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1
Al Khzem, Abdulaziz H., Mohamed S. Gomaa, Mansour S. Alturki, Nada Tawfeeq, Mohammad Sarafroz, Shareefa M. Alonaizi, Alhassan Al Faran, Laela Ahmed Alrumaihi, Fatimah Ahmed Alansari, and Abdullah Abbas Alghamdi. "Drug Repurposing for Cancer Treatment: A Comprehensive Review." International Journal of Molecular Sciences 25, no. 22 (November 19, 2024): 12441. http://dx.doi.org/10.3390/ijms252212441.
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Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.
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Aleksic, Sandra. "REPURPOSED FOR AGING." Innovation in Aging 8, Supplement_1 (December 2024): 139–40. https://doi.org/10.1093/geroni/igae098.0449.
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Abstract Chronic diseases represent the leading driver of health care cost, with detrimental impact on function, independence, and quality of life in the aging society. Geroscience-guided approaches seek to target aging biology to extend healthspan, defined as the period of life spent without major disease and disability. Repurposing Food and Drug Administration (FDA) - approved drugs as gerotherapeutics (geroscience-guided pharmacologic interventions) offers the advantage of known pharmacologic profile and existing clinical experience and can represent a cost-effective strategy to test interventions for extension of healthspan. Among FDA-approved drugs, candidates with geroscience potential can be identified based on the evidence of extension of healthspan and lifespan in model organisms coupled with clinical evidence of benefits extending beyond the diseases targeted by the drug, through mechanisms that involve modulation of hallmarks of aging. Given the inseparable connections between metabolism and aging, it is not surprising that several FDA-approved drugs developed for treatment of metabolic dysfunction are emerging as potential gerotherapeutics. Metformin (discussed by Dr. Sara Espinoza), a widely used oral antidiabetic drug, extends lifespan in preclinical models, while observational clinical evidence supports its role in prevention of several chronic diseases. Two newer antidiabetic drug classes, glucagon-like peptide 1 (GLP1) receptor agonists (discussed by Dr. John Newman) and sodium- glucose cotransporter 2 (SGLT2) inhibitors (discussed by Dr. Carolina Solis-Herrera), have demonstrated healthspan and lifespan benefits above and beyond treatment of diabetes. Emerging evidence for modulation of multiple hallmarks of aging supports gerotherapeutic properties of these drugs. Clinical trials targeting several aging-relevant outcomes are underway.
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Araújo, Diana, Eduarda Ribeiro, Irina Amorim, and Nuno Vale. "Repurposed Drugs in Gastric Cancer." Molecules 28, no. 1 (December 30, 2022): 319. http://dx.doi.org/10.3390/molecules28010319.
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Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.
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Olgen, Sureyya, and Lakshmi P. Kotra. "Drug Repurposing in the Development of Anticancer Agents." Current Medicinal Chemistry 26, no. 28 (October 25, 2019): 5410–27. http://dx.doi.org/10.2174/0929867325666180713155702.
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Background: Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established. Objective: This review provides an overview of anticancer drug development strategies which is one of the important areas of drug restructuring. Methods: Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anticancer agents are evaluated in this review. Results and Conclusion: Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development.
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Moura, Catarina, Ana Salomé Correia, Mariana Pereira, Eduarda Ribeiro, Joana Santos, and Nuno Vale. "Atorvastatin and Nitrofurantoin Repurposed in the Context of Breast Cancer and Neuroblastoma Cells." Biomedicines 11, no. 3 (March 15, 2023): 903. http://dx.doi.org/10.3390/biomedicines11030903.
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Chemotherapy still plays a central role in the treatment of cancer. However, it is often accompanied by off-target effects that result in severe side-effects and development of drug resistance. The aim of this work was to study the efficacy of different repurposed drugs on the viability of MCF-7 and SH-SY5Y breast cancer and neuroblastoma cells, respectively. In addition, combinations of these repurposed drugs with a classical chemotherapeutic drug (doxorubicin) were also carried out. The cytotoxic effects of the repurposed drugs were evaluated individually and in combination in both cancer cell lines, assessed by MTT assays and morphological evaluation of the cells. The results demonstrated that atorvastatin reduced the viability of both cell lines. However, nitrofurantoin was able to induce cytotoxic effects in MCF-7 cells, but not in SH-SY5Y cells. The combinations of the repurposed drugs with doxorubicin induced a higher inhibition on cell viability than the repurposed drugs individually. The combination of the two repurposed drugs demonstrated that they potentiate each other. Synergism studies revealed that the combination of doxorubicin with the two repurposed drugs was more effective in SH-SY5Y cells, compared to MCF-7 cells. Taken together, our preliminary study highlights the potential use of atorvastatin and nitrofurantoin in the context of breast cancer and neuroblastoma.
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Prosdocimi, Marco, Cristina Zuccato, Lucia Carmela Cosenza, Monica Borgatti, Ilaria Lampronti, Alessia Finotti, and Roberto Gambari. "A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs." Wellcome Open Research 7 (June 23, 2022): 150. http://dx.doi.org/10.12688/wellcomeopenres.17845.2.
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Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.
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Prosdocimi, Marco, Cristina Zuccato, Lucia Carmela Cosenza, Monica Borgatti, Ilaria Lampronti, Alessia Finotti, and Roberto Gambari. "A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs." Wellcome Open Research 7 (August 17, 2022): 150. http://dx.doi.org/10.12688/wellcomeopenres.17845.3.
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Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.
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Prosdocimi, Marco, Cristina Zuccato, Lucia Carmela Cosenza, Monica Borgatti, Ilaria Lampronti, Alessia Finotti, and Roberto Gambari. "A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs." Wellcome Open Research 7 (May 12, 2022): 150. http://dx.doi.org/10.12688/wellcomeopenres.17845.1.
