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PubMed1995

Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta-analysis.

The etiology and optimum treatment of panic disorder remain unclear. Imipramine and alprazolam are reasonably well established treatments. Several reports have suggested that serotonin reuptake inhibitors may also be effective for this condition. To investigate this issue, 27 published or presented placebo-controlled, double-blind studies of DSM-III or DSM-III-R panic disorder were subjected to meta-analysis. The serotonin reuptake inhibitors included paroxetine, fluvoxamine, zimelidine, and clomipramine. The standard treatments were imipramine or alprazolam. All three treatments were highly significantly superior to placebo in alleviating panic. The serotonin reuptake inhibitors were also significantly superior to both imipramine and alprazolam. The superiority of the serotonin reuptake inhibitors remained, but was less pronounced, when they were compared to the studies which used higher doses of imipramine or alprazolam. These findings underscore the importance of serotonin reuptake inhibitors in the treatment of panic disorder and indirectly add to the evidence that serotonergic abnormalities may have a role in its etiology.

Alprazolam↗

PubMed1998

Disopyramide, imipramine, and amitriptyline bind to a common site on the transient outward K+ channel.

Previous work demonstrated that several antiarrhythmic agents and antidepressive drugs block transient outward K+ current (I(to)) in rat ventricular myocytes. The antiarrhythmic drug, disopyramide, and the tricyclic antidepressants, imipramine and amitriptyline, block the I(to) channel mainly when it is in the open state. The rate of recovery from block induced by disopyramide is so slow that the drug produces a use-dependent block at 1 Hz, whereas the rate of recovery from block in the presence of imipramine and amitriptyline is fast enough so as not to induce any use-dependent block at this frequency. We studied the effects of the combinations of disopyramide-imipramine and disopyramide-amitriptyline on I(to) to detect possible interactions between the drugs on I(to) blockade. The effects of imipramine and amitriptyline on the use-dependent effect induced by disopyramide and on the rate of recovery of the channels blocked by this drug allow us to conclude that there is only one common receptor site in the channel molecule for the three drug molecules.

Amitriptyline↗

PubMed1985

Imipramine poisoning in a child: lack of efficacy of resin hemoperfusion.

A three-year-old boy ingested up to 1,500 mg of the tricyclic antidepressant imipramine (Tofranil). He entered our facility within two hours of discovery, and multiple resuscitative efforts, which proved unsuccessful, followed. Resin hemoperfusion was used in an effort to remove imipramine from the systemic circulation. Serum concentrations of imipramine and its major metabolite desipramine were determined from serum drawn before, during, and after hemoperfusion. Serum concentrations of imipramine and desipramine did not change appreciably. No improvement in the clinical condition was noted during the hemoperfusion period, which was due in part to the fact that our patient was clinically brain dead upon arrival in our intensive care unit. Our subsequent literature review documents that this case represents the first reported use of hemoperfusion in a pediatric tricyclic antidepressant ingestion, hemoperfusion removes an insignificant portion of the total amount of tricyclic antidepressant ingested, and some pediatric literature misleadingly suggests that hemoperfusion may be useful in such patients. Physicians treating tricyclic antidepressant ingestion cases should avoid using hemoperfusion; standard supportive care remains the essential management response.

Child, Preschool↗

PubMed1989

Treatment of severe imipramine poisoning complicated by a negative history of drug ingestion.

The wide use of imipramine (Tofranil) for the treatment of nocturnal enuresis continues in spite of the unique dangers associated with this drug. Young children are particularly susceptible to the potentially lethal central nervous system and cardiovascular toxicities, yet the toxic potential of imipramine remains unrecognized by both parents and too many physicians. Management of severe imipramine intoxication can be difficult. This report describes a 12-month-old patient with severe imipramine intoxication whose treatment was complicated by a negative history at presentation.

Acute Disease↗

PubMed1993

Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects.

The effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine caused a significant prolongation of imipramine half-life (from 22.8 +/- 6.4 to 40.5 +/- 5.0 h, means +/- SD, p < 0.01) and a marked decrease in imipramine apparent oral clearance (from 1.02 +/- 0.19 to 0.28 +/- 0.06 L/h/kg, p < 0.0001). No significant changes in desipramine kinetics were observed during fluvoxamine treatment. These findings indicate that, at the dosage tested, fluvoxamine markedly inhibits the demethylation of imipramine without affecting significantly the CYP2D6-mediated hydroxylation of desipramine.

