Vaccine. 2022 May 21:S0264-410X(22)00611-9. doi: 10.1016/j.vaccine.2022.05.028. Online ahead of print.

ABSTRACT

Repurposing of existing drugs and vaccines for diseases that they were not originally intended for is a promising research field. Recently there has been evidence that oral cholera vaccine might be used in the treatment of inflammatory disease and some common cancers. Specifically, Ji et al showed that the administration of cholera vaccine after a prostate cancer diagnosis reduced prostate cancer specific mortality rates by almost 50%. In a cohort of men from Stockholm, Sweden, with more detailed cancer data and a higher coverage of exposure to vaccine, we replicated these findings using a marginal structural Cox model. We showed that administration of cholera vaccine after prostate cancer diagnosis is associated with a significant reduction in mortality (HR 0.46, 95% CI 0.31-0.69, p-value 0.0001) even after adjusting for all known confounders. However, the same effect (or even stronger) could be seen for several other traveling vaccines and malaria prophylaxis. Therefore, we conclude that this effect is most likely due to a healthy traveler bias and is an example of residual confounding.

PMID:35610103 | DOI:10.1016/j.vaccine.2022.05.028

Nucleic Acids Res. 2022 May 24:gkac379. doi: 10.1093/nar/gkac379. Online ahead of print.

ABSTRACT

Integrative prioritisation promotes translational use of disease genetic findings in target discovery. I report 'PiER' (http://www.genetictargets.com/PiER), web-based facilities that support ab initio and real-time genetic target prioritisation through integrative use of human disease genetics, functional genomics and protein interactions. By design, the PiER features two facilities: elementary and combinatory. The elementary facility is designed to perform specific tasks, including three online tools: eV2CG, utilising functional genomics to link disease-associated variants (particularly located at the non-coding genome) to core genes likely responsible for genetic associations in disease; eCG2PG, using knowledge of protein interactions to 'network' core genes and additional peripheral genes, producing a ranked list of core and peripheral genes; and eCrosstalk, exploiting the information of pathway-derived interactions to identify highly-ranked genes mediating crosstalk between molecular pathways. Each of elementary tasks giving results is sequentially piped to the next one. By chaining together elementary tasks, the combinatory facility automates genetics-led and network-based integrative prioritisation for genetic targets at the gene level (cTGene) and at the crosstalk level (cTCrosstalk). Together with a tutorial-like booklet describing instructions on how to use, the PiER facilities meet multi-tasking needs to accelerate computational translational medicine that leverages human disease genetics and genomics for early-stage target discovery and drug repurposing.

PMID:35610036 | DOI:10.1093/nar/gkac379

Drug Discov Today. 2022 May 21:S1359-6446(22)00207-0. doi: 10.1016/j.drudis.2022.05.016. Online ahead of print.

ABSTRACT

Cyclophilin A (CypA) is linked to diverse human diseases including viral infections. With the worldwide emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2), drug repurposing has been highlighted as a strategy with the potential to speed up antiviral development. Because CypA acts as a proviral component in hepatitis C virus, coronavirus and HIV, its inhibitors have been suggested as potential treatments for these infections. Here, we review the structure of cyclosporin A and sanglifehrin A analogs as well as synthetic micromolecules inhibiting CypA; and we discuss their broad-spectrum antiviral efficacy in the context of the virus lifecycle.

PMID:35609743 | DOI:10.1016/j.drudis.2022.05.016

PLoS One. 2022 May 24;17(5):e0267095. doi: 10.1371/journal.pone.0267095. eCollection 2022.

ABSTRACT

MOTIVATION: The outbreak of coronavirus health issues caused by COVID-19(SARS-CoV-2) creates a global threat to public health. Therefore, there is a need for effective remedial measures using existing and approved therapies with proven safety measures has several advantages. Dexamethasone (Pubchem ID: CID0000005743), baricitinib(Pubchem ID: CID44205240), remdesivir (PubchemID: CID121304016) are three generic drugs that have demonstrated in-vitro high antiviral activity against SARS-CoV-2. The present study aims to widen the search and explore the anti-SARS-CoV-2 properties of these potential drugs while looking for new drug indications with optimised benefits via in-silico research.

