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Intravenous cocaine use in methadone patients has become a major problem because of both the complications of cocaine use and the potential spread of AIDS. During an eight week open trial we found that desipramine reduced cocaine craving and use in eight cocaine abusing methadone maintenance patients compared to eight patients getting no medication execept methadone.
Tricyclic antidepressants are bound extensively to alpha-1-acid glycoprotein (AAG) in serum. It has been suggested that the extent of drug-protein binding may influence the magnitude of cardiotoxicity associated with tricyclic antidepressant overdose. To study this question, desipramine (DMI), 45 mg/kg, was administered i.p. to anesthetized rats, producing an increase in QRS duration of 86.4 +/- 20.5% and a decrease in systolic blood pressure of 28.1 +/- 13.2%. Groups of six rats then received human AAG, 2.2 g/kg i.v. over 30 min, 4.4 g/kg i.v. over 60 min or control infusions of albumin. The serum AAG concentration increased to 29 times normal after AAG, 2.2 g/kg, and 46 times normal after AAG, 4.4 g/kg. The serum DMI concentration did not change with albumin infusion but increased 4.7-fold (1.9 +/- 0.7 to 9.0 +/- 1.6 micrograms/ml) after AAG, 2.2 g/kg, and 6.7-fold (2.3 +/- 0.5 to 15.7 +/- 7.0 micrograms/ml) after AAG, 4.4 g/kg. AAG infusion at either dose had no effect on systolic blood pressure compared to albumin. Animals treated with AAG, 2.2 g/kg, had less QRS prolongation 30 min after AAG infusion than animals treated with albumin (41 +/- 13% vs. 64 +/- 8%, P less than .01) but no difference in QRS duration was observed between groups after the higher dose (4.4 g/kg) of AAG or albumin. Cardiac DMI concentrations 90 min after AAG or albumin treatments did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)
Therapy for Tourette's syndrome with tricyclic antidepressants has had varied results. Previous reports have not addressed the frequent association of symptoms of attention deficit disorder (ADD) with Tourette's syndrome or the plasma levels of tricyclic antidepressants. A boy with Tourette's syndrome and ADD-like symptoms was treated with desipramine, and all the symptoms improved. This drug may be effective therapy for patients with Tourette's syndrome and ADD-like symptoms.
Prior work indicates that plasma tricyclic levels obtained 24 hours after a single dose correlate well with steady state levels achieved. Although this suggests that 24-hour levels could be used to predict the dose needed to reach a desired plasma level, this method has seldom been tested prospectively. In the current study we test this strategy and determine patients' tolerance of rapid dose adjustment. First, the relationship of 24-hour levels and steady state levels in a sample of 16 inpatients was determined using a fixed dose paradigm. In a second sample of 26 depressed inpatients, plasma desipramine levels obtained 24 hours after a single test dose were applied to the regression equation derived from the first sample in order to estimate the dose needed to achieve a steady state level of 140 ng/ml. Once determined, the full dose was then rapidly administered. Sixteen of the 18 (89%) patients who completed the dose adjustment study had steady state drug concentrations within a target range of 125 to 300 ng/ml. This distribution of levels differed significantly from that previously reported for a fixed dose sample in which only 19 of 83 (23%) patients had levels within this range. Dose adjustment using 24-hour levels was well tolerated and should help to attain a more rapid response to antidepressant treatment. This has important implications for reducing lengths of hospitalization for depressed inpatients. The technique should also prove useful in research where a uniform plasma level paradigm is desirable.
Results of liver function tests in 42 children and adolescents treated with desipramine for up to 24 months were unchanged. Although tricyclic-related hepatotoxicity cannot be ruled out with a small sample, it does not appear to be a dose- or time-related phenomenon in this age group.
Fourteen patients who met DSM-III criteria for agoraphobia with panic attacks received 200 mg desipramine (DMI) per day for 12 to 16 weeks on an open basis. Seven of eight patients who responded had steady state plasma DMI levels greater than 125 ng/ml, while five of six nonresponders had DMI levels less than 125 ng/ml. Following increases in dosage sufficient to raise DMI levels to greater than 150 ng/ml, four nonresponders improved dramatically. Implications of these findings are discussed briefly.