Adult↗

PubMed1994

Decreased plasma concentrations of imipramine and desipramine following cholestyramine intake in depressed patients.

The effect of cholestyramine (4 g t.i.d. for 5 days) on the steady-state plasma concentrations of imipramine and desipramine was assessed in six depressed patients receiving chronic treatment with imipramine (75-150 mg/day). Compared with baseline, cholestyramine treatment was associated with an average 23% decrease in plasma imipramine levels [from 211 +/- 95 to 159 +/- 67 nmol/L, (mean +/- SD), p < 0.05], whereas desipramine levels decreased only marginally. These data suggest that administration of cholestyramine at therapeutic doses impairs the gastrointestinal absorption of concurrently prescribed imipramine by an extent that is potentially clinically significant.

Adult↗

PubMed1987

Hypertension in neuroblastoma induced by imipramine.

Hypertension is a well-known finding in some patients with neuroblastoma. However, it has not previously been described in association with the use of Imipramine. We report the occurrence of severe hypertension (blood pressure 190/160) in a 4-year-old girl with neuroblastoma who was given Imipramine to control a behavior disorder. It was determined later that this patient's tumor was recurring at the time of her hypertensive episode. Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the Imipramine (when she was in florid relapse), we believe that this drug rather than her underlying disease alone caused her hypertension. The mechanism for this reaction is believed to be increased levels of vasoactive catecholamines due to interference of their physiologic inactivation by Imipramine. From this experience, we urge extreme caution in the use of tricyclic antidepressants in children with active neuroblastoma.

Adrenal Gland Neoplasms↗

PubMed2004

Imipramine for therapy resistant enuresis: a retrospective evaluation.

PURPOSE: Imipramine has a proven effect in enuresis but is now seldom used. We reviewed the records of children who had been treated with imipramine to determine prognostic indicators. MATERIALS AND METHODS: The records of all enuretic children treated with imipramine at our clinic were retrospectively evaluated, with special emphasis on history, and for most children bladder volume, renal concentrating capacity and urine production. RESULTS: All 49 children included in the study had previously received desmopressin, alarm and anticholinergic treatment without success. Of the children 31 (64.6%) were responders (R), with at least 50% reduction in enuresis frequency (22 became completely dry) and 17 (35.4%) were nonresponders (NR). Older age (R 11.4 +/- 3.4, NR 8.7 +/-1.8 years, p = 0.004) and low spontaneous bladder capacity (R 2.6 +/- 0.9, NR 3.4 +/- 0.9 ml/kg body weight, p = 0.03) were prognostically favorable, whereas constipation (p = 0.02) and a history of daytime incontinence (p = 0.04) indicated poor prognosis. Ten children experienced nausea or other minor problems. Seven children with attention deficit and hyperactivity became more focused during treatment. CONCLUSIONS: Imipramine is a useful treatment for enuresis when everything else has failed, especially among older children. Factors related to detrusor function provide prognostic information.

Adolescent↗

PubMed2005

Comparison of effects of treatment of primary nocturnal enuresis with oxybutynin plus desmopressin, desmopressin alone or imipramine alone: a randomized controlled clinical trial.

PURPOSE: We prospectively evaluated the efficacy of a combination of desmopressin and oxybutynin for treating children with nocturnal enuresis, compared to the single drugs imipramine and desmopressin. MATERIALS AND METHODS: We enrolled 158 patients from 2003 to 2004. Children were randomly assigned to 1 of 3 groups and treated with desmopressin, imipramine or a combination of desmopressin plus oxybutynin. Of these patients 145 (100 boys and 45 girls, mean age 7.8 +/- 2.5 years, range 5 to 15) were followed for more than 6 months. Efficacy was measured at 1, 3 and 6 months in terms of average enuretic frequency, 5-scale response based on change in nocturnal enuretic frequency after treatment and posttreatment enuretic frequency as a percentage of pretreatment baseline frequency. The latter efficacy was classified according to daytime voiding symptoms. Statistical evaluation was performed using chi-square tests and ANOVA. RESULTS: Of the 145 children followed 48 received combination therapy, 49 received desmopressin and 48 received imipramine. A total of 68 patients (47%) had monosymptomatic enuresis and 77 (53%) had polysymptomatic enuresis. Combination therapy produced the best and most rapid results regardless of whether the children had monosymptomatic or polysymptomatic enuresis. CONCLUSIONS: Combination therapy with desmopressin plus oxybutynin for the treatment of pediatric nocturnal enuresis was well tolerated, and gave significantly faster and more cost-effective results than single drug therapy using either desmopressin or imipramine.

