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Life Sciences Jun 2024Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established...
Gut microbiota biotransformation of drug glucuronides leading to gastrointestinal toxicity: Therapeutic potential of bacterial β-glucuronidase inhibition in mycophenolate-induced enteropathy.
AIMS
Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity.
MAIN METHODS
By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model.
KEY FINDINGS
We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions.
SIGNIFICANCE
Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.
PubMed: 38857657
DOI: 10.1016/j.lfs.2024.122792 -
Biological & Pharmaceutical Bulletin 2024Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such...
Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC value being 4.57 ± 0.02. The pIC values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 M (sertraline and buspirone), ≥10 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.
Topics: Humans; Anti-Anxiety Agents; Acetylcholinesterase; Hypnotics and Sedatives; Sertraline; Clomipramine; Mirtazapine; Paroxetine; Citalopram; Escitalopram; Amoxapine; Buspirone; Triazolam; Antidepressive Agents
PubMed: 38296462
DOI: 10.1248/bpb.b23-00719 -
Cell Biology and Toxicology Dec 2023GABA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of...
GABA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of pharmaco-toxicological effects including bidirectional changes to seizure threshold. Thus, detection of GABA receptor-mediated seizure liabilities is a big, partly unmet need in early preclinical drug development. This is in part due to the plethora of allosteric binding sites that are present on different subtypes of GABA receptors and the critical lack of screening methods that detect interactions with any of these sites. To improve in silico screening methods, we assembled an inventory of allosteric binding sites based on structural data. Pharmacophore models representing several of the binding sites were constructed. These models from the NeuroDeRisk IL Profiler were used for in silico screening of a compiled collection of drugs with known GABA receptor interactions to generate testable hypotheses. Amoxapine was one of the hits identified and subjected to an array of in vitro assays to examine molecular and cellular effects on neuronal excitability and in vivo locomotor pattern changes in zebrafish larvae. An additional level of analysis for our compound collection is provided by pharmacovigilance alerts using FAERS data. Inspired by the Adverse Outcome Pathway framework, we postulate several candidate pathways leading from specific binding sites to acute seizure induction. The whole workflow can be utilized for any compound collection and should inform about GABA receptor-mediated seizure risks more comprehensively compared to standard displacement screens, as it rests chiefly on functional data.
Topics: Animals; Receptors, GABA-A; Zebrafish; Seizures; Binding Sites; gamma-Aminobutyric Acid
PubMed: 37093397
DOI: 10.1007/s10565-023-09803-y -
The Journal of Pharmacy Technology :... Apr 2023Tertiary drug information resources are utilized frequently by health care providers. While pharmacists are uniquely trained and prepared to interpret the information...
Tertiary drug information resources are utilized frequently by health care providers. While pharmacists are uniquely trained and prepared to interpret the information available on these resources, including the results of drug-drug interaction evaluations, discrepancies between such resources pose a major concern for clinicians with regard to patient safety and medication regimen efficacy. It was postulated that drug-drug interaction evaluations between prescription medications and over-the-counter herbal supplements would be particularly problematic. The objective of this project was to distinguish the discrepancies between tertiary drug information resources in the setting of drug-drug interactions between tricyclic antidepressants (TCAs) and herbal supplements. The following medications and herbal supplements were evaluated on Lexicomp, Micromedex, and Medscape: amitriptyline, nortriptyline, doxepin, imipramine, desipramine, amoxapine, St. John's Wort, valerian root, ginkgo biloba, and ginseng. While all of the tertiary drug information resources identified a significant reaction between each TCA and St. John's Wort due to the risk of serotonin syndrome, several other discrepancies were noted, with regard to both the severity of the interaction indicated and whether or not an interaction was identified. It is imperative that clinicians be aware of potential discrepancies between tertiary drug information resources, including the potential for variation in both the clinical interpretation of its severity and the recognition of an interaction.
PubMed: 37051281
DOI: 10.1177/87551225231154405 -
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