J Med Virol. 2023 Mar 10. doi: 10.1002/jmv.28652. Online ahead of print.

ABSTRACT

The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity. This article is protected by copyright. All rights reserved.

PMID:36897017 | DOI:10.1002/jmv.28652

Front Pharmacol. 2023 Feb 21;14:1135516. doi: 10.3389/fphar.2023.1135516. eCollection 2023.

ABSTRACT

Olanzapine is an atypical antipsychotic drug that is clinically applied in patients with schizophrenia. It increases the risk of dyslipidemia, a disturbance of lipid metabolic homeostasis, usually characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides, and accompanied by decreased high-density lipoprotein (HDL) in the serum. In this study, analyzing the FDA Adverse Event Reporting System, JMDC insurance claims, and electronic medical records from Nihon University School of Medicine revealed that a co-treated drug, vitamin D, can reduce the incidence of olanzapine-induced dyslipidemia. In the following experimental validations of this hypothesis, short-term oral olanzapine administration in mice caused a simultaneous increase and decrease in the levels of LDL and HDL cholesterol, respectively, while the triglyceride level remained unaffected. Cholecalciferol supplementation attenuated these deteriorations in blood lipid profiles. RNA-seq analysis was conducted on three cell types that are closely related to maintaining cholesterol metabolic balance (hepatocytes, adipocytes, and C2C12) to verify the direct effects of olanzapine and the functional metabolites of cholecalciferol (calcifediol and calcitriol). Consequently, the expression of cholesterol-biosynthesis-related genes was reduced in calcifediol- and calcitriol-treated C2C12 cells, which was likely to be mediated by activating the vitamin D receptor that subsequently inhibited the cholesterol biosynthesis process via insulin-induced gene 2 regulation. This clinical big-data-based drug repurposing approach is effective in finding a novel treatment with high clinical predictability and a well-defined molecular mechanism.

PMID:36895943 | PMC:PMC9989177 | DOI:10.3389/fphar.2023.1135516

Arch Pharm Res. 2023 Mar 10. doi: 10.1007/s12272-023-01438-1. Online ahead of print.

ABSTRACT

Drug repositioning has gained significant attention over the past several years. The anti-rheumatoid arthritis drug auranofin has been investigated for the treatment of other diseases, including liver fibrosis. Because auranofin is rapidly metabolized, it is necessary to identify the active metabolites of auranofin that have detectable levels in the blood and reflect its therapeutic effects. In the present study, we investigated whether aurocyanide as an active metabolite of auranofin, can be used to evaluate the anti-fibrotic effects of auranofin. Incubation of auranofin with liver microsomes showed that auranofin was susceptible to hepatic metabolism. Previously, we found that the anti-fibrotic effects of auranofin are mediated via system xc--dependent inhibition of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therefore, we tried to identify active metabolites of auranofin based on their inhibitory effects on system xc- and NLRP3 inflammasome in bone marrow-derived macrophages. Among the seven candidate metabolites, 1-thio-β-D-glycopyrano-sato-S-(triethyl-phosphine)-gold(I) and aurocyanide potently inhibited system xc- and NLRP3 inflammasome. A pharmacokinetics study on mice detected significant plasma levels of aurocyanide after auranofin administration. Oral administration of aurocyanide significantly prevented thioacetamide-induced liver fibrosis in mice. Moreover, the in vitro anti-fibrotic effects of aurocyanide were assessed in LX-2 cells, where aurocyanide significantly decreased the migratory ability of the cells. In conclusion, aurocyanide is metabolically stable and detectable in plasma, and has inhibitory effects on liver fibrosis, suggesting that it is a potential marker of the therapeutic effects of auranofin.

PMID:36894745 | DOI:10.1007/s12272-023-01438-1

Eur J Med Chem. 2023 Feb 24;251:115219. doi: 10.1016/j.ejmech.2023.115219. Online ahead of print.