Adolescent↗

PubMed2005

An autopsy case of imipramine poisoning.

We present a fatal imipramine poisoning. Quantitative analysis of imipramine and its metabolite, desipramine, was performed by high-performance liquid chromatography. The concentrations of imipramine and desipramine were 18.67 microg/mL and 6.21 microg/mL in heart blood and 6.90 microg/mL and 1.77 microg/mL in the femoral venous blood, respectively. We concluded that the cause of death was due to imipramine poisoning.

Antidepressive Agents, Tricyclic↗

PubMed1990

The influence of clinical and pharmacological factors on enuresis treatment with imipramine.

1. The aim of this study has been to evaluate the response to imipramine treatment in enuretic children through the use of a series of clinical and pharmacological variables and by applying a multivariate (principal components) analysis technique. 2. The study was carried out on 146 children whose ages ranged from 5 to 14 years, and who received variable doses of imipramine (12.5 to 100 mg day-1). 3. The quantitative variables analyzed were: drug dosage, serum levels of imipramine and its metabolite desipramine, the relationship between them both, the duration of treatment, age and weight. 4. The qualitative variables were: compliance, presence of side-effects, enuretic and/or psychiatric antecedents, intelligence quotient (I.Q.), the existence (or absence) of related pathologies, sex, and the type of enuresis. 5. The response to treatment was quantified by means of the percentage of decrease in frequency of enuresis as compared with the initial frequency. 6. The results obtained show that the variables which are most associated with the reduction of enuresis are, in decreasing order: the dosage of imipramine administered, the duration of treatment, compliance and the level/dose ratio for the sum of the drug and metabolite levels.

Adolescent↗

PubMed1992

Inhibitors of imipramine metabolism by human liver microsomes.

1. The aromatic 2-hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of Vmax and Km for the high affinity site ranged from 3.2 to 5.7 nmol mg-1 h-1 and from 25 to 31 microM, respectively. 2. Quinidine was a potent inhibitor of the high affinity site for the 2-hydroxylation of imipramine in microsomes from all three human livers, with apparent Ki-values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3. The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent Ki-values of 0.36, 0.92 and 0.33 microM, respectively. Three other SSRIs, citalopram, desmethylcitalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent Ki-values of 19, 1.3 and 3.9 microM, respectively. 4. Among 20 drugs screened, fluvoxamine was the only potent inhibitor of the N-demethylation of imipramine, with a Ki-value of 0.14 microM. 5. Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N-demethylation of imipramine and the role of the S-mephenytoin hydroxylase for this oxidative pathway could not be confirmed.

Cytochrome P-450 CYP2D6↗

PubMed1995

Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms--a population study.

1. Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks 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 h.p.l.c. 2. The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMs) as compared with 27 poor metabolizers (PMs), but none of the ratios separated the two phenotypes completely. 3. There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample. The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: -0.20 and -0.27, P < 0.05). 4. The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5. CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMs, meaning that they were genotyped correctly. One PMs was D6-wt/D6-B, another PMs had the genotype D6-wt/ and hence both were misclassified as EMs. The remaining 25 PMs were D6-A/D6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs.

Experience of treating 80 consecutive patients with painful diabetic neuropathy and a double-blind study of imipramine in acute painful neuropathy are reported. A standard stepwise protocol was used, based on imipramine as the drug of first choice, substitution of amitriptyline or mianserin as second choice, and, thirdly, addition of phenothiazine or clonazepam if necessary. Sixty per cent were satisfied with imipramine alone and all but 3 (5%) were improved by the stepwise scheme. Paradoxically, the most effective analgesia was obtained in those with the most severe and unpleasant pain. Often 150 mg of imipramine or amitriptyline was necessary. The onset of analgesia and relapse after withdrawal of treatment were rapid, facilitating clinical use, and suggesting a peripheral rather than central drug action.

