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British Journal of Pharmacology Oct 19981. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in... (Comparative Study)
Comparative Study
1. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5-HT and NA reuptake to those of the selective 5-HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine. 2. Administered acutely, venlafaxine dose-dependently prolonged the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT50 values for 5-HT, while desipramine was more potent than venlafaxine at increasing the RT50 values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT50 values for 5-HT compared to that of NA. 3. A two-day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT50 values for both 5-HT and NA applications. The RT50 values for 5-HT were significantly increased at a dose of 10 mg kg(-1) day(-1), whereas those for NA were increased at a dose of 20 mg kg(-1) day(-1), consistent with the data obtained following the acute administration of venlafaxine. 4. Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.
Topics: Adrenergic Uptake Inhibitors; Animals; Cyclohexanols; Depression; Desipramine; Hippocampus; Injections, Intravenous; Iontophoresis; Male; Norepinephrine; Paroxetine; Rats; Rats, Sprague-Dawley; Serotonin; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 9806336
DOI: 10.1038/sj.bjp.0702074 -
Journal of Psychiatric Research Jan 2008Previous studies have shown that imidazoline receptors (IR-1) are increased in platelets and frontal cortex of depressed patients, and this up-regulation is normalized... (Clinical Trial)
Clinical Trial
OBJECTIVE
Previous studies have shown that imidazoline receptors (IR-1) are increased in platelets and frontal cortex of depressed patients, and this up-regulation is normalized (down-regulated) after antidepressant drug treatments. It has been hypothesized that IR-1 up-regulation during the depressive episode may be a state marker for depressive symptomatology. The goal of the present study was to address the state versus trait question.
METHOD
Twelve healthy subjects (six males and six females) met stringent inclusion and exclusion criteria for physical and mental health. They received desipramine for 6 weeks in order to simulate the length of time and dosing used previously to obtain an IR-1 down-regulation and a therapeutic response in depressed patients. Outcome and safety measures included clinical, psychological, and cardiovascular assessments obtained throughout the study. Plasma concentrations of desipramine were measured throughout the 6 weeks of treatment and again after 2 weeks following tapered discontinuation of desipramine. Platelet receptors were assessed by Western blotting and radioligand binding assays.
RESULTS
Healthy subjects taking desipramine experienced mild dysphoric effects but there were no adverse events. The binding of 8 nM p-[(125)I]clonidine to IR-1 and alpha(2)-adrenoceptors in healthy subjects did not change during desipramine treatment. The immunodensity of the 33 kDa band associated with IR-1 gradually increased to a maximum, by week-6, of 26% higher than baseline (p < 0.01 compared to baseline). Two weeks after desipramine discontinuation, there was a decline in alpha(2)-adrenoceptor binding and 33 kDa band's immunodensity (p = 0.04).
CONCLUSIONS
The findings support the hypothesis that platelet IR-1 binding sites are a marker of mood state rather than of antidepressant-induced pharmacological regulation. By comparison, platelet alpha(2)-adrenoceptors appear to be regulated by desipramine as a pharmacological effect independent of mood state.
Topics: Adult; Antidepressive Agents, Tricyclic; Blood Platelets; Brief Psychiatric Rating Scale; Depressive Disorder; Desipramine; Female; Gene Expression Regulation; Humans; Imidazoline Receptors; Male; Platelet Count; Radioligand Assay; Reference Values; Time Factors
PubMed: 17166518
DOI: 10.1016/j.jpsychires.2006.10.011 -
Anti-cancer Agents in Medicinal... 2023TRAIL has emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells while sparing normal cells. Autophagy, a highly...
BACKGROUND
TRAIL has emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells while sparing normal cells. Autophagy, a highly regulated cellular recycling mechanism, is known to play a cell survival role by providing a required environment for the cell. Recent studies suggest that autophagy plays a significant role in increasing TRAIL resistance in certain cancer cells. Thus, regulating autophagy in TRAIL-mediated cancer therapy is crucial for its role in cancer treatment.
OBJECTIVE
Our study explored whether the antidepressant drug desipramine could enhance the ability of TRAIL to kill cancer cells by inhibiting autophagy.
METHODS
The effect of desipramine on TRAIL sensitivity was examined in various lung cancer cell lines. Cell viability was measured by morphological analysis, trypan blue exclusion, and crystal violet staining. Flow cytometry analysis was carried out to measure apoptosis with annexin V-PI stained cells. Western blotting, rtPCR, and immunocytochemistry were carried out to measure autophagy and death receptor expression. TEM was carried out to detect autophagy inhibition.