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Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.
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Stone, Heather, Mili Duggal, Leonard Sacks, and Mayurika Ghosh. "1380. Safety of Repurposed Drugs for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: An Analysis of Adverse Events Reported in the Literature." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S501. http://dx.doi.org/10.1093/ofid/ofz360.1244.
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Abstract Background Multi and extensively drug-resistant (MDR and XDR) tuberculosis (TB) remains a treatment challenge due to drug adverse events (AEs) and long regimens. Our aim was to identify AEs which resulted from repurposing drugs for MDR and XDR-TB. Methods A PubMed search for case reports of repurposed drugs for MDR and XDR-TB from January 1, 2014 to October 23, 2018 identified 130 patients (78 MDR, 52 XDR) in 91 articles. There were 31 extrapulmonary, 81 pulmonary TB cases, and 18 with both. Drugs were regarded as repurposed if they were either not approved for TB by the FDA, or they were approved for TB but were used in novel populations, novel combinations, or nonstandard doses. Drug labels were reviewed for AEs. Results Linezolid (n = 65) and moxifloxacin (n = 48) were the most commonly repurposed drugs. The following were also frequently used: clofazimine (n = 47), levofloxacin (n = 45), amikacin (n = 43), amoxicillin-clavulanate (n = 40), kanamycin (n = 36), carbapenems (n = 22), and clarithromycin (n = 17). Of the drugs that are approved for TB, the following were repurposed in a novel population, dose, or combination: cycloserine (n = 20), bedaquiline (n = 13), capreomycin (n = 4), ethambutol (n = 3), and isoniazid (n = 3). Treatments were discontinued due to AEs in 41 patients. There were no discontinuations for amoxicillin-clavulanate and levofloxacin. Extended drug exposure is a unique treatment feature for MDR and XDR-TB, which often requires ~2 years of treatment. Approximately 87% of treatment discontinuations due to AEs occurred after >1 month of exposure. AEs leading to treatment discontinuation after > 6 months of drug exposure were seen in 15 cases, of which 12 were due to linezolid and cycloserine. Peripheral and optic neuropathy was the most common AE reported (linezolid n = 12, cycloserine n = 1). Most AEs were labeled events. Conclusion Several antimicrobials are being repurposed to treat MDR and XDR-TB. There were no AEs reported after prolonged use that was not described in drug labels. Physicians should review information in labeling if prescribing drugs in this manner. There is a need for comparative safety data for repurposed drugs assessed through clinical trials. Disclosures All authors: No reported disclosures.
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Jayaram, Saravanan, Emdormi Rymbai, Deepa Sugumar, and Divakar Selvaraj. "Drug Repurposing: A Paradigm Shift in Drug Discovery." INTERNATIONAL JOURNAL OF APPLIED PHARMACEUTICAL SCIENCES AND RESEARCH 5, no. 04 (June 30, 2020): 60–68. http://dx.doi.org/10.21477/ijapsr.5.4.2.
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The traditional methods of drug discovery and drug development are a tedious, complex, and costly process. Target identification, target validation; lead identification; and lead optimization are a lengthy and unreliable process that further complicates the discovery of new drugs. A study of more than 15 years reports that the success rate in the discovery of new drugs in the fields of ophthalmology, cardiovascular, infectious disease, and oncology to be 32.6%, 25.5%, 25.2% and 3.4%, respectively. A tedious and costly process coupled with a very low success rate makes the traditional drug discovery a less attractive option. Therefore, an alternative to traditional drug discovery is drug repurposing, a process in which already existing drugs are repurposed for conditions other than which were originally intended. Typical examples of repurposed drugs are thalidomide, sildenafil, memantine, mirtazapine, mifepristone, etc. In recent times, several databases have been developed to hasten drug repurposing based on the side effect profile, the similarity of chemical structure, and target site. This work reviews the pivotal role of drug repurposing in drug discovery and the databases currently available for drug repurposing.
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Pratiwi, Nurfi, Aida J. Ulfah, Rachmadina Rachmadina, Lalu M. Irham, Arief R. Afief, Wirawan Adikusuma, Darmawi Darmawi, Rahmat A. Kemal, Ina F. Rangkuti, and Maya Savira. "Promising candidate drug target genes for repurposing in cervical cancer: A bioinformatics-based approach." Narra J 4, no. 3 (December 12, 2024): e938. https://doi.org/10.52225/narra.v4i3.938.
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Cervical cancer is the fourth most common cancer among women globally, and studies have shown that genetic variants play a significant role in its development. A variety of germline and somatic mutations are associated with cervical cancer. However, genomic data derived from these mutations have not been extensively utilized for the development of repurposed drugs for cervical cancer. The objective of this study was to identify novel potential drugs that could be repurposed for cervical cancer treatment through a bioinformatics approach. A comprehensive genomic and bioinformatics database integration strategy was employed to identify potential drug target genes for cervical cancer. Using the GWAS and PheWAS databases, a total of 232 genes associated with cervical cancer were identified. These pharmacological target genes were further refined by applying a biological threshold of six functional annotations. The drug target genes were then cross-referenced with cancer treatment candidates using the DrugBank database. Among the identified genes, LTA, TNFRSF1A, PRKCZ, PDE4B, and PARP were highlighted as promising targets for repurposed drugs. Notably, these five target genes overlapped with 12 drugs that could potentially be repurposed for cervical cancer treatment. Among these, talazoparib, a potent PARP inhibitor, emerged as a particularly promising candidate. Talazoparib is currently being investigated for safety and tolerability in other cancers but has not yet been studied in the context of cervical cancer. Further clinical trials are necessary to validate this finding and explore its potential as a repurposed drug for cervical cancer.
