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PubMed1991

Low dose desipramine treatment of cocaine-related panic attacks.

Thirteen patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia that started during or shortly after cocaine exposure were treated in the UCLA Anxiety Disorders Program (Los Angeles, CA). Low starting doses (ranging from 2.5 to 10 mg/day) of desipramine were used. Doses were then slowly increased to an average daily dose of 25 mg. Eleven patients who were able to tolerate an initial increase in panic anxiety responded to this treatment strategy with almost full resolution of panic attacks. The authors discuss the possible value and mechanisms of low dose treatment of cocaine-related panic attacks.

Adult↗
PubMed1994

Desipramine treatment for cocaine dependence. Role of antisocial personality disorder.

As a test of the efficacy of desipramine (DMI) in the treatment of cocaine dependence, 59 cocaine-dependent males, maintained on methadone for the treatment of opiate dependence, completed a 12-week, random-assignment, placebo-controlled trial of this medication. At the end of treatment, there were no overall differences between the placebo and DMI groups on a range of outcome measures, including urine toxicology tests. However, an interaction between psychiatric diagnosis and outcome was seen when the sample was divided into those with (51%) and those without (49%) antisocial personality disorder (ASP). Patients with ASP made few gains with either DMI or placebo. Those without ASP made a number of gains with DMI but not placebo, particularly in the areas of psychiatric symptoms, legal status, and family problems. DMI had a significant effect on the psychiatric symptoms and personal adjustment problems, but not the cocaine use, of non-antisocial cocaine abusers. The negative influence of ASP that has been seen in studies of psychosocial therapies for substance-use disorders may also apply to pharmacological therapies.

Adult↗
PubMedDate not supplied

Effect of desipramine on the effects of alpha-adrenoceptor inhibitors on pressor responses and release of norepinephrine into plasma of pithed rats.

The role of neuronal uptake inhibition on the efficiency of alpha 1- and alpha 2-antagonists in inhibiting pressor responses and the release of plasma catecholamines in pithed rats were studied. Prazosin, in doses which selectively blocked alpha 1-adrenoceptors (0.01-0.1 mg/kg), was more effective than yohimbine, a relatively selective alpha 2-antagonist, in inhibiting stimulation-induced pressor responses. Yohimbine (0.1-1 mg/kg) potentiated or did not alter the pressor responses to stimulation, whereas it blocked pressor responses to administered norepinephrine (NE) more effectively than did prazosin. Inhibition of uptake by desipramine (DMI), 0.3 mg/kg, did not affect prazosin inhibition of stimulation-induced pressor responses though it increased NE overflow into circulation. In yohimbine-treated rats, DMI potentiated significantly (p less than 0.001) both pressor and NE responses to stimulation. DMI partially reversed prazosin inhibition of pressor response to administered NE (p less than 0.001) and potentiated the response in yohimbine-treated rats (p less than 0.01). The results are consistent with the view that endogenously released NE acts at intrajunctional alpha 1-adrenoceptors, whereas exogenous NE acts predominantly at extrajunctional alpha 2-adrenoceptors. The neuronal uptake site appears to be functionally (and perhaps anatomically) located outside the synaptic cleft, between intrajunctional alpha 1-postsynaptic receptors and extrajunctional alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1988

The effect of desipramine on ischemia-induced changes in extracellular K+, Na+, and H+ concentrations and noradrenaline release in the isolated rat heart during global ischemia.

Isolated Langendorff-perfused rat hearts set up to allow measurement of mechanical myocardial function (according to Bardenheuer and Schrader) were subjected to 60 min of global ischemia (gI). The hearts were perfused with a modified Krebs-Henseleit solution (KHS; control group) or KHS with desipramine (DMI group) 100 nM. Extracellular concentrations of K+, Na+, and H+ were determined using ion-selective membrane polyvinyl chloride (PVC) minielectrodes. The noradrenaline (NA) release was estimated by analyzing the NA overflow during a 10-min reperfusion period, using high pressure liquid chromatography (HPLC). Control hearts and DMI-treated hearts showed no differences in mechanical performance prior to gI. In control hearts, the onset of gI resulted in a rapid triphasic [K+]e accumulation (an increase from 4.25 +/- 0.25 to 8.76 +/- 0.37 mmol/L during the first 3.5 min, a decrease to 8.06 +/- 0.34 mmol/L until the seventh min, and a further increase to 33.0 +/- 2.42 mmol/L at 60 min), a rapid increase in [H+]e (45.9 +/- 2.3 to 1314.5 +/- 214 nmol/L during 23 min), and a slight initial increase of [Na+]e (138.8 +/- 0.4 to 141.9 +/- 0.8 mmol/L within 8 min) followed by a long-lasting decrease (119.1 +/- 4.5 mmol/L at 60 min). Treatment with DMI had only slight effects on ionic redistribution during the course of ischemia. The [K-]e and [H-]e accumulation tended to be diminished, whereas [Na-]e values were slightly higher in the course of gI compared to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Variant ventricular tachycardia in desipramine toxicity.

