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British Journal of Clinical Pharmacology Apr 1984In order to better define the role of pharmacokinetic variation in reported cross-ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics...
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.
Topics: Adult; Asian People; Desipramine; Female; Half-Life; Humans; Hydroxylation; Kinetics; Male; Middle Aged; White People
PubMed: 6721989
DOI: 10.1111/j.1365-2125.1984.tb02368.x -
Biomedicine & Pharmacotherapy =... Feb 2022Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have...
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha-adrenergic receptor (α-ADR) overexpression found in BDNF mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF plasmid or exposed to pro-BDNF peptide. Finally, we show that homozygous BDNF CAD patients have hyper-reactive platelets overexpressing abundant α-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.
Topics: Aged; Aged, 80 and over; Animals; Blood Coagulation; Brain-Derived Neurotrophic Factor; Coronary Artery Disease; Depression; Desipramine; Female; Humans; Male; Mice; Middle Aged; Norepinephrine; Polymorphism, Single Nucleotide; Receptors, Adrenergic, alpha-2; Thrombosis
PubMed: 34965503
DOI: 10.1016/j.biopha.2021.112557 -
The International Journal of... Aug 2011The dentate gyrus (DG), a part of the hippocampal formation, is a candidate target of antidepressants and may play a role in the development of depressive syndrome;...
The dentate gyrus (DG), a part of the hippocampal formation, is a candidate target of antidepressants and may play a role in the development of depressive syndrome; however, there is no direct neurobiological evidence supporting this theory. Here, we examined whether DG integrity is necessary for the behavioural effects of acute or chronic antidepressant treatment. Microinjection of colchicine into DG severely damaged the granule cells, as confirmed by morphological, electrophysiological, and behavioural analyses. Acute treatment with desipramine and fluoxetine decreased the immobility of saline-treated rats in the forced swimming test, whereas this decrease was inhibited in colchicine-treated rats. Chronic treatment with desipramine and fluoxetine also decreased the immobility of saline-treated rats; however, the extensive DG damage induced by colchicine had no effect on this decrease. In the novelty-suppressed feeding test, chronic treatment with desipramine and fluoxetine decreased the latency to feed in saline-treated rats while, once again, the extensive DG damage caused by colchicine had no effect on this decrease. Thus, we concluded that DG integrity was required for the behavioural effects of acute but not chronic antidepressant treatment; this disparity was not due to the time interval between surgery and behavioural tests. These findings indicate that treatment duration determines the influence of DG integrity on antidepressant effects.
Topics: Animals; Antidepressive Agents; Colchicine; Dentate Gyrus; Desipramine; Drug Administration Schedule; Excitatory Postsynaptic Potentials; Feeding Behavior; Fluoxetine; Immobility Response, Tonic; Male; Maze Learning; Microinjections; Rats; Rats, Sprague-Dawley
PubMed: 21044405
DOI: 10.1017/S1461145710001276 -
Methods and Findings in Experimental... May 2000Cizolirtine citrate (E-4018) is a new analgesic agent with antinociceptive activity against phenylquinone (ED50 33.7 mg/kg) and acetic acid (ED50 24.4 mg/kg) in mice,...
Cizolirtine citrate (E-4018) is a new analgesic agent with antinociceptive activity against phenylquinone (ED50 33.7 mg/kg) and acetic acid (ED50 24.4 mg/kg) in mice, against acetic acid in rats (ED50 21.3 mg/kg) and in the plantar test (ED50 26.8 mg/kg). It demonstrated antinociceptive activity in the tail-pinch and tail-flick tests (ED50s of 68.0 and 46.0 mg/kg, respectively), in both phases of the formalin test (ED50 13.8 and 2.31 mg/kg), and in the capsaicin test (ED50 7.14 mg/kg). Cizolirtine does not inhibit prostaglandin biosynthesis, it is not a ligand for opioid receptors, it does not have antiinflammatory or ulcerogenic activity, it has some antipyretic activity and shows no affinity for alpha 2-adrenergic receptors, but its analgesic effect was modified by idazoxan and by desipramine. Recent studies have shown that the analgesic effect of cizolirtine could be related, at least partially, to an inhibition of spinal substance P release.
Topics: Analgesics; Animals; Desipramine; Dinoprostone; Dose-Response Relationship, Drug; Gastric Mucosa; Idazoxan; Male; Mice; Naloxone; Pyrazoles; Rats; Rats, Wistar
PubMed: 10939032
DOI: 10.1358/mf.2000.22.4.584453 -
Scientific Reports Sep 2017The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis...
