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PubMed1991

Changes in saccharide and phospholipid content associated with drug storage in cultured rabbit aorta muscle cells.

In the investigation of cellular changes associated with intracellular drug storage, we incubated cultured rabbit aorta muscle cells with various amphiphilic agents. Disobutamide, chloroquine, and desipramine each increased cellular content of rhamnose, arabinose, mannose, glucose, and total saccharides; these agents also elevated total and individual phospholipid of all classes. Amiodarone did not alter total saccharide content, but increased total phospholipid. Tilorone, in contrast, decreased total saccharides, but phospholipid content was unchanged. All test agents decreased xylose content. By light microscopy, disobutamide, chloroquine, and tilorone induced clear cytoplasmic vacuoles; desipramine induced dense cytoplasmic granules; and amiodarone induced both cytoplasmic changes. By electron microscopy, the content of the cellular alterations induced by disobutamide was primarily electron lucent; that of the alterations induced by desipramine was primarily concentric lamellar bodies/flocculent electron-dense structures; and that of the alterations induced by amiodarone was a mixture of both. There was no correlation, therefore, between the induced cellular chemical contents and morphologic changes. Despite the physicochemical similarity of the amphiphilic drugs (all have cationic and lipophilic moieties), the chemical responses they induced were different. The results suggest that amphiphilic drugs alter processes involving saccharides as well as those of phospholipid metabolism. The origin of the saccharide moieties associated with the induced changes in monosaccharide contents is not known. Increased content of phosphatidylinositol, mannose, and glycosyl residues is consistent with the suggestion that amphiphilic drugs may cause an increase in membrane anchor synthesis. The inhibition of lysosomal enzyme activities responsible for the degradation of phospholipid and other anchors may also account for the observed increase in monosaccharides and phosphatidylinositol content.

Amines↗
PubMed1990

Fenfluramine augmentation in tricyclic-refractory depression.

The clinical efficacy of lithium augmentation in refractory depression is hypothesized to depend on the ability of lithium to enhance presynaptic 5-hydroxytryptamine (5-HT) function. Since fenfluramine promotes release and inhibits reuptake of presynaptic 5-HT, we assessed its efficacy in augmenting ongoing tricyclic antidepressant treatment of refractory depression. Fifteen patients with DSM-III major depression failed to respond to treatment with desipramine 2.5 mg/kg/day or more (plasma levels of at least 125 ng/ml) given for at least 4 weeks. Fenfluramine 40-120 mg/day was then added to the ongoing desipramine in a placebo substitution design. There was no statistically significant evidence of either transient or sustained clinical improvement during the 2 weeks of fenfluramine augmentation. One patient appeared to respond to the treatment, but one appeared to worsen. Fenfluramine more than doubled steady-state plasma levels of desipramine. These findings suggest that lithium's efficacy as an augmenting agent depends on properties that are not shared by fenfluramine. Fenfluramine cannot be recommended in the routine management of refractory depression.

Adult↗
PubMed1989

Involvement of protein kinase in the regulation of beta-adrenergic receptors by antidepressants.

The role of serotonin (5-HT) and protein kinases in the regulation of the beta-receptor induced by typical and atypical antidepressants was investigated. Treatment with either mianserin or maprotiline for seven days produced a significant decrease in the beta-receptor density measured 6h after the last dose. The reduction in beta-receptors disappeared within 24h. However, combined treatment of mianserin or maprotiline with either fluoxetine or 5-hydroxytryptophan significantly decreased beta-receptors even 24h after the last dose. Following treatment with p-chlorophenylalanine the reduction in beta-receptors induced by desipramine was reversible within 24h. These results demonstrate that an increase in the synaptic 5-HT availability may contribute to the prolongation of the beta-receptor down-regulation by antidepressants. The intraventricular infusion of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a potent protein kinase C (PK-C) activator for seven days caused a significant decrease in beta-receptors, while forskolin or dibutyryl cyclic adenosine monophosphate had no influence on the receptor. The TPA-induced and desipramine-induced decreases in beta-receptors were not additive, suggesting that a similar mechanism is involved. The infusion of the PK-C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) caused an inhibition of the desipramine-induced decrease in beta-receptors. It is suggested that the beta-receptor down-regulation by antidepressants might be also regulated by PK-C through 5-HT-Ca2+-inositol-phospholipid systems.