Adult↗

PubMed1983

Complex inhibition of [3H]imipramine binding by serotonin and nontricyclic serotonin uptake blockers.

Tricyclic antidepressant drugs inhibit [3H]imipramine binding to the rat brain cortex in a competitive manner, giving linear Hofstee plots and Hill coefficients of approximately 1.0. Serotonin, the only neurotransmitter to inhibit [3H]imipramine binding, does so in a complex manner, exhibiting a Hill coefficient of 0.40-0.50. Nontricyclic inhibitors of serotonin uptake such as fluoxetine, paroxetine, norzimelidine, and citalopram inhibit [3H]imipramine binding in the same complex manner as serotonin. These results are interpreted as suggesting that [3H]imipramine binds to a site associated with the serotonin uptake system but different from either the substrate recognition site for serotonin or the site of action of the nontricyclic inhibitors of neuronal uptake of serotonin.

Amitriptyline↗

PubMed1984

Binding of [3H]imipramine to human platelet membranes with compensation for saturable binding to filters and its implication for binding studies with brain membranes.

Apparent specific binding of [3H]imipramine to human platelet membranes at high concentrations of imipramine showed deviation from that expected of a single binding site, a result consistent with a low-affinity binding site. The deviation was due to displaceable, saturable binding to the glass fibre filters used in the assays. Imipramine, chloripramine, desipramine, and fluoxetine inhibited binding to filters whereas 5-hydroxytryptamine and ethanol were ineffective. Experimental conditions were developed that eliminated filter binding, allowing assay of high- and low-affinity binding to membranes. Failure to correct for filter binding may lead to overestimation of binding parameters, Bmax and KD for high-affinity binding to membranes, and may also be misinterpreted as indicating a low-affinity binding component in both platelet and brain membranes. Low-affinity binding (KD less than 2 microM) of imipramine to human platelet membranes was demonstrated and its significance discussed.

Binding, Competitive↗

PubMed1985

"Specific" binding of [3H]imipramine to protease-sensitive and protease-resistant sites.

A number of 5-hydroxytryptamine (5-HT) uptake inhibitors have been shown to displace the binding of [3H]imipramine to rat cortical membranes in a complex manner with Hill slopes less than unity. Norzimeldine displaced the binding of [3H]imipramine in a biphasic manner with IC50 values for the two components of about 30 nM and 30 microM. This latter site alone was found in tissues that had been treated with a protease. Binding to both of these sites was displaced by 10 microM desipramine. The protease-sensitive [3H]imipramine binding sites were found to be saturable, high-affinity binding sites with a KD of 8 nM. The number of these sites varied between brain regions and was positively correlated with the regional distribution of [14C]5-HT but not [3H]noradrenaline uptake. This was not the case however for the protease-resistant but desipramine-displaceable binding sites. Since most previous [3H]imipramine binding studies have been performed with high concentrations of desipramine (10 microM) to define "specific binding," these data would suggest that either protease-sensitivity or displacability by 1 microM norzimeldine would give more reliable estimates of the specific binding.

Animals↗

PubMed1986

High- and low-affinity binding of [3H]imipramine in rat hypothalamus.

In the rat hypothalamus [3H]imipramine binding is inhibited by tricyclic and nontricyclic antidepressant drugs in a complex manner, with biphasic curves and Hill coefficients less than 1.0. 5-Hydroxytryptamine (serotonin) inhibited with high affinity a decreasing proportion of the [3H]imipramine binding sites as the [3H]imipramine concentration was raised. In the absence of sodium ions, IC50 values for the inhibition by tricyclic and nontricyclic antidepressants were increased by approximately 1,000-fold, and the inhibition curves became classically monophasic with Hill coefficients close to 1.0. These data are interpreted as suggesting that [3H]imipramine binds to two independent sites in the rat hypothalamus. One site is sodium-dependent with a high affinity for the drugs tested; the other is sodium-independent and has a low affinity for these drugs.

Amitriptyline↗