Drug repurposing using real-world data

Tan, George S.Q.; Sloan, Erica K.; Lambert, Pete; Kirkpatrick, C. M. J.; Ilomäki, Jenni

doi:10.1016/j.drudis.2022.103422

Cited by 16 publications

(9 citation statements)

References 55 publications

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“…Its antimicrobial and antibiofilm activities, coupled with its mechanism of action involving disruption of protein homeostasis and cell membrane integrity, highlight its promising potential as a therapeutic candidate for the treatment of multidrug-resistant infections. The drug repurposing approach employed in this study underscores the significance of exploring existing drugs for hidden antibacterial activities, offering a cost-effective and efficient strategy for addressing the challenges posed by antibiotic-resistant pathogens . Overall, the findings of this study highlight the potential of candesartan cilexetil as a novel antibacterial agent against E.…”

Section: Discussionmentioning

confidence: 82%

Antibacterial Activity and Mechanism of Candesartan Cilexetil against Enterococcus faecalis

Chen,

Li,

Shang

et al. 2024

ACS Omega

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Enterococcus faecalis infections pose a significant clinical challenge due to their multidrug resistance and propensity for biofilm formation. Exploring alternative treatment options, such as repurposing existing drugs, is crucial in addressing this issue. This study investigates the antibacterial activity of candesartan cilexetil against E. faecalis and elucidates its mechanism of action. Candesartan cilexetil exhibited notable antibacterial activity against both E. faecalis and Enterococcus faecium, with minimum inhibitory concentration (MIC) of ≤25 μM. Time-kill curves demonstrated concentration-dependent bactericidal effects. Candesartan cilexetil could significantly inhibited biofilm formation at the concentration of 1/4× MIC and induced alterations in biofilm structure. Permeability assays revealed compromised bacterial membranes, accompanied by the dissipation of membrane potential in E. faecalis cells after treatment with candesartan cilexetil. Checkerboard analysis showed that bacterial membrane phospholipids phosphatidylglycerol and cardiolipin could neutralize the antibacterial activity of candesartan cilexetil in a dose-dependent manner. Biolayer interferometry (BLI) assay indicated specific interactions between candesartan cilexetil and phosphatidylglycerol or cardiolipin. This study demonstrates the promising antibacterial and antibiofilm activities of candesartan cilexetil against multidrug-resistant E. faecalis. The mechanism of action involves disruption of bacterial membranes, possibly by interacting with membrane phospholipids. These findings underscore the potential utility of candesartan cilexetil as an effective therapeutic agent for combating E. faecalis infections, offering a valuable strategy in the battle against antibiotic-resistant pathogens.

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Section: Discussionmentioning

confidence: 82%

Antibacterial Activity and Mechanism of Candesartan Cilexetil against Enterococcus faecalis

Chen,

Li,

Shang

et al. 2024

ACS Omega

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“…For example, we lacked clinical information, such as renal function, glycemic control (glycated hemoglobin levels), and body mass index. Thus, the associations in our study need to be further validated using richer clinical data 7 . Second, we assumed reduced hospitalization rates among SGLT2i initiators compared with DPP4i imply novel benefits of SGLT2i, but it may have been adverse events of DPP4i.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the associations in our study need to be further validated using richer clinical data. 7 Second, we assumed reduced hospitalization rates among SGLT2i initiators compared with DPP4i imply novel benefits of SGLT2i, but it may have been adverse events of DPP4i. Third, as we restricted our analyses to diagnosis groups with at least 300 hospitalization events in the second and third hierarchies, we did not evaluate associations between SGLT2i use and hospitalization rate for very rare diseases.…”