5,7-Dihydroxytryptamine↗
PubMed1985

Some pharmacological actions of nisoxetine, a bicyclic inhibitor of noradrenaline uptake.

Some peripheral actions of the phenoxyphenylpropylamine, nisoxetine, have been compared with those of the tricyclic antidepressant, desipramine. The two drugs were equipotent in inhibiting the accumulation of 3H-noradrenaline by the sympathetic nerve terminals of the rat vas deferens; and, in low doses, equipotent in potentiating the actions of noradrenaline at both alpha 1- and alpha 2-adrenoceptors in this tissue. In the vas deferens, the alpha 1-adrenoceptor blocking action of desipramine was evident at concentrations of 0.1 mumol l-1 and above; nisoxetine was less potent. Neither drug exhibited antagonist actions at alpha 2-adrenoceptors. Nisoxetine was also less potent than desipramine in inhibiting responses to histamine, carbachol and bradykinin on the guinea-pig isolated ileum. Thus nisoxetine is the more specific of the two neuronal uptake inhibitors and may be a useful tool to block neuronal uptake in experiments designed to classify adrenoceptors in other tissues.

Animals↗
PubMed1980

Modulatory role of alpha adrenoceptors on the release of [3H]norepinephrine elicited by preganglionic stimulation of the cat superior cervical ganglion.

In the isolated cat superior cervical ganglion labeled in vitro with [3H]norepinephrine ([3H]NE), the overflow of radioactivity evoked by preganglionic stimulation at 10 Hz (80 V, 2 msec duration for 5 min) was reduced to 50% of control values by the alpha adrenoceptor agonists clonidine (0.001 microM) and methoxamine (12.0 microM). The alpha adrenoceptor antagonist phenoxybenzamine (2.9 microM) produced a 2-fold increase in the overflow of [3H]NE elicited by nerve stimulation. Preincubation with drugs that reduce the neuronal uptake of norepinephrine in the isolated ganglion (8.8 microM cocaine and 0.33 microM desipramine) did not modify the release of [3H]NE by preganglionic stimulation. However, a higher concentration of desipramine (3.3 microM) produced a 4-fold increase in the overflow of tritium evoked by stimulation. As this concentration of desipramine produced a shift to the right in the concentration-response curve to methoxamine in the isolated nictitating membrane of the cat, the conclusion is drawn that a feedback mechanism mediated through presynaptic alpha adrenoceptors regulates the release of [3H]NE induced by preganglionic stimulation of the cat superior cervical ganglion. In addition, it is suggested that regulatory mechanisms for norepinephrine release by nerve stimulation are not restricted to nerve terminals but are also present in dendrites of the postganglionic adrenergic neurons.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Anti-nociceptive effect of tricyclic anti-depressants following intrathecal administration.

The anti-nociceptive effects of three tricyclic anti-depressants (desipramine, protriptyline, fluoxetine) were evaluated in mice following intrathecal administration. Nociceptive behavior was produced by intrathecal administration of Substance P and measured for 60 seconds following subcutaneous and intrathecal administration of vehicle and increasing doses of the drugs being tested. Systemically administered protriptyline produced dose related antinociception in this paradigm. A similar effect was seen following systemic desipramine; while fluoxetine was inactive systemically. Both protriptyline and desipramine given intrathecally were antinociceptive while fluoxetine had a biphasic effect, being analgesic only at low doses. These results indicate that tricyclic antidepressants may produce analgesia at the spinal level in rodents. This action may be related to the therapeutic success of tricyclic antidepressants in chronic pain syndromes.

Analgesics↗
PubMed1983

Effects of a new antidepressant drug on active avoidance behavior in rats. Comparative study with tricyclic antidepressants.

The effects of a new antidepressant drug, EGYT-475 (1-benzyl-4-(2'-pyridylcarbonyl)-piperazine) on the acquisition and extinction of conditioned avoidance behavior following short and long-term treatment were studied in rats. The effects were compared with those of amitriptyline, imipramine and desipramine. In a six-day acquisition period, EGYT-475 in a 200 mg/kg dose p.o facilitated the acquisition, while amitriptyline, imipramine and desipramine either had no effect or impaired the acquisition, depending upon the dose used. In a six-day extinction period, EGYT-475 delayed the extinction following either oral or intraperitoneal administration, while amitriptyline, imipramine, and desipramine in various doses facilitated the extinction. On prolonged treatment the delayed extinction was maintained even after 42 days in animals treated with EGYT-475. The results indicate that EGYT-475, in contrast to tricyclic antidepressants, does not impair the acquisition of avoidance conditioning but rather improves it while it does not facilitate the extinction of learned behavior but considerably delays it.