The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis survivors might develop hepatocellular/hepatobiliary injury and fibrosis. Here, we demonstrate that acid sphingomyelinase, an important regulator of hepatocyte apoptosis and hepatic stellate cell (HSC) activation, is linked to the promotion of liver dysfunction in the acute phase of sepsis as well as to fibrogenesis in the long-term. In both phases, we observed a beneficial effect of partial genetic sphingomyelinase deficiency in heterozygous animals (smpd1) on oxidative stress levels, hepatobiliary function, macrophage infiltration and on HSC activation. Strikingly, similar to heterozygote expression of SMPD1, either preventative (p-smpd1) or therapeutic (t-smpd1) pharmacological treatment strategies with desipramine - a functional inhibitor of acid sphingomyelinase (FIASMA) - significantly improved liver function and survival. The inhibition of sphingomyelinase exhibited a protective effect on liver function in the acute-phase, and the reduction of HSC activation diminished development of sepsis-associated liver fibrosis in the post-acute phase of sepsis. In summary, targeting sphingomyelinase with FDA-approved drugs is a novel promising strategy to overcome sepsis-induced liver dysfunction.
Topics: Animals; Apoptosis; Cell Line; Desipramine; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Male; Mice; Mice, Transgenic; Oxidative Stress; Sepsis; Sphingomyelin Phosphodiesterase; Treatment Outcome
PubMed: 28955042
DOI: 10.1038/s41598-017-11837-2 -
Psychopharmacology Jul 2012Depression is associated with medical comorbidities, particularly cardiovascular disease. However, mechanisms linking depression and cardiovascular disease remain...
RATIONALE
Depression is associated with medical comorbidities, particularly cardiovascular disease. However, mechanisms linking depression and cardiovascular disease remain unclear.
OBJECTIVES
This study investigated whether the rat resident-intruder model of social stress would elicit behavioral dysfunctions and autonomic changes characteristic of psychiatric/cardiovascular comorbidity. Furthermore, the efficacy of the corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, NBI-30775 (NBI), or the tricyclic antidepressant, desipramine (DMI), to prevent social stress-induced behavioral, neuroendocrine, and cardiovascular changes were evaluated.
METHODS
Adult male rats were exposed to resident-intruder stress (seven consecutive days) and systemically administered NBI (10 mg/kg/7 days), DMI (10 mg/kg/14 days), or vehicle. The efficacy of NBI and DMI to alter the behavioral and neuroendocrine responses to social stress was assessed. Furthermore, their effects on stress-induced forced swim behavior (FST), bladder and adrenal weight, and heart rate variability (HRV) were examined.
RESULTS
NBI, but not DMI, increased time spent in an upright, defensive posture and the latency to submit to the resident. Additionally, only NBI reduced social stress-induced adrenocorticotropic hormone and corticosterone release. Social stress increased FST immobility, caused bladder and adrenal hypertrophy, and decreased HRV. Both NBI and DMI blocked stress-induced increases in immobility during the FST. However, only NBI inhibited social stress-induced adrenal and bladder hypertrophy and decreases in heart rate variability.
CONCLUSIONS
Rat resident-intruder stress paradigm models aspects of psychiatric/medical comorbidity. Furthermore, the CRF system may contribute to both the behavioral response during social stress and its behavioral and autonomic consequences, offering insight into potential therapy to treat these comorbid conditions.
Topics: Animals; Antidepressive Agents, Tricyclic; Cardiovascular Diseases; Corticotropin-Releasing Hormone; Depression; Desipramine; Disease Models, Animal; Male; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Social Behavior; Stress, Psychological
PubMed: 22322324
DOI: 10.1007/s00213-012-2648-6 -
Translational Psychiatry Oct 2019Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of...
Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of depression in mice exposed in utero to excess glucocorticoids. The aim of this study was to investigate whether treatment with the noradrenaline reuptake inhibitor desipramine (DMI) could restore the alterations in circadian entrainment and prevent the onset of depression-like behavior. C57Bl/6 mice were exposed to dexamethasone (DEX-synthetic glucocorticoid analog, 0.05 mg/kg/day) between gestational day 14 and delivery. Male offspring aged 6 months (mo) were treated with DMI (10 mg/kg/day in drinking water) for at least 21 days before behavioral testing. We recorded spontaneous activity using the TraffiCage™ system and found that DEX mice re-entrained faster than controls after an abrupt advance in light-dark cycle by 6 h, while DMI treatment significantly delayed re-entrainment. Next we assessed the synchronization of peripheral oscillators with the central clock (located in the suprachiasmatic nucleus-SCN), as well as the mechanisms required for entrainment. We found that photic entrainment of the SCN was apparently preserved in DEX mice, but the expression of clock genes in the hippocampus was not synchronized with the light-dark cycle. This was associated with downregulated mRNA expression for arginine vasopressin (AVP; the main molecular output entraining peripheral clocks) in the SCN, and for glucocorticoid receptor (GR; required for the negative feedback loop regulating glucocorticoid secretion) in the hippocampus. DMI treatment restored the mRNA expression of AVP in the SCN and enhanced GR-mediated signaling by upregulating GR expression and nuclear translocation in the hippocampus. Furthermore, DMI treatment at 6 mo prevented the onset of depression-like behavior and the associated alterations in neurogenesis in 12-mo-old DEX mice. Taken together, our data indicate that DMI treatment enhances GR-mediated signaling and restores the synchronization of peripheral clocks with the SCN and support the hypothesis that altered circadian entrainment is a modifiable risk factor for depression.