ABSTRACT

Mitochondrial complex I (CI) as a critical multifunctional respiratory complex of electron transport chain (ETC) in mitochondrial oxidative phosphorylation has been identified as vital and essence in ATP production, biosynthesis and redox balance. Recent progress in targeting CI has provided both insight and inspiration for oncotherapy, highlighting that the development of CI-targeting inhibitors is a promising therapeutic approach to fight cancer. Natural products possessing of ample scaffold diversity and structural complexity are the majority source of CI inhibitors, although low specificity and safety hinder their extensive application. Along with the gradual deepening in understanding of CI structure and function, significant progress has been achieved in exploiting novel and selective small molecules targeting CI. Among them, IACS-010759 had been approved by FDA for phase I trial in advanced cancers. Moreover, drug repurposing represents an effective and prospective strategy for CI inhibitor discovery. In this review, we mainly elaborate the biological function of CI in tumor progression, summarize the CI inhibitors reported in recent years and discuss the further perspectives for CI inhibitor application, expecting this work may provide insights into innovative discovery of CI-targeting drugs for cancer treatment.

PMID:36893622 | DOI:10.1016/j.ejmech.2023.115219

J Infect Dis. 2023 Mar 9:jiad058. doi: 10.1093/infdis/jiad058. Online ahead of print.

ABSTRACT

BACKGROUND: Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.

METHODS: We screened approved 132 drugs using an MPXV infection cell system. We quantified antiviral activities of hit drugs by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.

RESULTS: Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations.

CONCLUSION: These data suggest that atovaquone would be potential candidates for treating mpox.

PMID:36892247 | DOI:10.1093/infdis/jiad058

Gigascience. 2022 Dec 28;12(1):giad011. doi: 10.1093/gigascience/giad011.

ABSTRACT

BACKGROUND: Widespread bioinformatics applications such as drug repositioning or drug-drug interaction prediction rely on the recent advances in machine learning, complex network science, and comprehensive drug datasets comprising the latest research results in molecular biology, biochemistry, or pharmacology. The problem is that there is much uncertainty in these drug datasets-we know the drug-drug or drug-target interactions reported in the research papers, but we cannot know if the not reported interactions are absent or yet to be discovered. This uncertainty hampers the accuracy of such bioinformatics applications.

RESULTS: We use complex network statistics tools and simulations of randomly inserted previously unaccounted interactions in drug-drug and drug-target interaction networks-built with data from DrugBank versions released over the plast decade-to investigate whether the abundance of new research data (included in the latest dataset versions) mitigates the uncertainty issue. Our results show that the drug-drug interaction networks built with the latest dataset versions become very dense and, therefore, almost impossible to analyze with conventional complex network methods. On the other hand, for the latest drug database versions, drug-target networks still include much uncertainty; however, the robustness of complex network analysis methods slightly improves.

CONCLUSIONS: Our big data analysis results pinpoint future research directions to improve the quality and practicality of drug databases for bioinformatics applications: benchmarking for drug-target interaction prediction and drug-drug interaction severity standardization.

PMID:36892110 | DOI:10.1093/gigascience/giad011

AIMS Microbiol. 2023 Jan 16;9(1):20-40. doi: 10.3934/microbiol.2023002. eCollection 2023.

ABSTRACT

BACKGROUND: Drug repurposing is a valuable strategy for rapidly developing drugs for treating COVID-19. This study aimed to evaluate the antiviral effect of six antiretrovirals against SARS-CoV-2 in vitro and in silico.

METHODS: The cytotoxicity of lamivudine, emtricitabine, tenofovir, abacavir, efavirenz and raltegravir on Vero E6 was evaluated by MTT assay. The antiviral activity of each of these compounds was evaluated via a pre-post treatment strategy. The reduction in the viral titer was assessed by plaque assay. In addition, the affinities of the antiretroviral interaction with viral targets RdRp (RNA-dependent RNA polymerase), ExoN-NSP10 (exoribonuclease and its cofactor, the non-structural protein 10) complex and 3CLpro (3-chymotrypsin-like cysteine protease) were evaluated by molecular docking.

RESULTS: Lamivudine exhibited antiviral activity against SARS-CoV-2 at 200 µM (58.3%) and 100 µM (66.7%), while emtricitabine showed anti-SARS-CoV-2 activity at 100 µM (59.6%), 50 µM (43.4%) and 25 µM (33.3%). Raltegravir inhibited SARS-CoV-2 at 25, 12.5 and 6.3 µM (43.3%, 39.9% and 38.2%, respectively). The interaction between the antiretrovirals and SARS-CoV-2 RdRp, ExoN-NSP10 and 3CLpro yielded favorable binding energies (from -4.9 kcal/mol to -7.7 kcal/mol) using bioinformatics methods.

