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Nanomedicine (London, England) Dec 2022Amoxapine (AMX) has been reported to be metabolized by CYP3A4 and CYP2D6. Naringin (NG) has been reported to inhibit CYP enzymes. Therefore, the current work was...
Amoxapine (AMX) has been reported to be metabolized by CYP3A4 and CYP2D6. Naringin (NG) has been reported to inhibit CYP enzymes. Therefore, the current work was designed to develop AMX solid lipid nanoparticles (AMX-SLNs) and NG-SLNs for better therapeutic performance. AMX-SLNs and NG-SLNs were prepared and characterized. AMX and NG interactions with CYP450s were studied with molecular docking to rationalize the effectiveness of the combination. AMX-SLNs and NG-SLNs showed nanometric size with a sustained drug-release profile. NG showed a higher predicted binding affinity for CYP3A4 and CYP2D6, suggesting the potential for inhibition. The developed formulations were thoroughly characterized along with molecular docking data indicating promising AMX and NG combinations that may show good therapeutic activity.
Topics: Amoxapine; Molecular Docking Simulation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Lipids; Nanoparticles; Particle Size; Drug Carriers
PubMed: 36786368
DOI: 10.2217/nnm-2022-0167 -
The Journal of Emergency Medicine Jan 2023Amoxapine is a second-generation tricyclic antidepressant with a greater seizure risk than other antidepressants. If administered in large amounts, amoxapine can cause...
BACKGROUND
Amoxapine is a second-generation tricyclic antidepressant with a greater seizure risk than other antidepressants. If administered in large amounts, amoxapine can cause severe toxicity and death. Therefore, it is necessary to terminate seizures immediately if amoxapine toxicity occurs. However, intractable seizures often occur in these patients. We describe a case of intractable seizures caused by amoxapine poisoning, in which intravenous lipid emulsion (ILE) was used successfully.
CASE REPORT
A 44-year-old woman with a history of depression ingested 3.0 g of amoxapine during a suicide attempt. Although she was initially treated with intravenous diazepam, her seizures persisted. Levetiracetam and phenobarbital were then administered, but seizures persisted. Hence, ILE was injected for over 1 min. At 2 min after ILE administration, the patient's status seizures ceased. Recurrence of seizures was observed 30 min after ILE, and the seizures disappeared after re-administration of ILE. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ILE may be effective in amoxapine intoxication. Emergency physicians may consider ILE as an adjunctive therapy for amoxapine poisoning with a high mortality rate. ILE should be implemented carefully with monitoring of total dosage and adverse events.
Topics: Female; Humans; Adult; Amoxapine; Fat Emulsions, Intravenous; Seizures; Suicide, Attempted; Diazepam; Antidepressive Agents, Second-Generation
PubMed: 36450616
DOI: 10.1016/j.jemermed.2022.10.016 -
Nature Communications Nov 2022When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including...
When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.
Topics: Mice; Animals; Retinal Ganglion Cells; Maprotiline; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Disease Models, Animal; Homeostasis; Receptors, Histamine
PubMed: 36357388
DOI: 10.1038/s41467-022-34682-y -
Microbiology Spectrum Oct 2022Antibiotic resistance poses a significant hurdle in combating global public health crises, prompting the development of novel therapeutics. Strategies to enhance the...
Antibiotic resistance poses a significant hurdle in combating global public health crises, prompting the development of novel therapeutics. Strategies to enhance the intracellular killing of mycobacteria by targeting host defense mechanisms offer numerous beneficial effects, which include reducing cytotoxicity caused by current lengthy anti-tubercular treatment regimens and slowing or circumventing the development of multidrug-resistant strains. The intracellular pathogen Mycobacterium tuberculosis infects macrophages and exploits host machinery to survive and multiply. Using a cell-based screen of FDA-approved drugs, we identified an antidepressant, Amoxapine, capable of inhibiting macrophage cytotoxicity during mycobacterial infection. Notably, this reduced cytotoxicity was related to the enhanced intracellular killing of Mycobacterium bovis BCG and M. tuberculosis within human and murine macrophages. Interestingly, we discovered that postinfection treatment with Amoxapine inhibited mTOR (mammalian target of rapamycin) activation, resulting in the induction of autophagy without affecting autophagic flux in macrophages. Also, inhibition of autophagy by chemical inhibitor 3-MA or knockdown of an essential component of the autophagic pathway, ATG16L1, significantly diminished Amoxapine's intracellular killing effects against mycobacteria in the host cells. Finally, we demonstrated that Amoxapine treatment enhanced host defense against M. tuberculosis in mice. In conclusion, our study identified Amoxapine as a novel host-directed drug that enhances the intracellular killing of mycobacteria by induction of autophagy, with concomitant protection of macrophages against death. The emergence and spread of multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB urges the development of new therapeutics. One promising approach to combat drug resistance is targeting host factors necessary for the bacteria to survive or replicate while simultaneously minimizing the dosage of traditional agents. Moreover, repurposing FDA-approved drugs presents an attractive avenue for reducing the cost and time associated with new drug development. Using a cell-based screen of FDA-approved host-directed therapies (HDTs), we showed that Amoxapine inhibits macrophage cytotoxicity during mycobacterial infection and enhances the intracellular killing of mycobacteria within macrophages by activating the autophagy pathway, both and . These findings confirm targeted autophagy as an effective strategy for developing new HDT against mycobacteria.
