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At least 19 recordsLinked to original sources
PubMed1981

Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers.

Disposition characteristics of desipramine and its metabolite, 2-hydroxy-desipramine, were determined in four healthy male volunteers following an oral 50 mg dose of desipramine. Nonlinear least-squares regression of concentration-time data indicated that parent drug disposition could be described by a one-compartment open pharmacokinetic model for two subjects and by a two-compartment model for two subjects. The early appearance of 2-hydroxy-desipramine and its high peak concentrations indicates that desipramine probably undergoes pre-systemic elimination partly through formation of 2-hydroxy-desipramine. The substantial production of 2-hydroxy-desipramine, as reflected by the area under its concentration-time curve which was 51% to 94% of that for desipramine, indicates that accumulation will occur following multiple dosing. As 2-hydroxy-desipramine may possess antidepressant activity, future studies designed to assess the therapeutic effect of desipramine should account for the presence of its pharmacologically active metabolite.

Adult↗
PubMed1996

Ovine desipramine antibody fragments reverse desipramine cardiovascular toxicity in the rat.

STUDY OBJECTIVE: To develop a model of severe desipramine cardiovascular toxicity and to determine whether partial neutralization of the antigen by desipramine-specific Fab antibody fragments ameliorates its cardiovascular effects. METHODS: We administered desipramine to rats until the QRS interval tripled in duration and mean arterial pressure (MAP) was less than 100 mm Hg. Animals were then assigned to one of six groups: (1) no treatment, (2) normal saline solution control treatment (.9% NaCl infusion equal to the volume of Fab infusion), (3) nonimmune Fab control treatment (infusion of Fab equal to that in the 9.6% neutralization treatment), (4) 9.6% desipramine Fab (infusion of ovine desipramine Fab equal to 9.6% of an equimolar neutralization), (5) 19.2% desipramine Fab, and (6) 30.0% desipramine Fab. RESULTS: QRS-interval duration, heart rate, and MAP were recorded for 60 minutes. Animals in groups 1 through 3 demonstrated slow and incomplete improvement. Animals in groups 4 through 6 showed improvement in QRS-interval duration and heart rate within 4 minutes (P<.05) compared with untreated animals. A dose-response relationship was evident; animals given the highest dose of desipramine-specific Fab showed the greatest improvement. CONCLUSION: Partial neutralization of desipramine by specific Fab fragments produces rapid improvement of QRS-interval duration and heart rate in a rat model of severe desipramine toxicity.

Animals↗
PubMed1985

Effects of desipramine on stimulation-induced contractions of the vas deferens of rats pretreated either chronically with desipramine or acutely with idazoxan.

In the present studies the effects of desipramine on the functional sensitivity of the prejunctional alpha 2-adrenoceptors of the vas deferens were studied in pithed rats; contractions of the tissue were evoked by electrical stimulation (6 Hz) of the spinal sympathetic outflow. Twenty-four hours after a single dose of desipramine (10 mg/kg, intraperitoneally) the inhibitory dose-response curves to either UK 14 304 or desipramine itself did not differ significantly from those seen in control animals, whereas both were displaced significantly to the right after 15 days pretreatment with desipramine. Thus the functional responsiveness of the prejunctional alpha 2-adrenoceptors of the vas deferens was reduced by chronic but not acute pretreatment with desipramine. In acute studies desipramine (0.3-4.3 mg/kg, intravenously) inhibited electrically induced contractions of the vas deferens of pithed rats. In the presence of the selective alpha 2-adrenoceptor antagonist idazoxan (1 mg/kg, intravenously) desipramine potentiated nerve stimulation. Although idazoxan (10-1440 micrograms/kg, intravenously) itself potentiated electrically induced contractions of the vas deferens the potentiation observed was markedly less than that obtained in rats pretreated acutely with desipramine (0.3 mg/kg, intravenously). Acute simultaneous blockade of both prejunctional alpha 2-adrenoceptors and uptake into nerve terminals can produce maximal potentiation of the contraction of the vas deferens to sympathetic nerve stimulation. Results are discussed in relation to the hypothesis that the combination of an uptake inhibitor and a prejunctional alpha 2-adrenoceptor antagonist, by enhancing noradrenergic transmission, may provide an antidepressant therapy with rapid onset of action.

Adrenergic alpha-Antagonists↗
PubMed1998

Lithium and desipramine versus desipramine alone in the treatment of severe major depression: a preliminary study.

Improvement following lithium augmentation is well-documented in depressed patients resistant to tricyclic antidepressants. However, response latency to lithium augmentation is extremely variable, suggesting other mechanisms may be involved. To evaluate whether long-term tricyclic treatment is necessary for lithium augmentation's effect, the rapidity and magnitude of response to lithium combined with desipramine from the start of treatment was compared to desipramine alone in severely depressed patients. Patients with DSM-III-R major depression were randomized to double-blind, placebo-controlled treatment with either lithium + desipramine or placebo + desipramine for 4 weeks. Response criteria were based on Hamilton Depression Rating Scale scores and global improvement. Analysis of covariance of Hamilton scores demonstrated that lithium + desipramine was superior to placebo + desipramine at week 1 (P < 0.009), week 2 (P < 0.028), and week 3 (P < 0.07), although not at week 4. There were more responders to the combination than to monotherapy (P < 0.042). These preliminary data suggest that lithium + desipramine may have some efficacy in severely depressed patients. Further studies with larger samples are needed to confirm these findings.