CONCLUSION: Lamivudine, emtricitabine and raltegravir showed in vitro antiviral effects against the D614G strain of SARS-CoV-2. Raltegravir was the compound with the greatest in vitro antiviral potential at low concentrations, and it showed the highest binding affinities with crucial SARS-CoV-2 proteins during the viral replication cycle. However, further studies on the therapeutic utility of raltegravir in patients with COVID-19 are required.

PMID:36891537 | PMC:PMC9988408 | DOI:10.3934/microbiol.2023002

Front Pharmacol. 2023 Feb 20;14:1161811. doi: 10.3389/fphar.2023.1161811. eCollection 2023.

NO ABSTRACT

PMID:36891268 | PMC:PMC9987033 | DOI:10.3389/fphar.2023.1161811

Bipolar Disord. 2023 Mar 8. doi: 10.1111/bdi.13319. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression.

METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similarly to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats).

RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test.

CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

PMID:36890661 | DOI:10.1111/bdi.13319

Clin Drug Investig. 2023 Mar 8. doi: 10.1007/s40261-023-01251-0. Online ahead of print.

ABSTRACT

Therapeutic repurposing emerged as an alternative to the traditional drug discovery and development model (DDD) of new molecular entities (NMEs). It was anticipated that by being faster, safer, and cheaper, the development would result in lower-cost drugs. As defined in this work, a repurposed cancer drug is one approved by a health regulatory authority against a non-cancer indication that then gains new approval for cancer. With this definition, only three drugs are repurposed for cancer: Bacillus Calmette-Guerin (BCG) vaccine (superficial bladder cancer, thalidomide [multiple myeloma], and propranolol [infantile hemangioma]). Each of these has a different history regarding price and affordability, and it is not yet possible to generalize the impact of drug repurposing on the final price to the patient. However, the development, including the price, does not differ significantly from an NME. For the end consumer, the product's price is unrelated to whether it followed the classical development or repurposing. Economic constraints for clinical development, and drug prescription biases for repurposing drugs, are barriers yet to be overcome. The affordability of cancer drugs is a complex issue that varies from country to country. Many alternatives for having affordable drugs have been put forward, however these measures have thus far failed and are, at best, palliative. There are no immediate solutions to the problem of access to cancer drugs. It is necessary to critically analyze the impact of the current drug development model and be creative in implementing new models that genuinely benefit society.

PMID:36884210 | DOI:10.1007/s40261-023-01251-0

J Cancer Res Clin Oncol. 2023 Mar 8. doi: 10.1007/s00432-023-04674-6. Online ahead of print.

ABSTRACT

PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs.

METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro.

RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased.

CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.

PMID:36884117 | DOI:10.1007/s00432-023-04674-6

Curr Drug Saf. 2023;18(2):122-124. doi: 10.2174/1574886317666220428133813.

ABSTRACT

The Coronavirus disease (COVID-19) outbreak is marked by infodemic amid conspiracy theories, false claims, rumors, and misleading narratives, which have had a significant impact on the global campaign against COVID-19. The drug repurposing provides a hope to curb the growing encumbrance of the disease but at the same time, it poses various challenges such as selfmedication using repurposed drugs and its associated harms. During the continuing pandemic, this perspective piece explores the potential hazards of self-medication and its attributing factors along with possible countermeasures.

PMID:36883267 | DOI:10.2174/1574886317666220428133813

ACS Pharmacol Transl Sci. 2023 Mar 7;6(4):578-586. doi: 10.1021/acsptsci.2c00225. eCollection 2023 Apr 14.