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Scholte, Mirre, Liam Bendicksen, Sabine E. Grimm, Teebah Abu-Zahra, Bianca Pauly, Manuela Joore, and Aaron S. Kesselheim. "A Regulatory Roadmap for Repurposing: Comparing Pathways for Making Repurposed Drugs Available In The EU, UK, And US." Journal of Law, Medicine & Ethics 52, no. 4 (2024): 940–49. https://doi.org/10.1017/jme.2024.171.
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AbstractTo help academic and non-profit investigators interested in drug repurposing navigate regulatory approval processes, we compared pathways for repurposed drugs to obtain approval at EMA, UK MHRA, and the US FDA. Though we found no pathways specifically for repurposed drugs, pathways to market are available in all repurposing scenarios.
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An, Qi, Chungen Li, Yao Chen, Yong Deng, Tao Yang, and Youfu Luo. "Repurposed drug candidates for antituberculosis therapy." European Journal of Medicinal Chemistry 192 (April 2020): 112175. http://dx.doi.org/10.1016/j.ejmech.2020.112175.
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Kornei, Katherine. "Repurposed drug battles ‘brain-eating’ amoeba." Science 379, no. 6632 (February 10, 2023): 524–25. http://dx.doi.org/10.1126/science.adh0581.
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Alffenaar, Jan-Willem C., Vitali Sintchenko, and Ben J. Marais. "Acquired Drug Resistance: Recognizing the Potential of Repurposed Drugs." Clinical Infectious Diseases 69, no. 11 (April 26, 2019): 2038–39. http://dx.doi.org/10.1093/cid/ciz334.
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Al Rihani, Sweilem, Matt Smith, Ravil Bikmetov, Malavika Deodhar, Pamela Dow, Jacques Turgeon, and Veronique Michaud. "Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy." Journal of Clinical Medicine 9, no. 8 (August 10, 2020): 2591. http://dx.doi.org/10.3390/jcm9082591.
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Determination of the risk–benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.
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Duarte, Diana, Inês Guerreiro, and Nuno Vale. "Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells." Current Issues in Molecular Biology 44, no. 10 (October 16, 2022): 4930–49. http://dx.doi.org/10.3390/cimb44100335.
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Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01–100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.
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Minghetti, Paola, Elena P. Lanati, Josie Godfrey, Oriol Solà-Morales, Olivier Wong, and Sonia Selletti. "From Off-Label to Repurposed Drug in Non-Oncological Rare Diseases: Definition and State of the Art in Selected EU Countries." Medicine Access @ Point of Care 1 (January 2017): maapoc.0000016. http://dx.doi.org/10.5301/maapoc.0000016.
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Introduction Almost 8,000 rare diseases exist worldwide, affecting approximately 350 million people. Nevertheless, only 5% receive a specific authorized or licensed treatment. The need for effective and rapidly available therapies is still unmet for many patients. Objective The objective is to define repurposing versus off-label drugs, and to evaluate pathways of repurposed drugs for rare non-oncological diseases in Italy, France, England, and Spain (the EU4 countries). Methods This original paper is based on 3 research activities: (i) a nonsystematic literature research; (ii) a questionnaire-based survey to regulatory experts; and (iii) research on approval timelines and therapy prices of repurposed non-oncology orphan drugs. Official approval dates in England are not available if the National Institute for Health and Care Excellence does not appraise the products. Results Only France provides a specific adaptive pathway from off-label to repurposed drugs. Pricing and reimbursement assessment for the drug samples varied across the EU4 countries: time-to-market for repurposed drugs versus new drugs is longer in all analyzed countries; that is, 979 days versus 462 days in Italy, 502 days versus 350 days in France, and 624 versus 378 days in Spain. Repurposed drugs have higher success rates from development to approval than novel drugs (30% vs. 11%). Small- and medium-sized enterprises owned 9 of 12 repurposed non-oncology orphan drugs, of which only 4 were reimbursed in all EU4 countries. Prices were more homogeneous across EU4 although the reimbursement rates were different. Conclusions Drug repurposing represents a great opportunity to treat rare non-oncological diseases. However, a more homogenous assessment across EU4 could ensure reimbursement and prices high enough to reward organizations investing in this field.
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Seung, K. J., U. Khan, F. Varaine, S. Ahmed, M. Bastard, S. Cloez, D. Damtew, et al. "Introducing new and repurposed TB drugs: the endTB experience." International Journal of Tuberculosis and Lung Disease 24, no. 10 (October 1, 2020): 1081–86. http://dx.doi.org/10.5588/ijtld.20.0141.
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In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015–2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.
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Alomari, Safwan, Irma Zhang, Adrian Hernandez, Caitlin Y. Kraft, Divyaansh Raj, Jayanidhi Kedda, and Betty Tyler. "Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery—A Comprehensive Review of the Literature." Biomolecules 11, no. 12 (December 13, 2021): 1870. http://dx.doi.org/10.3390/biom11121870.
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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.
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Telbisz, Ágnes, Csilla Ambrus, Orsolya Mózner, Edit Szabó, György Várady, Éva Bakos, Balázs Sarkadi, and Csilla Özvegy-Laczka. "Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters." Pharmaceutics 13, no. 1 (January 9, 2021): 81. http://dx.doi.org/10.3390/pharmaceutics13010081.
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During the COVID-19 pandemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering, or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, in this study, we examined the interactions of the repurposed drugs with the key human multidrug transporters present in the major tissue barriers and strongly affecting the pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine; the antihelmintic ivermectin; and the proposed antiviral compounds ritonavir, lopinavir, favipiravir, and remdesivir with the ABCB1/Pgp, ABCG2/BCRP, and ABCC1/MRP1 exporters, as well as the organic anion-transporting polypeptide (OATP)2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning on the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.
