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Medicine Mar 2024Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was... (Review)
Review
Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.
Topics: Humans; Quetiapine Fumarate; Amitriptyline; Citalopram; Fat Emulsions, Intravenous; Trazodone; Drug-Related Side Effects and Adverse Reactions; Dothiepin
PubMed: 38489675
DOI: 10.1097/MD.0000000000037612 -
Frontiers in Pharmacology 2023In addition to members of the family of Na/Cl dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane...
In addition to members of the family of Na/Cl dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane monoamine transporter (PMAT) may contribute to neuronal reuptake of according neurotransmitters. As opposed to the numerous blockers of monoamine transporters, only a very limited number of specific blockers of OCT3 and PMAT are available. In fact, decynium-22 is the only blocking agent with micromolar affinities for both transport proteins, and this molecule is frequently used to establish roles of OCT3 and/or PMAT as targets for antidepressant drugs and psychostimulants, respectively. To test for a function of these transporters in the sympathetic nervous system, uptake and release of [3H]1-methyl-4-phenylpyridinium (MPP) was investigated in primary cultures of rat superior cervical ganglia. Uptake was reduced by cocaine or desipramine, blockers of the noradrenaline transporter, by about 70% and by corticosterone or β-estradiol, blockers of OCT3, by about 30%; decynium-22 achieved complete inhibition of uptake with half maximal effects at 3 μM. Depolarization dependent release was enhanced by corticosterone or β-estradiol, but reduced by decynium-22. As the latter effect is unlikely to be related to actions at OCT3 and/or PMAT, electrophysiological recordings were performed to reveal that decynium-22 inhibits action potential firing and currents through voltage activated calcium channels in superior cervical ganglion neurons. These results demonstrate that decynium-22 can impair exocytotic neurotransmitter release by interfering with several types of ion channels. Such transporter-independent effects of decynium-22 that my interfere with basic neuronal functions need to be considered when interpreting results obtained with decynium-22 as prototypic inhibitor of transmitter reuptake via OCT3 and/or PMAT.
PubMed: 37881182
DOI: 10.3389/fphar.2023.1276100 -
The Journal of Neuroscience : the... Jan 2024Selective serotonin (5-HT) reuptake inhibitors are only 30% effective for remission in subjects with major depression, and the best treatments for SSRI-resistant...
Selective serotonin (5-HT) reuptake inhibitors are only 30% effective for remission in subjects with major depression, and the best treatments for SSRI-resistant patients remain unclear. To model SSRI resistance, we used cF1ko mice with conditional deletion of the repressor Freud-1/CC2D1A in adult 5-HT neurons. Within weeks, this deletion leads to overexpression of 5-HT1A autoreceptors, reduced serotonergic activity, and fluoxetine-resistant anxiety-depression phenotype. We hypothesized that desipramine (DES), which targets norepinephrine (NE), may be effective in cF1ko mice. The actions of chronic DES treatment on behavior, chronic cellular activation, and NE projections were examined in both sexes of cF1ko and WT mice. In contrast to fluoxetine, chronic DES reversed the behavioral phenotypes in cF1ko mice, while in WT littermates DES slightly increased anxiety and depression-like behaviors. Deficits in FosB+ cell counts were seen in the entorhinal cortex, hippocampal CA2/3 layer, and BLA of cF1ko mice and were reversed by chronic DES treatment, especially in GABAergic neurons. In cF1ko mice, widespread reductions were seen in NE axons, varicosities, and especially 30-60% reductions in NE synaptic and triadic contacts, particularly to inhibitory gephyrin-positive sites. DES treatment also reversed these reductions in NE innervation. These results indicate the dynamic plasticity of the adult noradrenergic system within weeks of altering serotonergic function that can be normalized by DES treatment. Accompanying these changes, DES but not fluoxetine reversed the behavioral alterations in cF1ko mice, suggesting a key role for noradrenergic plasticity in antidepressant response in this model of reduced serotonin activity.
Topics: Male; Female; Humans; Mice; Animals; Fluoxetine; Depression; Desipramine; Norepinephrine; Serotonin; Anxiety; Phenotype
PubMed: 38050173
DOI: 10.1523/JNEUROSCI.1147-23.2023 -
The American Journal of Case Reports Aug 2023BACKGROUND Tricyclic antidepressant (TCA) drugs are a common cause of fatal poisoning because of their cardiotoxic and arrhythmogenic effects. Classic supportive...