ABSTRACT

SARS-CoV-2 is the agent responsible for acute respiratory disease COVID-19 and the global pandemic initiated in early 2020. While the record-breaking development of vaccines has assisted the control of COVID-19, there is still a pressing global demand for antiviral drugs to halt the destructive impact of this disease. Repurposing clinically approved drugs provides an opportunity to expediate SARS-CoV-2 treatments into the clinic. In an effort to facilitate drug repurposing, an FDA-approved drug library containing 2400 compounds was screened against the SARS-CoV-2 non-structural protein 7 (nsp7) using a native mass spectrometry-based assay. Nsp7 is one of the components of the SARS-CoV-2 replication/transcription complex essential for optimal viral replication, perhaps serving to off-load RNA from nsp8. From this library, gallic acid was identified as a compound that bound tightly to nsp7, with an estimated K d of 15 μM. NMR chemical shift perturbation experiments were used to map the ligand-binding surface of gallic acid on nsp7, indicating that the compound bound to a surface pocket centered on one of the protein's four α-helices (α2). The identification of the gallic acid-binding site on nsp7 may allow development of a SARS-CoV-2 therapeutic via artificial-intelligence-based virtual docking and other strategies.

PMID:37082753 | PMC:PMC10111621 | DOI:10.1021/acsptsci.2c00225

Interact J Med Res. 2023 Mar 5. doi: 10.2196/39455. Online ahead of print.

ABSTRACT

BACKGROUND: Antidepressants are a type of medication used to treat clinical depression or prevent it recurring. Antidepressants exert an anticholinergic effect in varying degrees and various classes of antidepressants also can produce a different effect on immune function. While early usage of antidepressants has notional role on COVID-19 outcomes, the relationship between the risk of COVID-19 severity and the use of all kinds of antidepressants is not properly investigated before due to the exceeding cost involved with clinical trials. Large-scale observational data such as electronic health records and recent advancement of statistical analysis provide ample opportunity to virtualize clinical trial to discover detrimental effects of early usage of these drugs.

OBJECTIVE: By mining a large-scale electronic health record data set of COVID-19 positive patients, we aim to identify common drugs that are associated with COVID-19 outcome. However, whereas the statisticians have made great progress toward using such rich association estimation methods for risk estimation, precise effects of the medicines as treatments require causal models. Thus, our central aim of this paper lies on investigating electronic health record analytic for causal effect estimation and utilize that in discovering causal effects of early antidepressants use on COVID-19 outcomes. As a secondary aim, we develop methods for validating our causal effect estimation pipeline.

METHODS: We focus on antidepressants, a commonly used category of drugs that have been linked to unexpected effects on diverse inflammatory and cardiovascular outcomes and infer early use of such drug use effects on COVID-19 outcomes. However, whereas the machine learning and statistics community have made great progress toward using rich inference models, precise effects of the medicines as treatments require causal models, for which there is significantly less theoretical and practical guidance available. We used National COVID Cohort Collaborative (N3C), a database aggregating health history for over 12+ million people in the USA, including 5+ million with a positive COVID-19 test. We selected 241,952 COVID-19 positive patients with at least one year of medical history and age>13 that included 18,584-dimensional covariate vector for each person and 16 different antidepressants usage histories. We used propensity score weighting based on logistic regression method to estimate causal effect on whole data. Then we used Node2Vec embedding method to encode SNOMED medical code and apply random forest regression to estimate causal effect. We use both methods to estimate causal effects of antidepressants on COVID-19 outcome. We also selected few negatively effective conditions on COVID-19 outcomes and estimated their effects using our proposed methods to validate their efficacy.

RESULTS: Average Treatment Effect (ATE) of using any one of the antidepressants is -0.076 with 95% CI from -0.082 to - 0.069 with propensity score weighting method. The result is statistically significant at p<0.0001. In case of the method using SNOMED medical embedding, the ATE of using any one of the antidepressants is -0.423 with 95% CI from -0.382 to -0.463. This result is also statistically significant at p<0.0001.

CONCLUSIONS: In this study, we apply multiple causal inference methods incorporating with a novel application of health embeddings to investigate the effects of antidepressants on COVID-19 outcome. Additionally, we propose a novel non-affecting drug effect analysis-based evaluation technique to justify the efficacy of proposed method. This study offers causal inference methods on large-scale EHR data to discover common antidepressants' effects on COVID-19 hospitalization, or a worse outcome. The study finds that common antidepressants may increase risk of COVID-19 complications and uncovers a pattern where certain antidepressants are associated with lower risk of hospitalization. While discovering detrimental effects of these drugs on outcome could guide preventive care, identification of beneficial effects would allow us to propose drug repurposing for COVID-19 treatment.