METHOD: Here, we designed a unique drug-similarity model to repurpose existing drugs against SARS-CoV-2, using the anti-Covid properties of dexamethasone, baricitinib, and remdesivir as references. Known chemical-chemical interactions of reference drugs help extract interactive compounds withimprovedanti-SARS-CoV-2 properties. Here, we calculated the likelihood of these drug compounds treating SARS-CoV-2 related symptoms using chemical-protein interactions between the interactive compounds of the reference drugs and SARS-CoV-2 target genes. In particular, we adopted a two-tier clustering approach to generate a drug similarity model for the final selection of potential anti-SARS-CoV-2 drug molecules. Tier-1 clustering was based on t-Distributed Stochastic Neighbor Embedding (t-SNE) and aimed to filter and discard outlier drugs. The tier-2 analysis incorporated two cluster analyses performed in parallel using Ordering Points To Identify the Clustering Structure (OPTICS) and Hierarchical Agglomerative Clustering (HAC). As a result, itidentified clusters of drugs with similar actions. In addition, we carried out a docking study for in-silico validation of top candidate drugs.

RESULT: Our drug similarity model highlighted ten drugs, including reference drugs that can act as potential therapeutics against SARS-CoV-2. The docking results suggested that doxorubicin showed the least binding energy compared to reference drugs. Their practical utility as anti-SARS-CoV-2 drugs, either individually or in combination, warrants further investigation.

PMID:35609015 | DOI:10.1371/journal.pone.0267095

J Genet Eng Biotechnol. 2022 May 24;20(1):78. doi: 10.1186/s43141-022-00353-0.

ABSTRACT

BACKGROUND: COVID-19 is an illness caused by severe acute respiratory syndrome coronavirus 2. Due to its rapid spread, in March 2020 the World Health Organization (WHO) declared pandemic. Since the outbreak of pandemic many governments, scientists, and institutions started to work on new vaccines and finding of new and repurposing drugs. Drug repurposing is an excellent option for discovery of already used drugs, effective against COVID-19, lowering the cost of production, and shortening the period of delivery, especially when preclinical safety studies have already been performed. There are many approved drugs that showed significant results against COVID-19, like ivermectin and hydrochloroquine, including alternative treatment options against COVID-19, utilizing herbal medicine.

SHORT CONCLUSION: This article summarized 11 repurposing drugs, their positive and negative health implications, along with traditional herbal alternatives, that harvest strong potential in efficient treatments options against COVID-19, with small or no significant side effects. Out of 11 repurposing drugs, four drugs are in status of emergency approval, most of them being in phase IV clinical trials. The first repurposing drug approved for clinical usage is remdesivir, whereas chloroquine and hydrochloroquine approval for emergency use was revoked by FDA for COVID-19 treatment in June 2020.

PMID:35608704 | DOI:10.1186/s43141-022-00353-0

Nat Rev Cardiol. 2022 May 23. doi: 10.1038/s41569-022-00717-6. Online ahead of print.

ABSTRACT

Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine - computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities - support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.

PMID:35606425 | DOI:10.1038/s41569-022-00717-6

Toxicol Appl Pharmacol. 2022 May 20:116073. doi: 10.1016/j.taap.2022.116073. Online ahead of print.

ABSTRACT

The anthelmintic ivermectin has been reported to possess anticancer and antiviral efficacy. However, the effective concentrations reported in vitro are near the predicted aqueous solubility limit for this hydrophobic drug. We observed that ivermectin-induced cell death in two cervical cancer cell lines correlated with the formation of solid ivermectin precipitate in both serum-free and serum-supplemented culture media. Filtration of ivermectin particles greater than 0.2 μm abolished these cytolytic effects in both cell lines. An inhibitory effect on cell proliferation persisted for filtered solutions, but only for ivermectin concentrations higher than reportedly attainable in vivo. In addition to the importance of distinguishing between free and bound drug in solution, our data emphasize the importance of acknowledging the likely solubility limit of hydrophobic drugs when assessing their in vitro cytotoxicity.