Amitriptyline↗
PubMed1983

[Calorigenic action of dopamine and dobutamine].

In tests on narcotized rats dopamine and dobutamine show significant calorigenic actions By subcutaneous application dobutamine is nearly as effective as noradrenaline while dopamine acts approximately five times less. Pretreatment with desipramine increases the calorigenic action of noradrenaline and accelerates its onset and its dying down simultaneously. Such a pretreatment exerts no influence whatever on the calorigenic action of dobutamine, which begins and dies down remarkably fast. Calorigenic action of dopamine is lessened by desipramine pretreatment, unambiguously. If sympathomimetics are not taken up into the neurons or their uptake is blocked by substances like desipramine, their access to the receptors is facilitated and their biotransformation possibly favoured.

Animals↗
PubMed1982

Effect of pregnenolone-16 alpha-carbonitrile on the biliary and urinary excretion of imipramine and some of its metabolites in rats.

The influence of pregnenolone-16 alpha-carbonitrile (PCN) upon the biliary and urinary excretion of unchanged imipramine and some of its metabolites was investigated in female rats. The substrate and its metabolites were identified and quantified by thin-layer chromatography and/or gas-liquid chromatography. PCN augmented urinary excretion of desipramine and the imipramine- and desipramine-glucuronides. PCN pretreatment also diminished the urinary elimination of imipramine N-oxide whereas proadifen hydrochloride had an inverse effect, suggesting a shift in the metabolic pathways of imipramine. The biliary excretion of the imipramine and desipramine glucuronides was not significantly altered by PCN.

Animals↗
PubMed1995

Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription.

Clinical observations agree that antidepressant drugs are effective only after a lag phase of 1-3 weeks. This delay could be explained at the molecular level by an action on gene transcription. Transcription of many genes is directed by the cAMP/Ca(2+)-responsive element (CRE) and its cognate transcription factor CRE-binding protein (CREB). Membrane depolarization and cAMP induce the phosphorylation of CREB at Ser-119 and thereby stimulate the transcriptional activity of CREB. The effect of antidepressant drugs on CREB/CRE-directed gene transcription was investigated using transient transfections of reporter fusion genes in HIT and PC-12 cells. Clomipramine, imipramine, fluoxetine, doxepin, desipramine, amitriptyline, maprotiline, mianserin, and trazodone inhibited CRE-directed gene transcription that was stimulated by membrane depolarization, with IC50 values between 70 nM and 1.73 microM. Desipramine had no effect on transcription after stimulation by cAMP but blocked the synergistic effect of cAMP and membrane depolarization to the level of stimulation by cAMP alone. Upon membrane depolarization, desipramine reduced the phosphorylation of CREB at Ser-119 and also blocked the depolarization-induced increase in the intracellular free Ca2+ concentration in HIT cells. Thus, by interfering with the depolarization-induced activation of the transcription factor CREB, antidepressant drugs can inhibit CRE-directed gene transcription, which could underlie the pharmacological effects of these clinically important drugs.

Animals↗
PubMed1995

Modulation of left ventricular iodine-125-MIBG accumulation in cardiomyopathic Syrian hamsters using the renin-angiotensin system.