RESULTS
Desipramine treatment increased the TRAIL sensitivity in all lung cancer cell lines. Mechanistically, desipramine treatment induced death receptor expression to increase TRAIL sensitivity. This effect was confirmed when the genetic blockade of DR5 reduced the effect of desipramine in enhanced TRAIL-mediated cell death. Further investigation revealed that desipramine treatment increased the LC3 and p62 levels, indicating the inhibition of lysosomal degradation of autophagy. Notably, TRAIL, in combination with either desipramine or the autophagy inhibitor chloroquine, exhibited enhanced cytotoxicity compared to TRAIL treatment alone.
CONCLUSION
Our findings revealed the potential of desipramine to induce TRAIL-mediated cell death by autophagy impairment. This discovery suggests its therapeutic potential for inducing TRAIL-mediated cell death by increasing the expression of death receptors, which is caused by impairing autophagy.
Topics: Humans; Antidepressive Agents; Apoptosis; Autophagy; Cell Line, Tumor; Desipramine; Lung Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand
PubMed: 37859313
DOI: 10.2174/0118715206262252231004110310 -
The Journal of Pharmacology and... Sep 2003The effect of reboxetine on sympathetic neuroeffector transmission in rabbit isolated carotid artery was examined. Reboxetine (10-8-3 x 10-6 M) and cocaine (10-6-3 x...
The effect of reboxetine on sympathetic neuroeffector transmission in rabbit isolated carotid artery was examined. Reboxetine (10-8-3 x 10-6 M) and cocaine (10-6-3 x 10-5 M), but not desipramine (10-8-3 x 10-7 M), increased contractions evoked by electrical field stimulation. At higher concentrations, reboxetine (10-4 M), cocaine (3 x 10-4 M), and desipramine (3 x 10-7-10-5 M) inhibited the neurogenic contractions. The enhancement seen with reboxetine and cocaine was partially reversible, whereas the inhibition was readily reversible. Reboxetine (10-7 M) and cocaine (10-5 M) prevented the inhibitory action of bretylium (10-6 M). Reboxetine (10-8-10-5 M), desipramine (10-7-10-4 M), and cocaine (10-6-10-5 M) increased the stimulation-evoked [3H]norepinephrine release. Pargyline (5 x 10-4 M) augmented the facilitatory effect of reboxetine (3 x 10-9-10-6 M) and cocaine (10-7-3 x 10-5 M). Reboxetine (10-8-10-6 M), desipramine (10-8-10-6 M), and cocaine (3 x 10-8-10-5 M) reduced the [3H]norepinephrine (10-8 M) uptake. Reboxetine (10-7 M) and cocaine (10-5-2 x 10-4 M) enhanced the contractions evoked by phenylephrine and norepinephrine. Higher concentrations of reboxetine antagonized the contractions. Reboxetine (10-5-6 x 10-5 M) antagonized the contractions evoked by potassium. The contractions evoked by tyramine (3 x 10-6-10-3 M) was reduced by reboxetine (3 x 10-8-10-6 M) and by cocaine (10-7-10-5 M). We conclude that reboxetine inhibits the membrane amine pump (uptake-1) in the terminals of postganglionic adrenergic neurons in a cocaine-like manner.
Topics: Animals; Bretylium Compounds; Carotid Arteries; Cocaine; Desipramine; Morpholines; Neuroeffector Junction; Norepinephrine; Pargyline; Potassium; Rabbits; Reboxetine; Sympathetic Nervous System; Tritium
PubMed: 12754319
DOI: 10.1124/jpet.103.052233 -
British Journal of Pharmacology Apr 19961. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and...
1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.
Topics: Animals; Antidepressive Agents, Tricyclic; Behavior, Animal; Binding Sites; Brain; Desipramine; Dose-Response Relationship, Drug; Male; Olfactory Bulb; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Receptors, Serotonin; Time Factors
PubMed: 8730743
DOI: 10.1111/j.1476-5381.1996.tb15310.x -
Analytical and Bioanalytical Chemistry Oct 2022The effect of LC mobile phase composition and flow rate (2-50 µL/min) on mobility behavior in vacuum differential mobility spectrometry (vDMS) was investigated for...
The effect of LC mobile phase composition and flow rate (2-50 µL/min) on mobility behavior in vacuum differential mobility spectrometry (vDMS) was investigated for electrosprayed isobaric antidepressant drugs (AD); amitriptyline, maprotiline, venlafaxine; and structurally related antidepressants nortriptyline, imipramine, and desipramine. While at 2 µL/min, no difference in compensation voltage was observed with methanol and acetonitrile, at 50 µL/min, acetonitrile used for LC elution of analytes enabled the selectivity of the mobility separation to be improved. An accurate and sensitive method could be developed for the quantification of six AD drugs in human plasma using trap/elute micro-LC setup hyphenated to vDMS with mass spectrometric detection in the selected ion monitoring mode. The assay was found to be linear over three orders of magnitude, and the limit of quantification was of 25 ng/mL for all analytes. The LC-vDMS-SIM/MS method was compared to a LC-MRM/MS method, and in both cases, inter-assay precisions were lower than 12.5 and accuracies were in the range 91.5-110%, but with a four times reduced analysis time (2 min) for the LC-vDMS-SIM/MS method. This work illustrates that with vDMS, the LC mobile phase composition can be used to tune the ion mobility separation and to improve assay selectivity without additional hardware.