PMID:35605787 | DOI:10.1016/j.taap.2022.116073

Front Microbiol. 2022 May 4;13:757418. doi: 10.3389/fmicb.2022.757418. eCollection 2022.

ABSTRACT

Since the rapid spread of coronavirus disease (COVID-19) became a global pandemic, healthcare ministries around the world have recommended specific control methods such as quarantining infected peoples, identifying infections, wearing mask, and practicing hand hygiene. Since no effective treatment for COVID-19 has yet been discovered, a variety of drugs approved by Food and Drug Administration (FDA) have been suggested for repurposing strategy. In the current study, we predicted that doxycycline could interact with the nucleotide triphosphate (NTP) entry channel, and is therefore expected to hinder the viral replication of SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp) through docking analysis. Further, the molecular dynamics results revealed that the RdRp-Doxycycline complex was structurally relatively stable during the dynamic period (100 ns), and its complex maintained close contact with their active catalytic domains of SARS-CoV-2 RdRp. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculation of binding free energy also showed that the doxycycline has worthy affinities with SARS-CoV-2 RdRp. As expected, doxycycline effectively inhibited the viral replication of IHU strains of SARS-CoV-2 (IHUMI-3 and IHUMI-6), identified from the hospitalized patients in IHU Méditerranée Infection (IHUMI), Marseille, France. Moreover, doxycycline inhibited the viral load in vitro at both on-entry and after viral entry of IHU variants of SARS-CoV-2. The results suggest that doxycycline exhibits strains-dependant antiviral activity against COVID-19. As a result, the current study concludes that doxycycline may be more effective in combination with other drugs for better COVID-19 treatment efficacy.

PMID:35602049 | PMC:PMC9115549 | DOI:10.3389/fmicb.2022.757418

Front Microbiol. 2022 May 4;13:909866. doi: 10.3389/fmicb.2022.909866. eCollection 2022.

NO ABSTRACT

PMID:35602022 | PMC:PMC9115575 | DOI:10.3389/fmicb.2022.909866

Proc Natl Acad Sci India Sect B Biol Sci. 2022 May 17:1-11. doi: 10.1007/s40011-022-01371-1. Online ahead of print.

ABSTRACT

The WHO has declared the Covid-19 outbreak as a global health emergency with a mortality rate of approximately 3%, across 200 countries. There has been a considerable risk involved with drug repurposing in Covid-19 treatment, particularly in patients with underlying chronic disorders. Intervention of appropriate adjunct to primary drug therapy at subclinical or clinical doses may help to reduce unintended consequences involved in Covid-19 therapy. Metal nanoparticles due to their intrinsic structural and functional properties, not only contribute to anti-viral properties but also help to reduce the risk for associated complications. Although, silver nanoparticles hold great promise as an effective biocidal agent, while other metal nanoparticles also fueled interest against virus infection. The present review discusses the important properties of selected metal nanoparticles, their antiviral principle with possible toxic consequences, provides invaluable information for scientists and clinicians about an appropriate metal nanoparticle as an adjunct for Covid-19 treatment.

PMID:35601009 | PMC:PMC9113381 | DOI:10.1007/s40011-022-01371-1

Front Physiol. 2022 May 4;13:885593. doi: 10.3389/fphys.2022.885593. eCollection 2022.