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Telbisz, Ágnes, Csilla Ambrus, Orsolya Mózner, Edit Szabó, György Várady, Éva Bakos, Balázs Sarkadi, and Csilla Özvegy-Laczka. "Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters." Pharmaceutics 13, no. 1 (January 9, 2021): 81. http://dx.doi.org/10.3390/pharmaceutics13010081.
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During the COVID-19 pandemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering, or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, in this study, we examined the interactions of the repurposed drugs with the key human multidrug transporters present in the major tissue barriers and strongly affecting the pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine; the antihelmintic ivermectin; and the proposed antiviral compounds ritonavir, lopinavir, favipiravir, and remdesivir with the ABCB1/Pgp, ABCG2/BCRP, and ABCC1/MRP1 exporters, as well as the organic anion-transporting polypeptide (OATP)2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning on the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.
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Shaikh, Karimunnisa Sameer. "Repurposing ciclopirox for treating multiple forms of cancer: New reports and approaches." Journal of medical pharmaceutical and allied sciences 11, no. 2 (April 30, 2022): 4727–33. http://dx.doi.org/10.55522/jmpas.v11i2.2545.
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Ciclopirox is an anti-mycotic drug, used topically, that belongs to the hydroxypyridone molecular class and is not linked to azole drugs or other anti-fungal medication. Ciclopirox was first designed to treat vaginal candidiasis and fungal skin infections, and it is now widely used for these conditions. Drug repurposing is a method for discovering new applications for authorized or experimental medicines that go beyond the original medical indication. Ciclopirox received acknowledgement as repurposed anti-cancer agent (anti-bladder cancer, anti-Ewing sarcoma, anti-pancreatic cancer, hematologic malignancy inhibitor, proliferating cell lines inhibitor, etc.) owing to multiple therapeutic excellencies, where numerous signaling pathways plays role in treating diverse cancer forms. This review article paved a new way by eventually opening newer possibilities for the enthusiastic (medicinal)-chemists, pharmacologists, and researchers of allied branches to design better drugs, repurpose this drug further, and finally use it clinically against various forms of proliferating diseases like cancer.
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To, Kenneth K. W., and William C. Cho. "Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy." Pharmaceutics 15, no. 8 (August 21, 2023): 2166. http://dx.doi.org/10.3390/pharmaceutics15082166.
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Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.
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Assmus, Frauke, Jean-Sélim Driouich, Rana Abdelnabi, Laura Vangeel, Franck Touret, Ayorinde Adehin, Palang Chotsiri, et al. "Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19." Microorganisms 10, no. 8 (August 12, 2022): 1639. http://dx.doi.org/10.3390/microorganisms10081639.
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In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.
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Nasir, Aiman. "Can adapalene be repurposed for melanoma?" Journal of the Pakistan Medical Association 73, no. 10 (September 13, 2023): 2134. http://dx.doi.org/10.47391/jpma.8438.
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Madam, Melanoma, the most lethal skin cancer, accounts for 75% of deaths by skin cancer in the US.1 Nivolumab, Pembrolizumab, and a combination of Nivolumab and ipilimumab are used in adjuvant therapy for distant metastatic melanoma.2 The combination therapy of ipilimumab and nivolumab for melanoma per patient per month was estimated to be USD 71,689.3 Nevertheless, the efficiency of these treatments is limited.4 Furthermore, metastasis can reduce the effectiveness of cancer treatment. With time, cancer cells can also develop resistance to drugs. Hence alternative treatment regimens should be identified.5 The development of new therapies requires a vast amount of time, research, and investment. Drug repurposing provides an alternate approach to this passage. It refers to the new application of previously approved drugs. This process is rapid, potentially safer, and cost-effective.5 Continue...
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Das, Amiya, Pallavi Agarwal, Gaurav Kumar Jain, Geeta Aggarwal, Viney Lather, and Deepti Pandita. "Repurposing Drugs as Novel Triple-negative Breast Cancer Therapeutics." Anti-Cancer Agents in Medicinal Chemistry 22, no. 3 (February 2022): 515–50. http://dx.doi.org/10.2174/1871520621666211021143255.
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Background: Among all the types of breast cancer (BC), triple negative breast cancer (TNBC) is the most aggressive form having high metastasis and recurrence rate with limited treatment options. Conventional treatments such as chemotherapy and radiotherapy have lots of toxic side effects and also no FDA approved therapies are available till now. Repurposing of old clinically approved drugs towards various targets of TNBC is the new approach with lesser side effects and also leads to successful inexpensive drug development with less time consuming. Medicinal plants containg various phytoconstituents (flavonoids, alkaloids, phenols, essential oils, tanins, glycosides, lactones) plays very crucial role in combating various types of diseases and used in drug development process because of having lesser side effects. Objective: The present review focuses in summarization of various categories of repurposed drugs against multitarget of TNBC and also summarizes the phytochemical categories that targets TNBC singly or in combination with synthetic old drugs. Methods: Literature information was collected from various databases such as Pubmed, Web of Science, Scopus and Medline to understand and clarify the role and mechanism of repurposed synthetic drugs and phytoconstituents aginst TNBC by using keywords like “breast cancer”, “repurposed drugs”, “TNBC” and “phytoconstituents”. Results: Various repurposed drugs and phytochemicals targeting different signaling pathways that exerts their cytotoxic activities on TNBC cells ultimately leads to apoptosis of cells and also lowers the recurrence rate and stops the metastasis process. Conclusion: Inhibitory effects seen in different levels, which provides information and evidences to researchers towards drug developments process and thus further more investigations and researches need to be taken to get the better therapeutic treatment options against TNBC.