Recent reports have suggested that normal-weight bulimic patients without clinical evidence of major depressive disorder will have an abnormal response to dexamethasone. Of 23 normal-weight bulimic patients without clinical evidence of major depressive disorder, 11 had abnormal results on their dexamethasone suppression tests (DSTs). This finding closely matches those of other reports. After successful treatment with desipramine, repeat DSTs showed conversion to normal suppression in 6 of the 7 patients tested. Pretreatment DST results failed to predict the response to medication. The striking similarity of these findings to those reported in patients with major depression suggests that bulimia may be a consequence or an equivalent of major affective disorder.
Eighteen children with attention deficit disorder were treated with desipramine in a prospective open trial to assess its efficacy and safety. Improvement occurred within 4 weeks and was sustained without significant adverse effects for up to 52 weeks.
The role of mesolimbic monoaminergic innervation in the organization of rat behavior in the forced swim test (FST) and in the anti-immobilizing action of desipramine (DMI) in the test, was examined. The results can be summarized as follows: neither 6-hydroxydopamine (60HDA)-lesions nor electrical stimulation of the ventral tegmental area (A-10) and intra-accumbens dopamine (DA) microinjections produced specific (i.e. independent from changes in rats locomotion) effects on rat behavior or on DMI action in the FST. On the other hand, 60HDA lesions to the locus coeruleus (LC) antagonized the anti-immobilizing effect of DMI. It was also shown by us that the electrostimulation of the LC produced in the FST an effect similar to that of DMI. Moreover, the intra-accumbens injections of noradrenaline (NA) mimicked the effect of DMI in the test. Similar results were obtained after local administration of adrenergic receptor agonists--phenylephrine and isoproterenol. It is concluded that NA but not DA plays a crucial role in the organization of rat behavior in the FST and in the anti-immobilizing effect of DMI. The data suggest also a direct involvement of the nucleus accumbens septi in these neural processes.
Desipramine (DMI) effectively antagonized hypothermia induced by reserpine and clonidine in rats. DMI effects were attenuated or even abolished after electrolytic or 6-hydroxydopamine-induced lesion of the locus coeruleus (LC) as well as by administration of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a selective noradrenergic neurotoxin. Contrary to the LC lesions, electrolytic destruction of the ventral noradrenergic bundle did not change DMI action but antagonized reserpine-induced hypothermia by itself. Our results underline a possible involvement of the LC system in mechanism of antidepressive action, which was suggested previously in this laboratory.
A liquid chromatographic procedure has been developed for the assay, content uniformity, and identification of single active ingredient formulations of desipramine, fluphenazine, and promazine. The drugs are extracted from formulations with methanol or dilute hydrochloric acid and quantitated against an internal standard (norephedrine). The drugs are identified by comparison of retention times with those of the reference standards.
Concentrations of imipramine (IMI) and desipramine (DMI) in the rat brain after administration of IMI in aqueous solution by stomach gauge twice daily, in oil solution parenterally at 48 h intervals, and with drinking water were assayed. IMI administration with the drinking water for 21 days produced a pattern of the brain concentrations of IMI and DMI similar to that observed in rats receiving IMI by stomach tube for two weeks, at 12 h intervals. When IMI was given to rats ip in an oil solution at 48 h intervals for 10 days, the brain levels of both IMI and DMI were very high and rather stable during 48 h after administration of the last dose of IMI. However, the relation between brain concentration of IMI and DMI differed markedly from that found in rats receiving IMI with the drinking water. It seems that administration of IMI with drinking water may be recommended as a reliable and convenient dosage schedule in experiments which need prolonged treatment with IMI.