PMID:36881541 | DOI:10.2196/39455

Med Health Care Philos. 2023 Mar 7. doi: 10.1007/s11019-023-10140-4. Online ahead of print.

ABSTRACT

Drug repurposing is a strategy of identifying new potential uses for already existing drugs. Many researchers adopted this method to identify treatment or prevention during the COVID-19 pandemic. However, despite the considerable number of repurposed drugs that were evaluated, only some of them were labeled for new indications. In this article, we present the case of amantadine, a drug commonly used in neurology that attracted new attention during the COVID-19 outbreak. This example illustrates some of the ethical challenges associated with the launch of clinical trials to evaluate already approved drugs. In our discussion, we follow the ethics framework for prioritization of COVID-19 clinical trials proposed by Michelle N Meyer and colleagues (2021). We focus on four criteria: social value, scientific validity, feasibility, and consolidation/collaboration. We claim that launching amantadine trials was ethically justified. Although the scientific value was anticipated to be low, unusually, the social value was expected to be high. This was because of significant social interest in the drug. In our view, this strongly supports the need for evidence to justify why the drug should not be prescribed or privately accessed by interested parties. Otherwise, a lack of evidence-based argument could enhance its uncontrolled use. With this paper, we join the discussion on the lessons learned from the pandemic. Our findings will help to improve future efforts to decide on the launch of clinical trials on approved drugs when dealing with the widespread off-label use of the drug.

PMID:36881334 | DOI:10.1007/s11019-023-10140-4

Comput Struct Biotechnol J. 2023 Feb 8;21:1533-1542. doi: 10.1016/j.csbj.2023.02.004. eCollection 2023.

ABSTRACT

Discovering effective therapies is difficult for neurological and developmental disorders in that disease progression is often associated with a complex and interactive mechanism. Over the past few decades, few drugs have been identified for treating Alzheimer's disease (AD), especially for impacting the causes of cell death in AD. Although drug repurposing is gaining more success in developing therapeutic efficacy for complex diseases such as common cancer, the complications behind AD require further study. Here, we developed a novel prediction framework based on deep learning to identify potential repurposed drug therapies for AD, and more importantly, our framework is broadly applicable and may generalize to identifying potential drug combinations in other diseases. Our prediction framework is as follows: we first built a drug-target pair (DTP) network based on multiple drug features and target features, as well as the associations between DTP nodes where drug-target pairs are the DTP nodes and the associations between DTP nodes are represented as the edges in the AD disease network; furthermore, we incorporated the drug-target feature from the DTP network and the relationship information between drug-drug, target-target, drug-target within and outside of drug-target pairs, representing each drug-combination as a quartet to generate corresponding integrated features; finally, we developed an AI-based Drug discovery Network (AI-DrugNet), which exhibits robust predictive performance. The implementation of our network model help identify potential repurposed and combination drug options that may serve to treat AD and other diseases.

PMID:36879885 | PMC:PMC9984442 | DOI:10.1016/j.csbj.2023.02.004

Health Aff (Millwood). 2023 Mar;42(3):424-432. doi: 10.1377/hlthaff.2022.01083.

ABSTRACT

The COVID-19 pandemic created a large, sudden unmet public health need for rapid access to safe and effective treatments. Against this backdrop, policy makers and researchers have looked to drug repurposing-using a drug previously approved for one indication to target a new indication-as a means to accelerate the identification and development of COVID-19 treatments. Using detailed data on US clinical trials initiated during the pandemic, we examined the trajectory and sources of drug repurposing initiatives for COVID-19. We found a rapid increase in repurposing efforts at the start of the pandemic, followed by a transition to greater de novo drug development. The drugs tested for repurposing treat a wide range of indications but were typically initially approved for other infectious diseases. Finally, we documented substantial variation by trial sponsor (academic, industry, or government) and generic status: Industry sponsorship for repurposing occurred much less frequently for drugs with generic competitors already on the market. Our findings inform drug repurposing policy for both future emerging diseases and drug development in general.