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MacRaild, Christopher A., Muzaffar-Ur-Rehman Mohammed, Faheem, Sankaranarayanan Murugesan, Ian K. Styles, Amanda L. Peterson, Carl M. J. Kirkpatrick, et al. "Systematic Down-Selection of Repurposed Drug Candidates for COVID-19." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11851. http://dx.doi.org/10.3390/ijms231911851.
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SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
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Pereira, Mariana, and Nuno Vale. "Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine." Molecules 27, no. 1 (January 4, 2022): 291. http://dx.doi.org/10.3390/molecules27010291.
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Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.
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Moreira-Silva, Filipa, Vânia Camilo, Vítor Gaspar, João F. Mano, Rui Henrique, and Carmen Jerónimo. "Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?" Pharmaceutics 12, no. 5 (April 29, 2020): 410. http://dx.doi.org/10.3390/pharmaceutics12050410.
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Epigenetic alterations, as a cancer hallmark, are associated with cancer initiation, progression and aggressiveness. Considering, however, that these alterations are reversible, drugs that target epigenetic machinery may have an inhibitory effect upon cancer treatment. The traditional drug discovery pathway is time-consuming and expensive, and thus, new and more effective strategies are required. Drug Repurposing (DR) comprises the discovery of a new medical indication for a drug that is approved for another indication, which has been recalled, that was not accepted or failed to prove efficacy. DR presents several advantages, mainly reduced resources, absence of the initial target discovery process and the reduced time necessary for the drug to be commercially available. There are numerous old drugs that are under study as repurposed epigenetic inhibitors which have demonstrated promising results in in vitro tumor models. Herein, we summarize the DR process and explore several repurposed drugs with different epigenetic targets that constitute promising candidates for cancer treatment, highlighting their mechanisms of action.
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Mozhokina, G. N., A. G. Samoylov, and I. А. Vasilyeva. "Prospects for Expanding Drug Therapy for Multiple Drug Resistant and Extensively Drug Resistant Tuberculosis." Tuberculosis and Lung Diseases 100, no. 3 (April 6, 2022): 53–60. http://dx.doi.org/10.21292/2075-1230-2022-100-3-53-60.
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This review analyzes 64 publications on repurposed antibiotics and the prospects of their use in the treatment of multiple drug resistant and extensively drug resistant tuberculosis. The article describes mechanisms of action of beta-lactams and macrolides on tuberculous mycobacteria; the results of studies and safety profiles are given.
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Ogunbayo, Dapo, Diarmuid Coughlan, Ross Fairbairn, and Sola Akinbolade. "OP55 Classification System For Innovative Medicines In The Pipeline: New Or Repurposed?" International Journal of Technology Assessment in Health Care 38, S1 (December 2022): S21—S22. http://dx.doi.org/10.1017/s0266462322001088.
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IntroductionWhile various criteria exist to define or categorize innovative medicines as new or repurposed, to our knowledge there are no standardized systems that sufficiently capture the range of pipeline products. The National Institute for Health and Care Research Innovation Observatory (NIHR IO) undertakes routine horizon scanning to support health technology assessment (HTA) in England and maintains a comprehensive Medicines Innovation Database (MInD). The aim of this project is to develop a ‘technology type’ (new versus repurposed) classification system for application within the MInD and to provide a high-level analysis of the emergent data.MethodsWe reviewed gray literature, regulatory websites, and drug repositories to identify existing ‘technology type’ classification criteria. Preliminary definitions and classifications for use on the MInD were discussed, refined, and agreed by consensus. Innovative medicines on the MInD were classified as either new or repurposed based on their regulatory approval status (Marketing Authorization) using data from the electronic medicines compendium. For repurposed medicines, further classification was undertaken using abbreviated new drug application (ANDA) data from the FDA Orange Book to identify generic medicines (patency and exclusivity status). We combined a range of semi-automated and manually derived data during this process.ResultsSix technology types were identified and applied to the MInD: (i) new technology; (ii) repurposed technology (on-patent/branded); (iii) repurposed drug (off-patent/generic); (iv) repurposed technology (never commercialized); (v) new and repurposed technology (combinations); and (vi) repurposed technology (combinations). Preliminary analysis of a subset of MInD records identified in July 2021 (n = 113) found mainly 52 percent new technologies, 27 percent new and repurposed technologies (combinations) and 14 percent repurposed technology (never commercialized). Further analysis of approximately 7000 MInD records are ongoing and will report temporal trends, regulatory status, and key challenges.ConclusionsOur novel evidence-based approach to developing classifications for technology types of innovative medicines resulted in six mutually exclusive states that can be applied to a larger dataset. We believe this offers HTA stakeholders a mechanism to gain valuable insights into the innovation trends, gaps, and areas of unmet need.
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Jang, Woo Dae, Sangeun Jeon, Seungtaek Kim, and Sang Yup Lee. "Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay." Proceedings of the National Academy of Sciences 118, no. 30 (July 7, 2021): e2024302118. http://dx.doi.org/10.1073/pnas.2024302118.
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The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.
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Pires, Carla. "A Systematic Review on the Contribution of Artificial Intelligence in the Development of Medicines for COVID-2019." Journal of Personalized Medicine 11, no. 9 (September 18, 2021): 926. http://dx.doi.org/10.3390/jpm11090926.
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Background: COVID-2019 pandemic lead to a raised interest on the development of new treatments through Artificial Intelligence (AI). Aim: to carry out a systematic review on the development of repurposed drugs against COVID-2019 through the application of AI. Methods: The Systematic Reviews and Meta-Analyses (PRISMA) checklist was applied. Keywords: [“Artificial intelligence” and (COVID or SARS) and (medicine or drug)]. Databases: PubMed®, DOAJ and SciELO. Cochrane Library was additionally screened to identify previous published reviews on the same topic. Results: From the 277 identified records [PubMed® (n = 157); DOAJ (n = 119) and SciELO (n = 1)], 27 studies were included. Among other, the selected studies on new treatments against COVID-2019 were classified, as follows: studies with in-vitro and/or clinical data; association of known drugs; and other studies related to repurposing of drugs. Conclusion: Diverse potentially repurposed drugs against COVID-2019 were identified. The repurposed drugs were mainly from antivirals, antibiotics, anticancer, anti-inflammatory, and Angiotensin-converting enzyme 2 (ACE2) groups, although diverse other pharmacologic groups were covered. AI was a suitable tool to quickly analyze large amounts of data or to estimate drug repurposing against COVID-2019.