Topics: Mice; Humans; Animals; Amoxapine; BCG Vaccine; Mycobacterium tuberculosis; Macrophages; Autophagy; TOR Serine-Threonine Kinases; Tuberculosis; Mammals
PubMed: 36129262
DOI: 10.1128/spectrum.02509-22 -
Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma.Frontiers in Immunology 2022Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown...
Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.
Topics: Amoxapine; B7-H1 Antigen; Carcinoma, Hepatocellular; Glucuronidase; Humans; Liver Neoplasms; MicroRNAs; Neoplasm Recurrence, Local; Programmed Cell Death 1 Receptor
PubMed: 35812439
DOI: 10.3389/fimmu.2022.876048 -
Cancer Science Aug 2022Lysosomes function as the digestive system of a cell and are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and progrowth signaling....
Lysosomes function as the digestive system of a cell and are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and progrowth signaling. Although quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for glioblastoma (GBM). In this study, we found that ifenprodil, an FDA-approved drug with neuromodulatory activities, efficiently inhibited spheroid formation of patient-derived GBM cells in a combination with autophagy inhibition. Ifenprodil increased intracellular Ca level, resulting in mitochondrial reactive oxygen species-mediated cytotoxicity. The ifenprodil-induced Ca elevation was due to Ca release from lysosomes, but not endoplasmic reticulum, associated with galectin-3 punctation as an indicator of lysosomal membrane damage. As the Ca release was enhanced by ATG5 deficiency, autophagy protected against lysosomal membrane damage. By comparative analysis of 765 FDA-approved compounds, we identified another clinically available drug for central nervous system (CNS) diseases, amoxapine, in addition to ifenprodil. Both compounds promoted degradation of lysosomal membrane proteins, indicating a critical role of lysophagy in quality control of lysosomal membrane integrity. Importantly, a synergistic inhibitory effect of ifenprodil and chloroquine, a clinically available autophagy inhibitor, on spheroid formation was remarkable in GBM cells, but not in nontransformed neural progenitor cells. Finally, chloroquine dramatically enhanced effects of the compounds inducing lysosomal membrane damage in a patient-derived xenograft model. These data demonstrate a therapeutic advantage of targeting lysosomal membrane integrity in GBM.
Topics: Autophagy; Chloroquine; Glioblastoma; Glioma; Humans; Lysosomes; Macroautophagy
PubMed: 35657693
DOI: 10.1111/cas.15451 -
The Journal of Toxicological Sciences 2022In the event of an overdose, the pharmacokinetics of the drug may be altered, resulting in an unexpectedly rapid increase in blood and tissue drug concentrations....
In the event of an overdose, the pharmacokinetics of the drug may be altered, resulting in an unexpectedly rapid increase in blood and tissue drug concentrations. Because central nervous system (CNS)-acting drugs are the major cause of hospitalization for overdose, brain concentrations, which are closely related to the development of acute psychotropic symptoms, would be important. However, due to the lack of an appropriate model for overdose, it is difficult to predict the CNS symptoms of patients with acute poisoning. To clarify the toxicokinetics during intoxication with CNS-acting drugs, we investigated the relationship between the dose and concentrations in the blood and brain in mice. Therapeutic or toxic doses of phenobarbital, flunitrazepam, imipramine, and amoxapine were administered intraperitoneally to mice. Serum and extracellular fluid of the brain were collected up to 24 hr after administration and analyzed using LC-MS/MS to determine the pharmacokinetic parameters in the serum and brain. A comparison of the four psychotropic drugs showed that the toxicokinetics of amoxapine in the blood and brain are clearly different from others, with the brain concentrations being specifically highly susceptible to increase during dose escalation. These results are consistent with the CNS-related symptoms observed in amoxapine overdose. Therefore, the methodology of the current study could be useful for predicting CNS toxicity during psychotropic drug poisoning.
Topics: Animals; Brain; Chromatography, Liquid; Humans; Mice; Microdialysis; Psychotropic Drugs; Tandem Mass Spectrometry; Toxicokinetics
PubMed: 35236805
DOI: 10.2131/jts.47.99 -
The Journal of Organic Chemistry Mar 2022An efficient Cp*Rh(III)-catalyzed regioselective C(sp)-H mono- and dialkynylation of thioamides was described. This reaction was performed under mild conditions in high...
An efficient Cp*Rh(III)-catalyzed regioselective C(sp)-H mono- and dialkynylation of thioamides was described. This reaction was performed under mild conditions in high yields (up to 98%) with a broad substrate scope. Significantly, the versatility of this method was further demonstrated by controlled mono- and dialkynylation. Application of this protocol in the late stage functionalization of two drug molecules (Adapalene and Amoxapine) was also demonstrated.
Topics: Catalysis; Rhodium; Sulfur; Thioamides
PubMed: 35138097
DOI: 10.1021/acs.joc.1c02622 -
Systematic Reviews Aug 2021Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to...
Tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis.
BACKGROUND
Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder.
METHODS
This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool-version 2, our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with 'active placebo', placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosulepin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses.
DISCUSSION
Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42021226161 .
Topics: Adult; Antidepressive Agents, Tricyclic; Depressive Disorder, Major; Humans; Meta-Analysis as Topic; Quality of Life; Review Literature as Topic
PubMed: 34389045
DOI: 10.1186/s13643-021-01789-0