and tolerability was good. No significant changes in blood pressure and heart rate, ECG, or blood tricyclic levels were found. CONCLUSION: Addition of venlafaxine to clomipramine or imipramine could be an effective and safe augmentation strategy in depressive patients with partial response to maximum-dose monotherapy. A consistent replication of these initial findings is strongly needed.

Adult↗
PubMed1975

[Controlled double-blind study (SAMe-imipramine) in depressive syndromes].

Thirty one patients were treated with either S-Adenosylmethionine or Imipramine in a double-blind clinical trial comparing S-Adenosylmethionine (25 mg i.m. three times daily) with Imipramine (25 mg i.m. three times daily) administered for a period of three weeks. Hamilton Rating scores showed no significant differences between treatments, but such slight differences as were observed favoured S-Adenosylmethionine.

Administration, Oral↗
PubMed2001

[A case of potassium-sensitive periodic paralysis with cardiac dysrhythmia controlled with imipramine and acetazolamide].

We report a patient with potassium-sensitive periodic paralysis with cardiac dysrhythmia. The patient was a 16-year-old man. He presented with asymptomatic ventricular dysrhythmia and periodic paralysis when he was 6 and 12 years old, respectively. Physical examination revealed slight dysmorphic features such as hypoplastic mandible, low-set ears and clinodactyly. Through an exercise test, a potassium tolerance test and a muscle biopsy, his illness was diagnosed as potassium-sensitive periodic paralysis with cardiac dysrhythmia. For the treatment of his episodic paralysis, we started acetazolamide, which improved both the incidence and the severity of paralysis. However, the incidence of cardiac dysrhythmia was increased after the use of acetazolamide. Routine anti-arrhythmic drugs such as lidocaine failed to control his ventricular dysrhythmia. Only imipramine showed its efficacy by improving the degree and the incidence of cardiac dysrhythmia without aggravating periodic paralysis. This syndrome is relatively rare and there have been no standard protocols for the treatment. We propose the combination of acetazolamide and imipramine as the first choice for this clinical entity. We also discussed the efficacy of the exercise test. It enabled us to confirm the diagnosis of periodic paralysis safely and easily by recording the change of compound muscle action potential amplitudes.

Acetazolamide↗
PubMed1975

Imipramine-induced heart block. A longitudinal case study.

A 2:1 atrioventricular block developed during treatment with the tricyclic antidepressant imipramine in a 74-year-old man with a three-year history of right bundle-branch block. Serial cardiographic studies and determinations of blood imipramine concentrations showed that the heart block was directly related to the plasma concentration of the drug and occurred below the atrioventricular node in the His-Purkinje system.

Administration, Oral↗
PubMedDate not supplied

Repeated imipramine administration enhances the effects of NMDA receptor ligands on synchronous activity in rat frontal cortex in vitro.

This study assessed the effects of repeated administration (14 days) of imipramine on the function of NMDA receptors by measuring the frequency of spontaneous epileptiform discharges which develop in rat frontal cortical slices incubated in Mg2+-free conditions. Imipramine significantly enhanced both the excitatory effect of NMDA and the inhibitory effect of the competitive NMDA receptor antagonist CGP 37849 on the frequency of discharges. These results are consistent with studies indicating that chronic administration of antidepressant drugs induces adaptive changes in NMDA receptor/ channel complex in the cerebral cortex.

2-Amino-5-phosphonovalerate↗
PubMed1975

[Intracellular mechanism of the action of imipramine and diazepam].

The content of noradrenaline during the action of antidepressant imipramine and a tranquilizer diazepam was determined in rats by differential centrifugation of the hypothalamus tissues. Imipramine was found to decrease the noradrenaline content in synaptosomes, whereas diazepam failed to evoke any similar effects. Thus, in the action mechanism of the first substance the adrenergic compound was of definite importance, while in the mechanism of the second one it took no part.

Animals↗
PubMedDate not supplied

Effect of joint administration of imipramine and amantadine on binding of [3H]7-OH-DPAT to dopamine D3 receptors in peripheral blood lymphocytes of the patients with drug-resistant unipolar depression.

Treatment of the patients suffering from therapy-resistant unipolar depression with joint administration of imipramine (twice daily, 100-150 mg/day) and amantadine (twice daily, 150 mg/day) for four to six weeks resulted in the significant increase in the binding of [3H]7-OH-DPAT to dopamine D3 receptors in the peripheral blood lymphocytes. This effect correlated well with the clinical improvement, estimated with Hamilton's Depression Rating Scale. In the light of the above data, it seems justified to postulate that joint therapy with imipramine and amantadine may be successful in the treatment-resistant unipolar depression.

Adult↗
PubMed1992

Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome.

The density of serotonin reuptake receptors on peripheral platelets from 22 patients with primary fibromyalgia syndrome (FS) and the serum serotonin concentrations in 9 patients with FS were compared with those of matched healthy controls. The mean serum serotonin concentration was lower (p = 0.01) in FS than in controls, while the binding of 3H-imipramine was higher (p = 0.035) and normalized with treatment using a combination of ibuprofen and alprazolam. Improvement in selected clinical measures of FS disease activity during treatment correlated with the change in platelet 3H-imipramine binding. These findings support the proposed hypothesis of aberrant pain perception in FS resulting from a deficiency of serotonin.

Blood Platelets↗
PubMed1992

[Experimental model of depression: neurochemical changes and the effects of imipramine and citalopram].

A study was made of the influence of the antidepressants imipramine and citalopram (10 mg/kg, chronic administration, i.p.) on the depression-like condition in submissive male rats. The above condition developed under the effect of chronic emotional stress because of successive experience of defeat in social confrontations (Kudryavtseva, Bakshtanovskaya, 1988). Imipramine rather than citalopram exerted a remarkable antidepressive effect recorded by the Porsolt's test. Measurements of the content of serotonin, dopamine and noradrenaline in brain structures have demonstrated changes in the serotoninergic and catecholaminergic systems in males with the depressive symptomatology in relation to intact animals. It should be mentioned that at different stages of pathological process formation, the role of certain structures and mediator systems underwent definite changes.

Animals↗
PubMed1992

[Treatment of patients with panic disorder and an elevated urinary excretion of MHPG using imipramine or clonazepam].

The response to treatment with imipramine or clonazepam was evaluated in patients with panic disorder. These patients had a high urinary 3-methoxy-4-hydroxy-phenylglycol 24 h-excretion and normal plasma lactate levels. Both drugs were efficient as anti-panic agents, but clonazepam resulted more efficacious than imipramine by the scores of Hamilton Anxiety or Depression Scales. Moreover, clonazepam also reduced the anticipatory anxiety.

Adult↗