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Govender, Kamini, and Anil Chuturgoon. "An Overview of Repurposed Drugs for Potential COVID-19 Treatment." Antibiotics 11, no. 12 (November 22, 2022): 1678. http://dx.doi.org/10.3390/antibiotics11121678.
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The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.
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Balasubramanian, Arul, Thasin Ibrahim, and Kothai Ramalingam. "Antitubercular nanocarrier monotherapy: study of in-silico molecular docking and in-vitro efficacy of repurposed antiviral drug." Journal of Physics: Conference Series 2801, no. 1 (July 1, 2024): 012011. http://dx.doi.org/10.1088/1742-6596/2801/1/012011.
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Abstract There has to be a breakthrough in tuberculosis (TB) treatment to address issues with drug resistance, patient noncompliance, and dosage frequency. We produced durable therapeutic nanocarriers (NCs) and tested their efficiency in-vitro in macrophages infected with Mycobacterium tuberculosis. Our goal was to decrease adverse effects linked to systemic drug distribution and improve drug concentration at the target site. There are multiple pathways by which antiviral medications induce renal failure. Several novel drugs have been shown to cause direct renal tubular toxicity through their distinct impacts on kidney epithelial cells. In this present study the in-silico docking studies were performed and the silver nanoparticles of the antiviral drug Entecavir was prepared and characterized by using SEM and HR-TEM studies. The prepared nanoparticles were evaluated for its anti-tubercular activity by in-vitro and the results showed the repurposed antiviral drug showed remarkable anti-tubercular activity. There is mounting evidence that the repurposed antitubercular drug Entecavir is a viable new option for treating tuberculosis.
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Manikyam, Hemanth Kumar, Sandeep Balvant Patil, Nazim Hussain, R. Edison Eegai Vallal, Shikha Sharma, and Abhinandan Ravsaheb Patil. "High-Throughput Insilico Drug Screen against Mpox Targeted Proteins in Comparison with Repurposed Antiviral Drugs against Natural Compounds." Journal of Pharmaceutical Research International 36, no. 11 (October 15, 2024): 41–52. http://dx.doi.org/10.9734/jpri/2024/v36i117599.
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The recent resurgence of the Monkeypox Virus (MPXV) has prompted increased efforts to discover effective antiviral treatments. This study utilized an in silico docking approach with CB Dock2 to assess both natural compounds and repurposed antiviral medications. We concentrated on several critical viral targets for inhibition, specifically VP39 2'-O Methyltransferase, viral topoisomerase-DNA complexes, and poxin. Our results identified a number of natural substances, including Physalin A, Sitoindoside IX, Withanolide, Shatavarin 1, Kutkoside, and Berberine HCl, as promising inhibitors. Tecovirimat was found to be the most effective among the repurposed antivirals. Notably, natural products like Withanolide, Sitoindoside IX, and Physalin A showed significant inhibitory potential based on their Vina scores and binding affinities, suggesting they may serve as alternative therapeutic options. Tecovirimat consistently proved to be the most powerful inhibitor among repurposed antivirals across all examined targets, reinforcing its importance in combating MPXV.
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Lam, Hilbert Yuen In, Jia Sheng Guan, and Yuguang Mu. "In Silico Repurposed Drugs against Monkeypox Virus." Molecules 27, no. 16 (August 18, 2022): 5277. http://dx.doi.org/10.3390/molecules27165277.
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Monkeypox is an emerging epidemic of concern. The disease is caused by the monkeypox virus and an increasing global incidence with a 2022 outbreak that has spread to Europe amid the COVID-19 pandemic. The new outbreak is associated with novel, previously undiscovered mutations and variants. Currently, the US Food and Drug Administration (FDA) approved poxvirus treatment involves the use of tecovirimat. However, there is otherwise limited pharmacopoeia and research interest in monkeypox. In this study, virtual screening and molecular dynamics were employed to explore the potential repurposing of multiple drugs previously approved by the FDA or other jurisdictions for other applications. Several drugs are predicted to tightly bind to viral proteins, which are crucial in viral replication, including molecules which show high potential for binding the monkeypox D13L capsid protein, whose inhibition has previously been demonstrated to suppress viral replication.
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Rausch, Magdalena, Adriano Rutz, Pierre-Marie Allard, Céline Delucinge-Vivier, Mylène Docquier, Olivier Dormond, Paul J. Dyson, Jean-Luc Wolfender, and Patrycja Nowak-Sliwinska. "Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma." Cancers 13, no. 16 (August 6, 2021): 3978. http://dx.doi.org/10.3390/cancers13163978.
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Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.
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Lu, Chen, Xinyan Li, Yongya Ren, and Xiao Zhang. "Disulfiram: a novel repurposed drug for cancer therapy." Cancer Chemotherapy and Pharmacology 87, no. 2 (January 10, 2021): 159–72. http://dx.doi.org/10.1007/s00280-020-04216-8.
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Koh, Cho Yeow, Rohan Bendre, and R. Manjunatha Kini. "Repurposed drug to the rescue of snakebite victims." Science Translational Medicine 12, no. 542 (May 6, 2020): eabb6700. http://dx.doi.org/10.1126/scitranslmed.abb6700.