BACKGROUND Tricyclic antidepressant (TCA) drugs are a common cause of fatal poisoning because of their cardiotoxic and arrhythmogenic effects. Classic supportive management includes sodium bicarbonate, gastrointestinal chelating agents, and vasopressors. Recently, intravenous lipid emulsion (supported by a low evidence level) has also been used. CASE REPORT We report the case of a 55-year-old woman admitted to our Intensive Care Unit (ICU) with acute imipramine self-poisoning. She arrived at the emergency department 7 hours after imipramine ingestion; she had severe rhabdomyolysis upon admission, with creatine phosphokinase levels at about 52 500 IU/L (normal, <200 IU/L). She quickly developed cardiogenic shock and malign arrhythmia requiring veno-arterial extra corporeal membrane oxygenation (VA-ECMO). Continuous renal replacement therapy (CRRT) with CytoSorb® (CytoSorbents, Monmouth Junction, New York, United Sates of America) was started 19 hours after admission. We performed serial blood measurements of imipramine and its active metabolite desipramine as well as viewing the levels on the CRRT-circuit monitor. Cardiac function improved and ECMO was explanted after 4 days. She also had severe acute respiratory distress syndrome, which resolved spontaneously. The neurologic outcome was favorable despite early myoclonus. The patient regained consciousness on the fifth day. Her clinical evolution was marked by acute ischemia of the lower left limb due to the arterial ECMO cannula. CONCLUSIONS These measurements document the efficacy of the CytoSorb® adsorber in removing a lipophilic drug from a patient's bloodstream. To our knowledge, this is the first published case of CytoSorb® extracorporeal blood purification therapy for acute TCA poisoning.
Topics: Female; Humans; Middle Aged; Shock, Cardiogenic; Antidepressive Agents, Tricyclic; Extracorporeal Membrane Oxygenation; Imipramine
PubMed: 37542369
DOI: 10.12659/AJCR.939884 -
Molecular Psychiatry Jun 2024Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we...
Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders.
PubMed: 38844534
DOI: 10.1038/s41380-024-02619-0 -
Molecular Pharmaceutics Feb 2024Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life...
Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.
Topics: Mice; Animals; Enkephalin, Leucine; Receptors, Opioid, delta; Prodrugs; Pain; Analgesics; Antidepressive Agents
PubMed: 38243899
DOI: 10.1021/acs.molpharmaceut.3c00807 -
Talanta Jun 2024This article describes the synthesis of sorptive phases for bioanalysis based on the modification of cellulose paper with natural beeswax as sorbent, resulting in a...
This article describes the synthesis of sorptive phases for bioanalysis based on the modification of cellulose paper with natural beeswax as sorbent, resulting in a substrate completely renewable and sustainable. The preparation of the sorptive phases consisted of the dissolution of beeswax in hexane, followed by its drop-casting on cellulose paper and subsequent evaporation of the solvent. The beeswax modification of paper renders it hydrophobic, enabling the extraction of the target analytes, i.e., imipramine, desipramine, amitriptyline and trimipramine, via hydrophobic interactions. The main variables affecting the extraction performance were investigated (e.g., pH, ionic strength, extraction time, eluent composition, agitation speed). The analytical workflow combines a straightforward sampling, simultaneous extraction of 30 samples in 1 h, and the rapid (<2 min) determination of the analytes via direct infusion mass spectrometry. The method provided limits of detection in the range 2.0 and 3.2 μg L, and the precision, expressed as relative standard deviation, was better than 5.4 % and 8.5 % for intra and inter-day analyses, respectively. The accuracy, in terms of relative recovery, ranged from 90 % to 121 % using saliva as model biofluid.
Topics: Antidepressive Agents, Tricyclic; Cellulose; Amitriptyline; Waxes
PubMed: 38479029
DOI: 10.1016/j.talanta.2024.125860 -
Frontiers in Biophysics 2024P-glycoprotein (Pgp) is known for its dichotomous roles as both a safeguarding efflux transporter against xenobiotics and as a catalyst for multidrug resistance. Given...
P-glycoprotein (Pgp) is known for its dichotomous roles as both a safeguarding efflux transporter against xenobiotics and as a catalyst for multidrug resistance. Given the susceptibility of numerous therapeutic compounds to Pgp-mediated resistance, compliance with Food and Drug Administration (FDA) guidelines mandates an in-depth transport assay during drug development. This study introduces an innovative transport assay that aligns with these regulatory imperatives but also addresses limitations in the currently established techniques. Using Pgp-reconstituted liposomes and employing surface plasmon resonance (SPR), this study developed a distinct method of measuring the relative transport rates of Pgp substrates in a controlled microenvironment. The Pgp substrates selected for this study-quinidine, methadone, and desipramine-resulted in transport ratios that corroborate with trends previously observed. To assess the kinetics of Pgp-mediated transport, the results were analyzed by fitting the data to both currently proposed Pgp substrate translocation models-the vacuum cleaner and flippase models. While the resulting kinetic analysis in this study lends support predominantly to the vacuum cleaner model, this study most notably developed a novel method of assessing Pgp-mediated transport rates and real-time kinetics using surface plasmon resonance.
PubMed: 38645731
DOI: 10.3389/frbis.2024.1367511 -
International Journal of Molecular... Jan 2024Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it...
Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse.
Topics: Animals; Rats; Dopamine; Animals, Newborn; Astrocytes; Corpus Striatum; Membrane Transport Proteins; RNA, Messenger
PubMed: 38255983
DOI: 10.3390/ijms25020911 -
International Journal of Molecular... May 2024Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their...
Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders.
Topics: Animals; Astrocytes; Dopamine; Rats; Corpus Striatum; Haloperidol; Kinetics; Dopamine Plasma Membrane Transport Proteins; Apomorphine; Cells, Cultured; Male; Receptors, Dopamine D1; Biological Transport; Levodopa
PubMed: 38791173
DOI: 10.3390/ijms25105135