Adult↗
PubMed1991

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment with imipramine.

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated. It was also found that the number of specific [3H]desipramine binding sites was different in the various brain areas, and that prolonged administration of imipramine led to a decrease of their number in some of those regions. No correlation was found between the regional cerebral distribution of desipramine and the regional density of specific [3H]desipramine binding sites.

Animals↗
PubMed1992

A comparative study on desipramine pharmacokinetics in the rat brain after administration of desipramine or imipramine.

Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg-1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg-1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in-vivo.

Administration, Oral↗
PubMed1986

Electrocardiogram changes and therapeutic desipramine and 2-hydroxy-desipramine concentrations in elderly depressives.

ECG parameters in elderly depressed in-patients were assessed during routine desipramine treatment. Significant changes (prolonged PR and PRS intervals and a decreased QTc interval) were found, related only to steady state concentrations of desipramine's major metabolite--2-hydroxy-desipramine. Potentially clinically significant changes developed in 40% of the patients. All serum drug concentrations were within therapeutic limits. Previous assurances about desipramines's cardiac safety in the elderly may need to be re-evaluated.

Aged↗
PubMed2000

Metabolism of desipramine in Japanese psychiatric patients: the impact of CYP2D6 genotype on the hydroxylation of desipramine.

We investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine hydrochloride per os. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight was observed in the subjects with two mutated alleles than in the subjects with either no mutated alleles or one mutated allele (two mutated alleles versus no mutated alleles=530.4+/-215.2 versus 118.1+/-63.9 ng/ml/mg/kg, t=5.68, P<0.001; two mutated alleles versus one mutated allele=530.4+/-215.2 versus 176.2+/-62.3 ng/ml/mg/kg, P<0.001; One-way analysis of variance followed by Bonferroni's multiple comparison test, respectively). Significantly higher ratio of desipramine/2-hydroxy-desipramine was observed in the subjects with two mutated alleles compared to subjects with no mutated alleles or the subjects with one mutated allele (two mutated alleles versus one mutated allele= 4.39+/-0.36 versus 2.00+/-0.64, t=5.12, P<0.001; two mutated alleles versus no mutated alleles=4.39+/-0.36 versus 2.02+/-0.59, t=4.42, P<0.01). The genotyping of CYP2D6 only grossly predicts the steady state concentration of desipramine, mainly predicts the risk of getting very high plasma levels. Within each genotype there is marked interindividual variability.

Adult↗
PubMed1992

Adipose tissue distribution and chemical structure of basic lipophilic drugs: desipramine, N-acetyl desipramine, and haloperidol.

Single-dose intravenous injections of desipramine to rats resulted in a distribution pattern typical of basic lipophilic drugs, i.e., highest concentrations in lung and lowest in adipose tissue and plasma. In contrast, after N-acetyldesipramine, a non-basic analogue of desipramine with comparable lipophilicity, concentrations of this drug in adipose tissue were much higher than in lean tissue or plasma as a result of redistribution into the former and rapid disappearance from the latter tissue. N-Acetyldesipramine had much lower plasma and tissue half-lives than desipramine, but at the same time a much higher adipose/plasma concentration ratio and adipose storage index. Chronic administration of the basic lipophilic drug, haloperidol, to rats in their diet over 21 days resulted in a steady-state distribution pattern with highest concentrations in lung and lowest concentrations without accumulation in adipose tissue. This study provides additional evidence for the influence of basic groups on the distribution of lipophilic drugs. Thus, basic lipophilic drugs do not undergo redistribution into adipose tissues, possibly because of a competition by stronger binding to lean tissue as a result of lysosomotropism.

Adipose Tissue↗
PubMed1987

Lack of relationship between effect of desipramine on forced swimming test and brain levels of desipramine or its demethylated metabolite in rats.

Animals were injected with 20 mg/kg desipramine (DMI) 1 h (acute) or 24, 5 and 1 h (subchronic) or once daily for 7 consecutive days (chronic) before the forced swimming test (FST). DMI was also injected at a dose of 40 mg/kg acutely. Animals were killed immediately after test for evaluation of brain concentrations of DMI and its demethylated metabolite desmethyldesipramine (DDMI). Acute and chronic DMI 20 mg/kg gave rise to similar brain concentrations but only chronic DMI was active on FST. Acute DMI 20 mg/kg and 40 mg/kg gave rise to different brain concentrations but similar effects on FST. DDMI concentrations were similar after the various DMI treatments. Results seem to indicate that no relationship exists between effect of DMI on FST and brain concentrations of either DMI or DDMI.