PMID:36877896 | DOI:10.1377/hlthaff.2022.01083

Cancer Res Commun. 2022 May 4;2(5):293-306. doi: 10.1158/2767-9764.CRC-22-0037. eCollection 2022 May.

ABSTRACT

Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation.

SIGNIFICANCE: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.

PMID:36875717 | PMC:PMC9981200 | DOI:10.1158/2767-9764.CRC-22-0037

Hemasphere. 2023 Feb 28;7(3):e848. doi: 10.1097/HS9.0000000000000848. eCollection 2023 Mar.

ABSTRACT

Drug repurposing is a valuable strategy for rare diseases. Sickle cell disease (SCD) is a rare hereditary hemolytic anemia accompanied by acute and chronic painful episodes, most often in the context of vaso-occlusive crisis (VOC). Although progress in the knowledge of pathophysiology of SCD have allowed the development of new therapeutic options, a large fraction of patients still exhibits unmet therapeutic needs, with persistence of VOCs and chronic disease progression. Here, we show that imatinib, an oral tyrosine kinase inhibitor developed for the treatment of chronic myelogenous leukemia, acts as multimodal therapy targeting signal transduction pathways involved in the pathogenesis of both anemia and inflammatory vasculopathy of humanized murine model for SCD. In addition, imatinib inhibits the platelet-derived growth factor-B-dependent pathway, interfering with the profibrotic response to hypoxia/reperfusion injury, used to mimic acute VOCs. Our data indicate that imatinib might be considered as possible new therapeutic tool for chronic treatment of SCD.

PMID:36874380 | PMC:PMC9977487 | DOI:10.1097/HS9.0000000000000848

Front Pharmacol. 2023 Feb 17;14:1128387. doi: 10.3389/fphar.2023.1128387. eCollection 2023.

ABSTRACT

Background: Growing evidence supports a bidirectional association between diabetes and depression; promising but limited and conflicting data from human studies support the intriguing possibility that antidiabetic agents may be used to relieve effectively depressive symptoms in diabetic patients. We investigated the potential antidepressant effects of antidiabetic drugs in a high-scale population data from the two most important pharmacovigilance databases, i.e., the FDA Adverse Event Reporting System (FAERS) and the VigiBase. Material and methods: From the two primary cohorts of patients treated with antidepressants retrieved from FDA Adverse Event Reporting System and VigiBase we identified cases (depressed patients experiencing therapy failure) and non-cases (depressed patients experiencing any other adverse event). We then calculated the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Empirical Bayes Regression-Adjusted Mean (ERAM) for cases versus non-cases in relation with the concurrent exposure to at least one of the following antidiabetic agent: A10BA Biguanides; A10BB Sulfonylureas; A10BG Thiazolidinediones; A10BH DPP4-inhibitors; A10BJ GLP-1 analogues; A10BK SGLT2 inhibitors (i.e., those agents for which preliminary evidence from literature supports our pharmacological hypothesis). Results: For GLP-1 analogues, all the disproportionality scores showed values <1, i.e., statistically significant, in both analyses [from the FAERS: ROR confidence interval of 0.546 (0.450-0.662); PRR (p-value) of 0.596 (0.000); EBGM (CI) of 0.488 (0.407-0.582); ERAM (CI) of 0.480 (0.398-0.569) and VigiBase: ROR (CI) of 0.717 (0.559-0.921); PRR (p-value) of 0.745 (0.033); EBGM (CI) of 0.586 (0.464-0.733); ERAM of (CI): 0.515 (0.403-0.639)]. Alongside GLP-1 analogues, DPP-4 Inhibitors and Sulfonylureas showed the greatest potential protective effect. With regard to specific antidiabetic agents, liraglutide and gliclazide were associated with a statistically significant decrease in all disproportionality scores, in both analyses. Conclusion: The findings of this study provide encouraging results, albeit preliminary, supporting the need for further clinical research for investigating repurposing of antidiabetic drugs for neuropsychiatric disorders.

PMID:36873988 | PMC:PMC9981969 | DOI:10.3389/fphar.2023.1128387