Alkalinization of the blood by administration of sodium bicarbonate or hyperventilation is widely recommended for treatment of cardiac toxicity due to tricyclic antidepressant overdose, yet its efficacy and mechanism of action are poorly defined. We studied the effects and possible mechanism of action of 1 M NaHCO3 on desipramine (DMI) toxicity in anesthetized, paralyzed rats. Administration of DMI (45 mg/kg i.p.) produced a mean increase in QRS duration of 142% and a mean decrease in mean arterial pressure of 46%. Treatments were administered i.v. 35 min after DMI and their effects were assessed 10 min later. NaHCO3 (1 M) at doses of 3 and 6 mEq/kg decreased mean QRS duration 15 +/- 5 and 24 +/- 6%, respectively (mean +/- S.D.) and was superior to no treatment (P less than .01). NaCl (1 M) was as effective as NaHCO3 in decreasing QRS duration, as was 1 M NaHCO3 supplemented with 48 mM KCl. Respiratory alkalosis and 10% mannitol did not decrease QRS duration. NaHCO3, NaCl and NaHCO3/KCl all produced comparable increases in mean arterial blood pressure. Respiratory alkalosis and mannitol did not increase mean arterial pressure, but did prevent the decline seen in control animals. Acidosis produced by ventilation with 10% CO2 exacerbated QRS prolongation due to DMI. In acidotic animals, NaHCO3 and NaCl were equally effective in reversing QRS prolongation and hypotension. Correction of respiratory acidosis by discontinuation of inhaled CO2 did not improve QRS duration or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
The regional distribution of imipramine (IMI) and desipramine (DMI) in rat brain after single and chronic oral administration of IMI was studied. The distribution of IMI and DMI in all examined brain regions was similar, except for hippocampus + septum. After chronic administration of IMI the disappearance of the parent drug and its metabolite was slowing down in all investigated brain regions as well as in the plasma. The accumulation of IMI and DMI after chronic treatment of IMI was significantly higher in plasma than in all examined brain regions.
Effects of desipramine (DPr), a tricyclic antidepressant, on isolated trabeculae of the right rabbit atrial myocardium were studied using a standard microelectrode technique. Between 10(-7) and 10(-4) g/ml DPr reduced the maximum upstroke velocity Vmax of the action potentials. The membrane responsiveness was found to be depressed for DPr increased the time constant of the recovery of Vmax in a concentration-dependent manner distinctly. The voltage-Vmax relationships were shifted to more positive potentials and were flattend by increasing the concentration of DPr. DPr prolonged the duration of the action potentials on all levels of repolarization. Between 10(-7) and 10(-5) g/ml both resting and overshoot potential were found to be unchanged. At concentrations higher than 10(-5) g/ml slow response action potential insensitive to 10(-5) mol/l TTX were evoked, the resting transmembrane potential depolarized, spatial inhomogeneities in transmembrane potential and triggered activity could be observed. DPr may act antiarrhythmogenically in a quinidine-like manner at concentrations between 10(-7) and 10(-5) g/ml by (1) decreasing the fast channel conductance, (2) delaying the recovery of the fast channel. At concentrations higher than 10(-5) g/ml DPr could effect arrhythmogenic actions by a complete depression of fast response action potentials, unmasking of slow response action potentials and generation of severe spatial inhomogeneities.
In metabolic tests in narcotized rats it could be demonstrated that isoprenaline under continuous intramuscular infusion is, calorigenically, about three times more effective than noradrenalin. By blocking the uptake of sympathomimetics into peripheral adrenergic neurones by means of desipramine the calorigenic effect of noradrenalin is increased thirteenfold while under isoprenaline it decreases slightly.
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has numerous etiologies, including medical illness, stress, and various pharmacologic agents. While a number of psychotropic agents may induce SIADH, only a few reports of tricyclic-antidepressant-induced SIADH exist. A case of SIADH associated with desipramine treatment in an elderly depressed woman is described.
The authors investigated absorption of noradrenalin by neurons and glia cells cultivated in vitro. Material was taken from locus coreuleus of 3, 6, 12, 18, 24, and 36 days old rats. On the basis of observations, the authors found out that absorption of egzogenic noradrenalin changes with the growth of animals. In animals less than 24 days old, noradrenalin is absorbed not only by neurons but also by glia cells. Desipramin affects the egzogenic noradrenalin absorption clearly over the 12th day of life.