UNLABELLED: Genetically inbred cardiomyopathic hamsters were examined to investigate the mechanism of reduced myocardial accumulation of metaiodobenzylguanidine (MIBG) in the cardiomyopathic heart. METHODS: Bio 14.6 Syrian hamsters (hypertrophic stage: n = 15, early heart failure stage: n = 17) and control F1b strain golden hamsters (n = 36) were injected with 296 kBq of [125I] MIBG and killed 30 min or 4 hr later. Thirty-three of these hamsters were pretreated with 10 mg/kg of desipramine to determine non-neuronal MIBG accumulation. To evaluate the nonexocytotic MIBG release from nerve endings, desipramine was administered to four Bio 14.6 hamsters 15 min after [125I]MIBG injection. To determine the role of the activated renin-angiotensin system (RAS) in MIBG washout from sympathetic nerve terminals in cardiomyopathy at early heart failure stage, 10 mg/kg/day cilazapril, an angiotensin-converting enzyme inhibitor, was given orally to 7 controls and 16 cardiomyopathic hamsters for 16 wk. RESULTS: In the absence of desipramine pretreatment, left ventricular [125I]MIBG accumulation 4 hr after injection was 0.376% +/- 0.015 %kg dose/g (mean +/- s.e.m.) in the hypertrophic hamsters (versus 0.418 +/- 0.019 in controls of the same age; ns), and 0.195 +/- 0.025 in early heart failure hamsters. Treatment with cilazapril partially restored MIBG accumulation in the Bio 14.6 hamsters but did not affect the controls. CONCLUSION: Decreased [125I]MIBG accumulation in cardiomyopathic hamsters during the early heart failure stage is caused by neuronal release which is partially modulated by the activated RAS.

3-Iodobenzylguanidine↗
PubMed1994

On the characterization of dopamine-induced contractile response of rat anococcygeus muscle preparation.

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Compulsive exhibitionism successfully treated with fluvoxamine: a controlled case study.

BACKGROUND: Paraphilias are psychosexual disorders that are usually conceptualized as deviant in nature. Yet in some cases, paraphilia can be conceptualized as an obsessive compulsive disorder. METHOD: We describe an exhibitionist treated under partial single-blind conditions (patient was blind to placebo but was aware he was receiving desipramine and fluvoxamine) with the serotonin selective reuptake inhibitor fluvoxamine, followed by desipramine and a placebo that looked like fluvoxamine, in an ABACA design. He was serially assessed with the Yale-Brown Obsessive Compulsive Scale. RESULTS: Fluvoxamine eliminated the undesired impulse and behavior without affecting sexual desire. Desipramine and single-blind fluvoxamine-placebo treatment were both associated with relapses. CONCLUSION: A subset of paraphiliacs may be suffering from obsessive-compulsive-related disorders and may benefit from serotonergic agents.

Adult↗
PubMed1997

Effects of proposed treatments for cocaine addiction on hemodynamic responsiveness to cocaine in conscious rats.

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.

Animals↗
PubMed1976

Gas-chromatographic analysis for therapeutic concentration of imipramine and disipramine in plasma, with use of a nitrogen detector.

We describe a method for the simultaneous gas-chromatographic analysis of imipramine and desipramine (the active N-desmethyl metabolite) at therapeutic concentrations in human plasma, with use of a nitrogen detector. Imipramine is measured as the unchanged base and desipramine as its N-tribluoroacetyl derivative. Promazine is the internal standard. The lower limit of sensitivity is 5 mug/liter for each drug, and the within-day coefficients of variation for the determination of imipramine and desipramine, respectively, are 6.0% and 3.3%. We measured concentrations of these drugs both in patients receiving therapeutic doses of imipramine and in those who had ingested an overdose.

Chromatography, Gas↗
PubMed1998

Noradrenergic versus serotonergic antidepressants: predictors of treatment response.

Serotonin selective reuptake inhibitors (SSRIs) have generally proven to be as effective as tricyclic antidepressants (TCAs) in the treatment of major depression and have an improved side effect profile. However, data suggest that the SSRIs are not as effective as the TCAs in certain subsets of depressed patients, indicating the importance of norepinephrine reuptake inhibition for such patients. Evidence for the role of norepinephrine in depression comes from early studies on excretion of catecholamines and more recent studies on receptor function, second messenger systems, and gene modification. These data are reviewed in this article. Data from a multicenter, randomized, controlled clinical trial comparing desipramine, a relatively norepinephrine-selective TCA, and the SSRI fluoxetine in moderate to marked major depression suggest a differential response depending on the antidepressant. The 2 drugs were overall similar in efficacy; however, in severely ill patients, there was a suggestion that desipramine was more likely to induce remission than fluoxetine. Urinary metabolite 3-methoxy-4-hydroxyphenylglycol levels were a better predictor of likelihood of remission than severity of episode or drug treatment. Desipramine and fluoxetine produced different longitudinal effects in catecholamine excretion, indicating that the 2 agents act through different mechanisms. Given the good therapeutic profile but relative risks associated with TCA therapy, selective norepinephrine reuptake inhibitors, such as reboxetine, which has a good safety profile, could be a major step forward in the treatment of depression.