Topics: Acetonitriles; Amitriptyline; Antidepressive Agents; Desipramine; Humans; Imipramine; Maprotiline; Mass Spectrometry; Methanol; Nortriptyline; Reproducibility of Results; Spectrum Analysis; Vacuum; Venlafaxine Hydrochloride
PubMed: 35976423
DOI: 10.1007/s00216-022-04276-0 -
British Journal of Clinical Pharmacology Mar 1997The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
AIMS
The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.
METHODS
The effect of oral ketoconazole (200 mg day-1 for 14 days) on the kinetics of a single oral dose of imipramine (100 mg) and desipramine (100 mg) was evaluated in two groups of six healthy male subjects.
RESULTS
Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16 +/- 0.21 to 0.96 +/- 0.20 l h-1 kg-1, mean +/- s.d.; P < 0.02), a prolongation in imipramine half-life (from 16.7 +/- 3.3 to 19.2 +/- 5.4 h, P < 0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507 +/- 1707 to 3180 +/- 1505 nmol l-1 h, P < 0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.
CONCLUSIONS
These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N-demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.
Topics: Administration, Oral; Adult; Antidepressive Agents, Tricyclic; Antifungal Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Desipramine; Drug Interactions; Humans; Imipramine; Ketoconazole; Kinetics; Male; Middle Aged; Mixed Function Oxygenases
PubMed: 9088587
DOI: 10.1046/j.1365-2125.1997.00539.x -
Anesthesiology Jun 1998The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central...
INTRODUCTION
The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective alpha2-adrenergic agonist, were studied in rats.
METHODS
Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined.
RESULTS
Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of alpha2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal.
CONCLUSIONS
These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an alpha1-adrenergic mechanism.
Topics: Adrenergic alpha-Agonists; Analgesics, Non-Narcotic; Anesthetics, Inhalation; Animals; Antidepressive Agents, Tricyclic; Desipramine; Drug Synergism; Imidazoles; Male; Medetomidine; Norepinephrine; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex
PubMed: 9637658
DOI: 10.1097/00000542-199806000-00028 -
American Journal of Hematology Oct 2017Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the β3 adrenergic receptor. Preclinical studies have...
Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the β3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 10 CD34 cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 10 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 10 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.
Topics: Adolescent; Adrenergic Uptake Inhibitors; Adult; Aged; Antigens, CD34; Benzylamines; Cyclams; Desipramine; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Male; Middle Aged; Multiple Myeloma; Pilot Projects; Receptors, Adrenergic, beta-3; Young Adult
PubMed: 28675459
DOI: 10.1002/ajh.24843 -
Journal of Biomedicine & Biotechnology 2012Abnormal increase in sympathetic nerve sprouting was responsible for the ventricular arrhythmogenesis after myocardial infarction. This study investigated whether the...
Abnormal increase in sympathetic nerve sprouting was responsible for the ventricular arrhythmogenesis after myocardial infarction. This study investigated whether the norepinephrine transporter inhibitor, desipramine, can modulate sympathetic remodeling and ventricular fibrillation threshold (VFT) after myocardial ischemia-reperfusion. Rats were administered desipramine (0.8 mg/kg, i.v.) before or after myocardial ischemia. VFT, infarct size, tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43)-positive nerve fibers were measured after one week. The VFT of preischemic treatment group was 11.0 ± 2.65 V and significantly higher than that of control ischemic group (7.2 ± 1.30 V, P < 0.05). Infarct size in the preischemic treatment group (23.3 ± 2.4%) was significantly lower than that in the control ischemic group (30.8 ± 1.3%, P < 0.05) and the delayed application group (27.1 ± 2.6%, P < 0.05). The density of TH and GAP43-positive nerve fibers in the control ischemic group was significantly higher than that in the other three groups (P < 0.05). The density of nerve fibers improved after desipramine treatment. Moreover, there was a negative correlation between the VFT and both TH and GAP43-positive nerve fiber density in the infarct border zone (P < 0.05). Desipramine treatment before acute myocardial ischemia can decrease infarct size, improve sympathetic remodeling, and increase VFT and electrical stability of ischemic hearts. Desipramine appears to cause myocardial ischemic preconditioning.
Topics: Adrenergic Uptake Inhibitors; Animals; Desipramine; Male; Myocardial Ischemia; Premedication; Rats; Sympathetic Nervous System; Treatment Outcome; Ventricular Fibrillation
PubMed: 23093858
DOI: 10.1155/2012/732909