We report a case of variant ventricular tachycardia induced by desipramine toxicity. Unusual features of the arrhythmia are repetitive group beating, progressive shortening of the R-R interval, progressive widening of the QRS complex with eventual failure of intraventricular conduction, and changes in direction of the QRS axis. Recognition of variant ventricular tachycardia is important because therapy differs from that of classic ventricular tachycardia.

Adult↗
PubMed1984

Monitoring of serum levels of imipramine and desipramine and individualization of dose in enuretic children.

The serum levels of imipramine (IMI) and its active metabolite desipramine (DMI) were monitored in 90 children with primary nocturnal enuresis. Ages ranged between 5 and 14 years. Serum concentrations were determined in 21 children at 24 h after administration of a dose of 75 mg and once when steady state had been reached, 12 h after the last dose; a good correlation was seen between the total levels (IMI + DMI) on those two occasions (r = 0.81; p less than 0.01). This serves as a basis to predict the steady-state levels of IMI + DMI reached in an individual patient. In the remaining patients the serum levels of IMI + DMI were determined at steady state. Dosage regimens were adjusted individually to obtain a favorable response with regard to the frequency of enuresis and to the possible occurrence of side effects. Good correlation was established between the serum concentrations of IMI + DMI at steady state and the frequency of enuresis, with a favorable response being obtained for levels greater than 80 ng/ml. Monitoring of serum levels leads to better compliance with the regimen throughout treatment.

Adolescent↗
PubMed1991

Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine, and mephenytoin.

A 34-year-old man with bipolar manic depressive illness suffered from severe adverse effects during treatment with amitriptyline, 50 mg/day. It was subsequently shown that the patient was a slow metabolizer of amitriptyline. However, he tolerated a dose of 200 mg of imipramine/day, which was necessary in order to reach a therapeutic level of about 900 nM for imipramine plus desipramine. Since both antidepressants are subject to the genetic sparteine/debrisoquine oxidation polymorphism, the patient was phenotyped with sparteine. The test performed during paroxetine treatment indicated that the patient was a poor metabolizer. Subsequent tests performed during a drug-free period, however, showed the patient to be an extensive metabolizer, with a sparteine metabolic ratio (MR) of 1.7 and 2.8 and debrisoquine MR of 2.3. It was subsequently shown that paroxetine is a potent, competitive inhibitor of 1'-hydroxybufuralol formation in a human liver microsome preparation (K1 approximately 800 nM). This patient thus illustrates two problems: (a) the erroneous phenotyping due to concurrent medication, and (b) the existence of a very slow amitriptyline elimination apparently not related to the sparteine/debrisoquine oxidation polymorphism.

Administration, Oral↗
PubMed1993

Concurrent liquid chromatographic measurement of fluoxetine, amitriptyline, imipramine, and their active metabolites norfluoxetine, nortriptyline, and desipramine in plasma.

An expedient and specific liquid chromatographic method for a concurrent measurement of fluoxetine (FLU), norfluoxetine (NFLU), amitriptyline (AMI), nortriptyline (NTRIP), imipramine (IMI), and desipramine (DES) is described. Using a mixture of acetonitrile:methanol:0.056 M ammonium acetate:1 M ammonium hydroxide (100:10:4.5:2.6, by volume) as mobile phase, the compounds along with doxepin (DOX) (internal standard) were separated on a 10 mu, 8 mm x 10 cm C18 Resolve cartridge in conjunction with radial compression liquid chromatographic module, and were detected in the effluent spectrophotometrically at 220 nm. A hexane:isoamyl alcohol (98:2, by volume) solution was used for extraction of plasma and the drugs were removed from the organic phase with 0.03% phosphoric acid prior to injection. Under these conditions, no interference in the assay was observed, and the retention times of NFLU, DOX, FLU, AMI, IMI, NTRIP, and DES were 7.8, 11.6, 16, 17.8, 20.9, 31, and 35 min, respectively. The assay was highly linear (r > 0.994), and the within- and between-day coefficient of variance was consistently < or = 9.8%. This assay is currently being used to simultaneously measure these drugs in patients and to investigate their steady-state pharmacokinetics when used in combination.

Amitriptyline↗
PubMed1996

Phenobarbital induces the 2-hydroxylation of desipramine.