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Pathipaka, Rachana, Anita Thyagarajan, and Ravi P. Sahu. "Melatonin as a Repurposed Drug for Melanoma Treatment." Medical Sciences 11, no. 1 (January 14, 2023): 9. http://dx.doi.org/10.3390/medsci11010009.
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Melanoma is the most aggressive type of skin cancer, with a greater risk of metastasis and a higher prevalence and mortality rate. This cancer type has been demonstrated to develop resistance to the known treatment options such as conventional therapeutic agents and targeted therapy that are currently being used as the standard of care. Drug repurposing has been explored as a potential alternative treatment strategy against disease pathophysiologies, including melanoma. To that end, multiple studies have suggested that melatonin produced by the pineal gland possesses anti-proliferative and oncostatic effects in experimental melanoma models. The anticarcinogenic activity of melatonin is attributed to its ability to target a variety of oncogenic signaling pathways, including the MAPK pathways which are involved in regulating the behavior of cancer cells, including cell survival and proliferation. Additionally, preclinical studies have demonstrated that melatonin in combination with chemotherapeutic agents exerts synergistic effects against melanoma. The goal of this review is to highlight the mechanistic insights of melatonin as a monotherapy or combinational therapy for melanoma treatment.
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Ribeiro, Eduarda, Diana Araújo, Mariana Pereira, Bruna Lopes, Patrícia Sousa, Ana Catarina Sousa, André Coelho, et al. "Repurposing Benztropine, Natamycin, and Nitazoxanide Using Drug Combination and Characterization of Gastric Cancer Cell Lines." Biomedicines 11, no. 3 (March 6, 2023): 799. http://dx.doi.org/10.3390/biomedicines11030799.
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Gastric cancer (GC) ranked as the fifth most incident cancer in 2020 and the third leading cause of cancer mortality. Surgical prevention and radio/chemotherapy are the main approaches used in GC treatment, and there is an urgent need to explore and discover innovative and effective drugs to better treat this disease. A new strategy arises with the use of repurposed drugs. Drug repurposing coupled with drug combination schemes has been gaining interest in the scientific community. The main objective of this project was to evaluate the therapeutic effects of alternative drugs in GC. For that, three GC cell lines (AGS, MKN28, and MKN45) were used and characterized. Cell viability assays were performed with the reference drug 5-fluororacil (5-FU) and three repurposed drugs: natamycin, nitazoxanide, and benztropine. Nitazoxanide displayed the best results, being active in all GC cells. Further, 5-FU and nitazoxanide in combination were tested in MKN28 GC cells, and the results obtained showed that nitazoxanide alone was the most promising drug for GC therapy. This work demonstrated that the repurposing of drugs as single agents has the ability to decrease GC cell viability in a concentration-dependent manner.
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Nunes, Mariana, Miguel Henriques Abreu, Carla Bartosch, and Sara Ricardo. "Recycling the Purpose of Old Drugs to Treat Ovarian Cancer." International Journal of Molecular Sciences 21, no. 20 (October 20, 2020): 7768. http://dx.doi.org/10.3390/ijms21207768.
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The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.
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Ntafoulis, Ioannis, Stijn L. W. Koolen, Olaf van Tellingen, Chelsea W. J. den Hollander, Hendrika Sabel-Goedknegt, Stephanie Dijkhuizen, Joost Haeck, et al. "A Repurposed Drug Selection Pipeline to Identify CNS-Penetrant Drug Candidates for Glioblastoma." Pharmaceuticals 17, no. 12 (December 14, 2024): 1687. https://doi.org/10.3390/ph17121687.
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Background: Glioblastoma is an aggressive and incurable type of brain cancer. Little progress has been made in the development of effective new therapies in the past decades. The blood–brain barrier (BBB) and drug efflux pumps, which together hamper drug delivery to these tumors, play a pivotal role in the gap between promising preclinical findings and failure in clinical trials. Therefore, selecting drugs that can reach the tumor region in pharmacologically effective concentrations is of major importance. Methods: In the current study, we utilized a drug selection platform to identify candidate drugs by combining in vitro oncological drug screening data and pharmacokinetic (PK) profiles for central nervous system (CNS) penetration using the multiparameter optimization (MPO) score. Furthermore, we developed intracranial patient-derived xenograft (PDX) models that recapitulated the in situ characteristics of glioblastoma and characterized them in terms of vascular integrity, BBB permeability and expression of ATP-binding cassette (ABC) transporters. Omacetaxine mepesuccinate (OMA) was selected as a proof-of-concept drug candidate to validate our drug selection pipeline. Results: We assessed OMA’s PK profile in three different orthotopic mouse PDX models and found that OMA reaches the brain tumor tissue at concentrations ranging from 2- to 11-fold higher than in vitro IC50 values on patient-derived glioblastoma cell cultures. Conclusions: This study demonstrates that OMA, a drug selected for its in vitro anti-glioma activity and CNS- MPO score, achieves brain tumor tissue concentrations exceeding its in vitro IC50 values in patient-derived glioblastoma cell cultures, as shown in three orthotopic mouse PDX models. We emphasize the importance of such approaches at the preclinical level, highlighting both their significance and limitations in identifying compounds with potential clinical implementation in glioblastoma.
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Gautam, Sakshi, Anamika Thakur, Akanksha Rajput, and Manoj Kumar. "Anti-Dengue: A Machine Learning-Assisted Prediction of Small Molecule Antivirals against Dengue Virus and Implications in Drug Repurposing." Viruses 16, no. 1 (December 27, 2023): 45. http://dx.doi.org/10.3390/v16010045.