Animals↗
PubMed1997

Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study.

OBJECTIVE: The clinical relevance of the CYP2D6 oxidation polymorphism in the treatment of depression with desipramine (DMI) was studied prospectively in depressed outpatients. METHODS: After CYP2D6 phenotype determination with dextromethorphan, 31 patients were treated with oral DMI at a dosage of 100 mg per day for 3 weeks. At the end of the 3rd week of treatment, severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale and steady-state plasma concentrations of DMI and its metabolite 2-hydroxydesipramine (2-OH-DMI) were measured by high-performance liquid chromatography (HPLC). RESULTS: Plasma DMI levels were significantly correlated with dextromethorphan metabolic ratio. The two patients with the poor metabolizer phenotype showed the highest plasma concentrations of DMI and complained of severe adverse effects, requiring dosage reduction. No significant correlation was found between plasma levels of either DMI or DMI plus 2-OH-DMI and antidepressant effect. CONCLUSION: These findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects. On the other hand, this index of CYP2D6 activity does not seem to predict the degree of clinical amelioration.

Adult↗
PubMed1992

Developmental changes in serum concentrations of desipramine and 2-hydroxydesipramine during treatment with desipramine.

Steady-state serum concentrations of desipramine (DMI) and its metabolite, 2-hydroxydesipramine (OHDMI), were measured in 40 children, 36 adolescents, and 27 adult psychiatric patients. The authors predicted that younger patients would show more efficient elimination of DMI, with greater amounts of OHDMI. OHDMI averaged 52% lower than DMI. DMI per weight-corrected dose (ng/mL: mg/kg) rose significantly with maturation, from 50 in children and 56 in adolescents to 91 in adults. Contrary to expectation, OHDMI per DMI dose also rose with age, from 17 in children and 20 in adolescents to 26 in adults. It was concluded that: (1) similar mg/kg doses of DMI result in lower DMI and OHDMI in children; (2) children metabolize both DMI and OHDMI more rapidly than adults; and (3) children do not have high circulating concentrations of OHDMI.

Adolescent↗
PubMed1993

Electrocardiographic effects of desipramine and 2-hydroxydesipramine in children, adolescents, and adults treated with desipramine.

OBJECTIVE: To assess the developmental effects of desipramine (DMI) treatment on the electrocardiogram (ECG), we investigated serum concentrations of DMI ([DMI]), and its major active metabolite 2-hydroxydesipramine ([OHDMI]) and ECG parameters. METHODS: ECGs and [DMI] and [OHDMI] were analyzed from 50 children, 39 adolescents, and 30 adult psychiatric patients receiving DMI. RESULTS: There were modest overall correlations between [DMI], [OHDMI], or [OHDMI+DMI], and the PR and QRS intervals when data from all 119 subjects were pooled. Within the pediatric age groups there were no significant associations between serum drug levels and heart rate or conduction intervals; and in all subjects with ECG abnormalities, there were some findings of higher [DMI], [OHDMI], and [OHDMI+DMI]. CONCLUSIONS: These findings indicate that only modest associations of [DMI] and [OHDMI] with ECG conduction intervals were found, and are not likely to be clinically significant in any of the age groups studied. Compared with adults, children and adolescents do not appear to be at increased risks for ECG changes related to DMI treatment or to circulating concentrations of [DMI] or [OHDMI].

Adolescent↗
PubMed1987

Urinary desipramine hydroxylation index and steady-state plasma concentrations of imipramine and desipramine.

An index of desipramine (DMI) hydroxylation, calculated as the ratio between the amounts of DMI and 2-hydroxydesipramine (2-OH-DMI) excreted in urine after 25 mg orally, was determined in 16 depressed patients. The index varied almost 100-fold between the patients and correlated significantly to the steady-state plasma concentrations of DMI (rs = 0.85; p less than 0.01) but not to the plasma levels of imipramine (IMI) when the patients were treated with 75 mg of IMI daily. Eleven of the 16 patients were subsequently treated with DMI and a significant relationship was again found between the plasma levels of DMI and the urinary DMI-hydroxylation index (rs = 0.87; p less than 0.01). The latter may be utilized in therapeutic drug monitoring to identify individuals with unusually rapid or slow hydroxylation of DMI.

Adult↗
PubMed1987

Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients.

The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.

Adolescent↗
PubMed1991

Determination of the in vivo antigen-antibody affinity constant from the redistribution of desipramine in rats following administration of a desipramine-specific monoclonal antibody.

Quantitative expressions have been derived to determine the affinity constant for the in vivo interaction of an antigen with its elicited monoclonal antibody by analysing the redistribution of antigen following antibody administration. Using this method, the intrinsic binding constant for the interaction of subtoxic doses of DMI in rats with anti-TCA was found to be about two orders of magnitude less than the value obtained in vitro. The disparity is probably due to the presence of endogenous ligands for the antibody.

Animals↗