The kinetics of a single oral dose of desipramine (DMI; 100 mg) were studied in eight epileptic patients chronically treated with phenobarbital (PB) and in eight drug-free healthy controls. All subjects were extensive metabolizers with respect to the genetically determined CYP2D6-related metabolic polymorphism. Compared with controls, epileptic patients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 107 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-curve values (1,943 +/- 461 vs. 3,234 +/- 1,145 nmol L-1 h; p < 0.01), and shorter DMI elimination half-lives (15.1 +/- 2.1 vs. 20.6 +/- 3.4 h; p < 0.01). The proportion of the dose excreted as 2-hydroxydesipramine (2-OH-DMI) was significantly higher in the patients (54 +/- 8 vs. 40 +/- 9%; p < 0.05). In one single poor metabolizer volunteer, a 3-week treatment with PB was associated with no major changes in DMI kinetics, but the urinary excretion of 2-OH-DMI tended to increase. These results suggest that PB is an inducer of the 2-hydroxylation of DMI, a reaction primarily catalyzed by CYP2D6, but do not provide further information on the specific P450 isoenzyme(s) being induced.

Adult↗
PubMed2005

Fluvoxamine and desipramine on fixed-ratio responding: effects of reinforcement magnitude.

Fluvoxamine, a serotonin reuptake blocker, was previously shown to decrease ethanol-maintained behavior at doses lower than those needed to decrease food-maintained behavior. While these effects could have been due to different response rates and histories of the two groups being compared, a subsequent study found differential effects using a within-subjects design, in which rates of responding were well equated. Another explanation for such differential effects is that food and ethanol reinforcement differ in a quantitative fashion. This is difficult to resolve when comparing between behaviors maintained by different events. To examine how such quantitative differences in reinforcement magnitude might influence the effects of fluvoxamine, we used a multiple schedule of fixed-ratio 30 responding in the pigeon. In each of the three fixed-ratio 30 components, behavior was maintained by a different duration of grain presentation (2, 4, and 8 s). The effects of fluvoxamine and also desipramine were examined. Both dose-dependently decreased fixed-ratio responding. Their effects were independent of the duration of grain presentation maintaining responding. These results do not support the idea that the differential effects of fluvoxamine on ethanol-maintained behavior, as compared with food-maintained behavior, are a result of quantitative differences in reinforcement magnitude.

Adrenergic Uptake Inhibitors↗
PubMed1984

Desipramine pharmacokinetics in Chinese and Caucasian volunteers.

In order to better define the role of pharmacokinetic variation in reported cross-ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics of the tricyclic antidepressant desipramine (DMI) were studied in 14 Chinese and 16 Caucasian healthy volunteers. DMI and 2-OH-DMI concentrations were assayed with h.p.l.c. in serial plasma and 24 h urine samples over 5 days following an oral 100 mg dose of DMI. Mean total clearance of DMI ( CLDMI ) from plasma was significantly (P less than 0.05) higher in the Caucasians (123 +/- 57 l/h) than in the Chinese (73.5 +/- 38.8 l/h). There was no significant difference in the apparent clearance of DMI by hydroxylation, fraction of dose metabolized to the hydroxy metabolite, DMI t1/2 or plasma protein binding between the two groups. Trimodal distribution of CLDMI was found, with 4/14 (29%) Chinese demonstrating slow CL (less than 33 l/h) and 4/16 (25%) Caucasians rapid CL (greater than 195 l/h). Correcting CL values for the greater mean weight of the Caucasians did not alter the pattern of distribution. CLDMI did not correlate with body weight. Although environmental factors cannot be ruled out, these results are consistent with genetically based differences in hepatic metabolism, probably affecting pathways in addition to hydroxylation, and suggest that 30% of Orientals would be at risk for toxicity from routine doses of tricyclics or similarly metabolized drugs.

Adult↗
PubMed1986

Acute treatment with desipramine stimulates melatonin and 6-sulphatoxy melatonin production in man.

Acute administration of the antidepressant drug desipramine (DMI) in man, increased evening melatonin secretion, which reached peak plasma levels 2-4 h earlier than after placebo administration. The increase at set time points 21.00 h-22.00 h was directly proportional to an individual's integrated night-time secretion of melatonin. We have shown that this stimulation was not an effect of DMI inhibition on the hepatic metabolism of melatonin to 6-sulphatoxy melatonin (aMT6s), indeed aMT6s is in itself a good index of the evening melatonin rise. The stimulation of early evening melatonin by DMI might be exploited as a simple pineal function test.