Topics: Animals; Antidepressive Agents, Tricyclic; Circadian Rhythm; Depression; Desipramine; Dexamethasone; Female; Glucocorticoids; Hippocampus; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neurogenesis; Photoperiod; Pregnancy; Prenatal Exposure Delayed Effects; Suprachiasmatic Nucleus
PubMed: 31624238
DOI: 10.1038/s41398-019-0594-3 -
CPT: Pharmacometrics & Systems... May 2017Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high...
Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping. Once developed and qualified in adults, we characterized the dynamic changes in metabolism and pharmacokinetics of desipramine after birth by scaling the system-specific parameters of the model from adults to pediatrics. The developed modeling strategy provides a prototypical workflow that can also be applied to other drugs with similar properties and a high volume of distribution.
Topics: Adult; Antidepressive Agents, Tricyclic; Child; Desipramine; Humans; Models, Biological; Tissue Distribution
PubMed: 28398693
DOI: 10.1002/psp4.12180 -
BMC Neuroscience Nov 2013The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced...
BACKGROUND
The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not.
RESULTS
To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expression BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phenotypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neurogenesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine activity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and corticotropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330).
CONCLUSIONS
Several antidepressant treatment responses are similar in individuals with different sensitivities to stress, including the upregulation of Igf2 and the genes involved in neurogenesis. However, the findings also reveal that many responses to antidepressant treatments, involving the action of individual genes engaged in neurogenesis, neurotransmitter transport and neuroprotection, depend on constitutive hippocampal transcriptomic profiles and might be genotype dependent. The results suggest that, when and if this becomes feasible, antidepressant treatment should take into consideration individual sensitivity to stress.
Topics: Animals; Antidepressive Agents, Tricyclic; Desipramine; Hippocampus; In Situ Hybridization; Male; Mice; Oligonucleotide Array Sequence Analysis; Phenotype; Real-Time Polymerase Chain Reaction; Stress, Psychological; Transcriptome
PubMed: 24225037
DOI: 10.1186/1471-2202-14-144 -
Journal of Analytical Toxicology Apr 2016In forensic bioanalytical methods, there is a general agreement that calibrators should be prepared by fortifying analytes in matrix-based blank samples (matrix-based)....
Liquid-Phase Microextraction and Gas Chromatographic-Mass Spectrometric Analysis of Antidepressants in Vitreous Humor: Study of Matrix Effect of Human and Bovine Vitreous and Saline Solution.
In forensic bioanalytical methods, there is a general agreement that calibrators should be prepared by fortifying analytes in matrix-based blank samples (matrix-based). However, in the case of vitreous humor (VH), the collection of blank samples for the validation and for routine analysis would require the availability of many cadavers. Besides the difficulty of obtaining enough blank VH, this procedure could also represent an ethical issue. Here, a study of matrix effect was performed taking into consideration human and bovine vitreous and saline solution (SS) (NaCl 0.9%). Tricyclic antidepressants [amitriptyline (AMI), nortriptyline (NTR), imipramine (IMI) and desipramine (DES)] were used as model analytes and were extracted from samples by means of liquid-phase microextraction and detected by gas chromatography-mass spectrometry. Samples of human and bovine VH and SS were prepared in six different concentrations of antidepressants (5, 40, 80, 120, 160 and 200 ng/mL) and were analyzed. Relative matrix effect was evaluated by applying a two-tailed homoscedastic Student's t-test, comparing the results obtained with the set of data obtained with human VH and bovine VH and SS. No significant matrix effect was found for AMI and NTR in the three evaluated matrices. However, a great variability was observed for IMI and DES for all matrices. Once compatibilities among the matrices were demonstrated, the method was fully validated for AMI and NTR in SS. The method was applied to six VH samples deriving from real cases whose femoral whole blood (FWB) was analyzed by a previously published method. An average ratio (VH/FWB) of ∼ 0.1 was found for both compounds.
Topics: Amitriptyline; Animals; Antidepressive Agents; Cattle; Desipramine; Gas Chromatography-Mass Spectrometry; Humans; Imipramine; Liquid Phase Microextraction; Sodium Chloride; Vitreous Body
PubMed: 26755541
DOI: 10.1093/jat/bkv141