Section: Articlementioning

confidence: 99%

“…Real-world data can overcome some of these limitations and uncover novel associations. 7 This study aimed to identify novel associations between SGLT2i use and health outcomes using real-world data. Using a hypothesis-free approach, we conducted an outcome-wide study to investigate associations between initiation of SGLT2is and a wide range of cause-specific hospitalizations.…”

mentioning

confidence: 99%

“…However, RCTs are limited by restricted study populations, small sample sizes, short follow‐up, and high costs. Real‐world data can overcome some of these limitations and uncover novel associations 7 . This study aimed to identify novel associations between SGLT2i use and health outcomes using real‐world data.…”

mentioning

confidence: 99%

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SGLT‐2 Inhibitor Use and Cause‐Specific Hospitalization Rates: An Outcome‐Wide Study to Identify Novel Associations of SGLT‐2 Inhibitors

Tan,

Morton,

Wood

et al. 2024

Clin Pharma and Therapeutics

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Sodium‐glucose co‐transporter 2 inhibitors (SGLT2is) have demonstrated multifaceted pharmacological effects. In addition to type 2 diabetes, they are now indicated for heart failure and chronic kidney disease. This study aimed to identify novel associations between SGLT2i use and health outcomes using real‐world data. Using linked data from a nationwide diabetes registry in Australia, we compared hospitalization rates in people living with type 2 diabetes commencing treatment with SGLT2i and dipeptidyl peptidase‐4 inhibitor (DPP4i) between December 1, 2013, and June 30, 2019. Cause‐specific hospitalizations were categorized across three hierarchies of diagnoses (first, first three, and first four digits of International Classification of Diseases, Tenth Version, Australian Modification codes). Incidence rate ratio (IRR) and 95% confidence interval (95% CI) for each cause‐specific hospitalization were estimated using negative binomial regression. In the first hierarchy, hospitalization rates were lower across most diagnosis groups among SGLT2i initiators (n = 99,569) compared with DPP4i initiators (n = 186,353). In the second and third hierarchies, there were lower hospitalization rates relating to infections, anemias, and obstructive airway diseases among SGLT2i initiators compared with DPP4i initiators. These included sepsis (IRR: 0.60, 95% CI: 0.51–0.72) anemia (IRR: 0.55, 95% CI: 0.46–0.66), and chronic obstructive pulmonary diseases (IRR: 0.52, 95% CI: 0.40–0.68), as well as for previously known associations (e.g., heart failure (IRR: 0.63, 95% CI: 0.56–0.70)). SGLT2is have previously uncharacterized associations on a range of important clinical outcomes; validation of these associations requires further study, some of which may suggest novel benefits or new indications for SGLT2is.

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PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

Zhang,

Huang,

Feng

et al. 2024

Interdisciplinary Medicine

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Phosphodiesterase‐5 (PDE5) inhibitors are used clinically for the treatment of erectile dysfunction, pulmonary arterial hypertension, and other urological diseases. Emerging evidences have suggested the therapeutic capacity of PDE5 inhibitors as the repurposed drugs in oncology. However, the essential immune function of PDE5 inhibitors against cancer in tumor microenvironment (TME) remains unclear. This review aimed to summarize the recent advances regarding the repurposing of PDE5 inhibitors as anti‐cancer agents for cancer management to enhance the anti‐tumor immune response by mediating various immune cells, which included the myeloid‐derived suppressor cells, macrophages, T cells, fibroblasts, and natural killer cells in TME. Moreover, artificial intelligence (AI), as a new approach, is composed of traditional machine learning and deep learning methods and could be potentially used to identify the targets of immune cells in TME and predict the efficacy for repurposed drug toward malignancies. In summary, these endeavors provide novel insights into the comprehensive strategies for PDE5 inhibitors mediating immune cells against cancer and AI‐based approach for future drug repurposing exploration.

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Drug repurposing using real-world data

Cited by 16 publications

References 55 publications

Antibacterial Activity and Mechanism of Candesartan Cilexetil against Enterococcus faecalis

Antibacterial Activity and Mechanism of Candesartan Cilexetil against Enterococcus faecalis

SGLT‐2 Inhibitor Use and Cause‐Specific Hospitalization Rates: An Outcome‐Wide Study to Identify Novel Associations of SGLT‐2 Inhibitors

PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

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