Adult↗
PubMed1990

The effect of reserpine, desipramine and thyroid hormone on alpha 1a- and alpha 1b-adrenoceptor binding sites: evidence for a subtype-specific regulation.

Using radioligand binding techniques we studied whether alpha 1a- and alpha 1b-adrenoceptor recognition sites can be regulated independently by drugs and hormones. In rat cerebral cortex subchronic treatment with reserpine enhanced the number of [3H]-prazosin binding sites and the proportion of alpha 1b binding sites. Desipramine treatment which did not alter Bmax values, increased the proportion of alpha 1a and decreased alpha 1b binding sites. In rat myocardium hypothyroidism decreased alpha 1b-adrenoceptor binding sites. These results suggest that alpha 1-adrenoceptors are regulated in a subtype-selective manner.

Animals↗
PubMed1992

Interindividual variability in the N-sulphation of desipramine in human liver and platelets.

1. The activity of N-sulphotransferase (N-ST) with desipramine (DMI) as substrate was measured in 118 human liver specimens, in platelets obtained from 105 subjects, in 12 specimens of human ileum and colon mucosa and in five specimens of human kidney and lung. 2. N-ST activity ranged between 5.71 and 157 pmol min-1 mg-1 protein in human liver and between 0.27 and 17.3 pmol min-1 mg-1 protein in human platelets. 3. Probit analysis was compatible with a unimodal distribution of the data from both liver and platelets. 4. The frequency distribution histograms of N-ST were asymmetric, with a positive skew in data from both liver and platelets. The mode, median and mean of N-ST were 16.4, 30.2 and 40.4 pmol min-1 mg-1 protein in liver, and 2.12, 3.61 and 3.82 pmol min-1 mg-1 protein in platelets, respectively. After logarithmic transformation of N-ST activity, the frequency distribution histogram was symmetric for data from both liver and platelets. 5. In extrahepatic tissues, the average (+/- s.d.) N-ST activity (pmol min-1 mg-1 protein) was 22.2 +/- 22.8 (ileum), 20.9 +/- 26.9 (colon), 12.4 +/- 5.5 (renal cortex), 9.3 +/- 2.8 (renal medulla) and 4.2 +/- 1.1 (lung). N-ST is widely distributed in the body and the intestine is the extrahepatic tissue with the highest N-ST activity.

Adult↗
PubMed1994

Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans.

1. Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2. Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3. Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4. The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6-sulphatoxymelatonin (aMT6s) excretion. 5. On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6. Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7. The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.

Adult↗
PubMed1995

Differential actions of desipramine on sympathoadrenal release of noradrenaline and adrenaline.

Spillovers noradrenaline (NA) and adrenaline (A) into plasma were examined before and after i.v. administration of 0.3-0.5 mg kg-1 desipramine (DMI) in 19 normal volunteers. DMI decreased the total body spillover of NA by 20 +/- 4%, but increased that of A by 45 +/- 10%. The results indicate differential sympathoadrenal actions of DMI, characterized by inhibition of NA release from sympathetic nerves and stimulation of A secretion from the adrenals. These effects of DMI provide an explanation for some of the cardiovascular complications of tricyclic antidepressant therapy and may also help to explain how sympathoadrenal function is differentially regulated.

Adult↗
PubMed1985

A sensitive colorimetric method for the determination of imipramine hydrochloride and desipramine hydrochloride.

A simple and rapid colorimetric method for the determination of imipramine hydrochloride and desipramine hydrochloride in their tablet formulations and in biological fluids is presented. The method is based on the reaction of these drugs with 3-methyl-2-benzothiazolone hydrazone in the presence of ferric chloride, with direct measurement at 635 nm. Cyclohexane was used to extract these drugs from serum and urine, at basic pH, by a single manual extraction. The method can detect 0.5 microgram/ml of each drug. The main advantages of this method are its simplicity and high sensitivity.

Colorimetry↗
PubMed1992

Dosage optimization methods applied to imipramine and desipramine in enuresis treatment.

Three methods for estimating maintenance dosage requirements of imipramine were compared retrospectively in 146 enuretic patients. The dosing methods evaluated included individual (serum levels data) and/or population (average pharmacokinetic parameter) information. The use of imipramine and desipramine serum concentrations, as opposed to average population parameters only, improved forecast precision and accuracy for dosage individualization. The clinical acceptability of this was achieved through knowledge of a single serum concentration. No significant differences were seen between non-linear regression and the Bayesian method, this is in agreement with the high contribution of the patient's data to the Bayesian fitting (FF = 0.8). When one or two serum level data were available, a better performance was obtained by estimating pharmacokinetic parameters than level:dose ratios.

Adolescent↗