Adrenergic Uptake Inhibitors↗
PubMed2000

Atmospheric pressure ionization time-of-flight mass spectrometry coupled with fast liquid chromatography for quantitation and accurate mass measurement of five pharmaceutical drugs in human plasma.

The quantitative determination and accurate mass measurement of five tricyclic amine pharmaceutical drugs (doxepin, desipramine, imipramine, amitriptyline and trimipramine) fortified in human plasma within a per sample run time of 18 s was accomplished by atmospheric pressure ionization (API) time-of-flight (TOF) mass spectrometry using a turboIonspray liquid chromatography/mass spectrometry (LC/MS) interface coupled with high-performance liquid chromatography (HPLC). The relatively short HPLC separation (18 s) was achieved using a short C18 column (15 x 2.1 mm i.d.) with a high aqueous mobile phase maintained at a flow-rate of 1.4 ml min(-1). An acquisition speed of 0.2 s per spectrum accommodates these fast separation conditions. This method employs a one-step liquid-liquid extraction procedure to isolate the five tricyclic amines from biological matrix components The overall extraction recovery was 75% for desipramine and >90% for the other four tricyclic amines. The lower level of quantitation was 1-2 ng ml(-1) for each compound. The calibration curve was linear from 2 to 100 ng ml(-1) for desipramine and from 1 to 50 ng ml(-1) for the other four tricyclic amines. A deuterated internal standard, imipramine-d3, was used for all five tricyclic amines. Acceptable intra- and inter-assay precision (1.0-17.7%) and accuracy (0.2-14.5%) were obtained. The linear dynamic range was extended to 200 based on a software upgrade for correcting ion current detection saturation. The accurate masses of the five tricyclic amines were determined by on-line LC/TOFMS analyses of biological extracts using two-point internal mass calibration. This was done by infusing a reference standard, Jeffamine D230, post-column into the HPLC effluent. All results showed a mass error not greater than 9 ppm for all the target compounds. These results were obtained from both synthetic mixtures when as little as 100 pg were injected or extracts of spiked human plasma samples with analytical concentration as low as 5 ng ml(-1). The factors influencing accurate mass measurements are discussed.

Antidepressive Agents, Tricyclic↗
PubMed1997

Regulation of norepinephrine release from the rat bed nucleus of the stria terminalis: in vivo microdialysis studies.

The microdialysis technique was used to study the in vivo extracellular levels of norepinephrine in the bed nucleus of the stria terminalis. A basal level of 2.34 +/-0.25 fmol/microl of norepinephrine was observed. Desipramine (2 and 10 microM), a norepinephrine uptake blocker, significantly increased extracellular levels of norepinephrine. Reversed perfusion with high potassium in the presence of 2 microM desipramine induced the release of norepinephrine. Instead, in the presence of 10 microM desipramine, a significant decrease in the induced release of norepinephrine was observed. Clonidine, an alpha2-adrenergic agonist, significantly decreased basal extracellular levels of norepinephrine and the K+-induced release of norepinephrine. In contrast, yohimbine and RX821002, two alpha2-adrenergic antagonists, significantly increased basal extracellular levels of norepinephrine but not the release of norepinephrine induced by 70 mM K+. Perfusion of tetrodotoxin through the probe located in the bed nucleus of the stria terminalis significantly decreased both the basal extracellular level and the K+-induced release of norepinephrine. Furthermore, perfusion of tetrodotoxin through a microdialysis probe implanted in the medial forebrain bundle also decreased basal extracellular levels of norepinephrine in the bed nucleus of the stria terminalis. The results show that in vivo there is a significant noradrenergic tonic activity in the bed nucleus of the stria terminalis. This tonic activity depends on the impulse flow through medial forebrain bundle nerve fibers. Under these conditions, extracellular levels of norepinephrine in the bed nucleus of the stria terminalis are regulated by the magnitude of norepinephrine uptake and by presynaptic alpha2-adrenergic receptors.

Animals↗