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  • 1
    ISSN: 1432-1041
    Keywords: amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1041
    Keywords: imipramine ; sparteine ; desipramine ; drug oxidation ; monogenic polymorphism ; debrisoquine ; therapeutic outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean ± SD) 713±132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50–400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 43 (1992), S. 251-255 
    ISSN: 1432-1041
    Keywords: Diabetes ; Mianserin ; peripheral neuropathy ; pain ; imipramine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of the non-tricyclic antidepressant mianserin on symptoms of diabetic neuropathy has been studied in 18 patients in a double-blind, cross-over study with imipramine as a positive control. The patients were treated with placebo, mianserin, and imipramine, each for two weeks, in randomized order, with 1–3 weeks between the treatments. The symptoms were assessed by observer and self-rating scales. Mianserin was given in the fixed dosage of 60 mg per day, whereas the dose of imipramine was adjusted to yield the optimal plasma concentration of imipramine plus desipramine of 400–600 nmol · l−1. The mianserin plus desmethylmianserin plasma concentration ranged from 85 to 850 nmol · l−', with the highest concentration in a patient who was a poor metabolizer of both sparteine and mephenytoin. The symptoms of neuropathy were significantly reduced during imipramine treatment, although somewhat less than in earlier studies. In contrast, mianserin produced no change in symptoms in comparison with placebo. As there was no evidence that higher mianserin (plus metabolite) steady-state concentrations were associated with a more favourable effect, the negative outcome appeared not to be related to underdosing with mianserin. In contrast to drugs with documented effects on the symptoms of diabetic neuropathy, mianserin has a very weak or no inhibitory effect on 5-HT and noradrenaline reuptake and this may explain its poor clinical effect.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 30 (1986), S. 43-49 
    ISSN: 1432-1041
    Keywords: imipramine ; desipramine ; hydroxymetabolites ; plasma concentration monitoring ; dose-dependent kinetics ; drug interaction ; levomeprazine ; perphenazine ; therapeutic response ; sparteine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seventeen hospitalized patients (age 39–66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40–637 nmol/l for imipramine, 49–1148 nmol/l for desipramine and 89–1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548–910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50–400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: diabetic polyneuropathy ; imipramine ; adverse effects ; neurophysiological tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of imipramine on symptomatic peripheral diabetic neuropathy in 9 patients was examined in a double-blind cross-over study against placebo. The dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 300–750 nM. Imipramine had a clear benificial effect on the symptoms of the neuropathy, whereas no changes in a range of neurophysiological measurements was detected. Despite some adverse effects, especially of an anticholinergic nature, the patients generally preferred imipramine to placebo.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 37 (1989), S. 155-160 
    ISSN: 1432-1041
    Keywords: imipramine ; desipramine ; quinidine ; sparteine oxidation ; cytochrome P450 isoforms ; genetic polymorphism ; drug interaction ; metabolic clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day. During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30–100 nmol · l−1) but not during quinidine. It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.
    Type of Medium: Electronic Resource
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