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Dengue outbreaks persist in global tropical regions, lacking approved antivirals, necessitating critical therapeutic development against the virus. In this context, we developed the “Anti-Dengue” algorithm that predicts dengue virus inhibitors using a quantitative structure–activity relationship (QSAR) and MLTs. Using the “DrugRepV” database, we extracted chemicals (small molecules) and repurposed drugs targeting the dengue virus with their corresponding IC50 values. Then, molecular descriptors and fingerprints were computed for these molecules using PaDEL software. Further, these molecules were split into training/testing and independent validation datasets. We developed regression-based predictive models employing 10-fold cross-validation using a variety of machine learning approaches, including SVM, ANN, kNN, and RF. The best predictive model yielded a PCC of 0.71 on the training/testing dataset and 0.81 on the independent validation dataset. The created model’s reliability and robustness were assessed using William’s plot, scatter plot, decoy set, and chemical clustering analyses. Predictive models were utilized to identify possible drug candidates that could be repurposed. We identified goserelin, gonadorelin, and nafarelin as potential repurposed drugs with high pIC50 values. “Anti-Dengue” may be beneficial in accelerating antiviral drug development against the dengue virus.
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Nunes, Mariana, Diana Duarte, Nuno Vale, and Sara Ricardo. "Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma." Cancers 14, no. 18 (September 7, 2022): 4357. http://dx.doi.org/10.3390/cancers14184357.
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Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou–Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.
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Manjunath, Yariswamy, Suvilesh Kanve Nagaraj, Yulia I. Nussbaum, Mohamed Gadelkarim, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Guangfu Li, et al. "Abstract 205: Patient-derived organoids from surgically treated, localized non-small cell lung cancer as high-throughput drug testing platforms for conventional and repurposed drugs." Cancer Research 83, no. 7_Supplement (April 4, 2023): 205. http://dx.doi.org/10.1158/1538-7445.am2023-205.
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Abstract Background: Non-metastatic NSCLC treated with curative surgery has a five-year survival of ~50%, mostly due to development of recurrences. Despite being considered as potential drug screening platforms, patient-derived xenograft (PDX) models are inefficient due to low tumor engraftment rates and complex animal care. Patient-derived organoid (PDO) models overcome these limitations as potential clinically applicable drug testing platforms. Our objective was to develop PDO models from non-metastatic NSCLC patients to study epithelial cell type heterogeneity and drug sensitivities for precision medicine. Hypothesis: PDO models reliably capitulate the patient primary tumor and serve as versatile platforms for high-throughput screening of standard-of-care and repurposed drugs. Methods: Single cell suspensions prepared from resected lung tumor tissues from ten NSCLC patients (both adenocarcinoma and squamous cell carcinoma) were mixed with Matrigel (growth factor-reduced) and cultured in organoid growth medium. Organoids and matched primary tumors were compared by histopathology [H&E staining and immunohistochemistry for cytokeratin (CK) 5/6, CK7, Napsin A, Thyroid transcription factor-1 (TTF-1) and p40] and by bulk RNA sequencing. Upon passaging, PDOs were seeded in triplicates, treated with carboplatin/paclitaxel doublet chemotherapy, and drug responses were determined using bright-field 3D imaging (z-stack method). Tumor growth (%) was determined on day 3 and 6 of treatments. RNA sequencing analyses identified a potential drug targets and repurposed drug (aldoketoreductase inhibitor Epalrestat) was tested to overcome chemoresistance in PDOs. Results: NSCLC PDO growth was established from 11/12 (91.7%) primary tumors with a median time of 11 days (range 4-18 days) to reach volume of 100 μm3. PDOs retained histopathological features and biomarker expression of the matched tumors. As determined by growth differences (p<0.05), 5/9 (55.6%) PDOs were chemosensitive and 4/9 (44.4%) PDOs were chemoresistant against carboplatin/paclitaxel. Whole transcriptome analysis confirmed conservation of the epithelial cell composition in all PDOs in comparison to the matched primary tumors. Potentially druggable genes associated with chemotherapy resistance were identified and the aldoketoreductase inhibitor Epalrestat was repurposed and shown to be effective in overcoming chemoresistance towards carboplatin/paclitaxel. Conclusions: PDOs can be established from resectable NSCLC patients with high success rates, while preserving histopathological, cellular, and molecular characteristics of the matched primary tumors. Considering the time frames of growth and drug testing, PDOs can serve as clinically applicable drug response testing platforms to traditional and repurposed drugs. Citation Format: Yariswamy Manjunath, Suvilesh Kanve Nagaraj, Yulia I. Nussbaum, Mohamed Gadelkarim, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Guangfu Li, Wesley Warren, Chi-Ren Shyu, Matthew Ciorba, Jonathan B. Mitchem, Jussuf T. Kaifi. Patient-derived organoids from surgically treated, localized non-small cell lung cancer as high-throughput drug testing platforms for conventional and repurposed drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 205.
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Nair, Rahul. "Drug Repurposing: Finding New Therapeutic Uses for Existing Pharmaceuticals." Universal Research Reports 11, no. 3 (June 30, 2024): 37–43. http://dx.doi.org/10.36676/urr.v11.i3.1285.
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This paper explores the concept of drug repurposing as a viable strategy for discovering new therapeutic uses for existing pharmaceuticals. It examines various approaches to drug repurposing, including serendipitous discoveries, target-based screening, pathway analysis, computational methods, drug combination therapy, and clinical data mining. The paper discusses the advantages of drug repurposing over traditional drug development and highlights successful examples of repurposed drugs. It also addresses challenges and future directions in the field of drug repurposing.
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Campbell, Courtney M., Avirup Guha, Tamanna Haque, Tomas G. Neilan, and Daniel Addison. "Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review." Journal of Clinical Medicine 9, no. 9 (September 11, 2020): 2935. http://dx.doi.org/10.3390/jcm9092935.
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The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.