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BMC Psychiatry Jun 2020Antidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and... (Observational Study)
Observational Study
BACKGROUND
Antidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and antidepressants' classes. The objective of this study was to assess the putative association of each antidepressant and antidepressants' classes with movement disorders.
METHODS
Using VigiBase®, the WHO Pharmacovigilance database, disproportionality of movement disorders' reporting was assessed among adverse drug reactions related to any antidepressant, from January 1967 to February 2017, through a case/non-case design. The association between nine subtypes of movement disorders (akathisia, bruxism, dystonia, myoclonus, parkinsonism, restless legs syndrome, tardive dyskinesia, tics, tremor) and antidepressants was estimated through the calculation first of crude Reporting Odds Ratio (ROR), then adjusted ROR on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders.
RESULTS
Out of the 14,270,446 reports included in VigiBase®, 1,027,405 (7.2%) contained at least one antidepressant, among whom 29,253 (2.8%) reported movement disorders. The female/male sex ratio was 2.15 and the mean age 50.9 ± 18.0 years. We found a significant increased ROR for antidepressants in general for all subtypes of movement disorders, with the highest association with bruxism (ROR 10.37, 95% CI 9.62-11.17) and the lowest with tics (ROR 1.49, 95% CI 1.38-1.60). When comparing each of the classes of antidepressants with the others, a significant association was observed for all subtypes of movement disorders except restless legs syndrome with serotonin reuptake inhibitors (SRIs) only. Among antidepressants, mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan and fluvoxamine were associated with the highest level to movement disorders and citalopram, paroxetine, duloxetine and mirtazapine were the most frequently associated with movement disorders. An association was also found with eight other antidepressants.
CONCLUSIONS
A potential harmful association was found between movement disorders and use of the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine and vilazodone. Clinicians should beware of these adverse effects and monitor early warning signs carefully. However, this observational study must be interpreted as an exploratory analysis, and these results should be refined by future epidemiological studies.
Topics: Adult; Aged; Antidepressive Agents; Female; Humans; Male; Middle Aged; Movement Disorders; Pharmacovigilance; Selective Serotonin Reuptake Inhibitors; Sertraline
PubMed: 32546134
DOI: 10.1186/s12888-020-02711-z -
Pathogens (Basel, Switzerland) Apr 2021Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of...
Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes , , and encode TYR-oxidoreductases. Some serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by , respectively. We show that phenelzine significantly inhibits the growth of by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in pathogenesis and nutritional virulence.
PubMed: 33924374
DOI: 10.3390/pathogens10040469 -
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 -
MBio Mar 2020Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier...
Frequent and excessive use of antibiotics primes patients to infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
Topics: Amoxapine; Animals; Clostridioides difficile; Clostridium Infections; Doxapram; Drug Repositioning; Female; Immunity, Innate; Immunomodulation; Male; Mice; Mice, Inbred C57BL; Microbiota; RNA-Seq; Specific Pathogen-Free Organisms; Trifluoperazine
PubMed: 32156806
DOI: 10.1128/mBio.00053-20 -
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 -
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 -
Neurotherapeutics : the Journal of the... Jul 2021The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and...
The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.
Topics: Algorithms; Amyotrophic Lateral Sclerosis; Central Nervous System Stimulants; Drug Repositioning; Gene Regulatory Networks; Humans; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors
PubMed: 33987813
DOI: 10.1007/s13311-021-01064-z -
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