ABSTRACT

For hard tissue formation, cellular mechanisms, involved in protein folding, processing, and secretion play important roles in the endoplasmic reticulum (ER). In pathological and regeneration conditions, ER stress hinders proper formation and secretion of proteins, and tissue regeneration by unfolded protein synthesis. 4-Phenylbutyric acid (4PBA) is a chemical chaperone that alleviates ER stress through modulation in proteins folding and protein trafficking. However, previous studies about 4PBA only focused on the metabolic diseases rather than on hard tissue formation and regeneration. Herein, we evaluated the function of 4PBA in dentin regeneration using an exposed pulp animal model system via a local delivery method as a drug repositioning strategy. Our results showed altered morphological changes and cellular physiology with histology and immunohistochemistry. The 4PBA treatment modulated the inflammation reaction and resolved ER stress in the early stage of pulp exposure. In addition, 4PBA treatment activated blood vessel formation and TGF-β1 expression in the dentin-pulp complex. Micro-computed tomography and histological examinations confirmed the facilitated formation of the dentin bridge in the 4PBA-treated specimens. These results suggest that proper modulation of ER stress would be an important factor for secretion and patterned formation in dentin regeneration.

PMID:35600310 | PMC:PMC9114641 | DOI:10.3389/fphys.2022.885593

Virus Res. 2022 May 19:198816. doi: 10.1016/j.virusres.2022.198816. Online ahead of print.

ABSTRACT

Group B coxsackievirus is an enterovirus that can cause a variety of diseases, including myocarditis, aseptic meningitis, and hand, foot, and mouth disease. Currently, there is no effective antiviral drug against this virus. In this study, we used a cytopathic effect-based viral inhibition assay to screen an FDA-approved drug library and found that doxepin hydrochloride had potential antiviral activity. Doxepin hydrochloride exhibited strong antiviral activity against coxsackievirus B types 1-3 with a 50% inhibitory concentration of 10.12 ± 0.85 μM. Moreover, doxepin hydrochloride did not exert antiviral activity against other enteroviruses, including enterovirus A71 (subtypes BrCr/C4) and coxsackievirus A (subtypes 6/10/16). Furthermore, doxepin hydrochloride inhibited virus replication in the early stage of the infection cycle rather than affecting the entry or assembly process. In addition, a few mechanism-related pharmacophores were discovered through gene association network analysis. These findings identify a possible lead compound for treating coxsackievirus B infection and simultaneously offer valuable clues for drug repositioning.

PMID:35598772 | DOI:10.1016/j.virusres.2022.198816

Virology. 2022 May 16;572:64-71. doi: 10.1016/j.virol.2022.05.004. Online ahead of print.

ABSTRACT

Recurrent waves of COVID19 remain a major global health concern. Repurposing either FDA-approved or clinically advanced drug candidates can save time and effort required for validating the safety profile and FDA approval. However, the selection of appropriate screening approaches is key to identifying novel candidate drugs with a higher probability of clinical success. Here, we report a rapid, stratified two-step screening approach using pseudovirus entry inhibition assay followed by an infectious prototypic SARS CoV2 cytotoxic effect inhibition assay in multiple cell lines. Using this approach, we screened a library of FDA-approved and clinical-stage drugs and identified four compounds, apilimod, berbamine, cepharanthine and (S)-crizotinib which potently inhibited SARS CoV2-induced cell death. Importantly, these drugs exerted similar inhibitory effect on the delta and omicron variants although they replicated less efficiently than the prototypic strain. Apilimod is currently under clinical trial (NCT04446377) for COVID19 supporting the validity and robustness of our screening approach.

PMID:35598394 | DOI:10.1016/j.virol.2022.05.004

Comput Methods Programs Biomed. 2022 May 11;221:106866. doi: 10.1016/j.cmpb.2022.106866. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: With the advent of bioinformatics, biological databases have been constructed to computerize data. Biological systems can be described as interactions and relationships between elements constituting the systems, and they are organized in various biomedical open databases. These open databases have been used in approaches to predict functional interactions such as protein-protein interactions (PPI), drug-drug interactions (DDI) and disease-disease relationships (DDR). However, just combining interaction data has limited effectiveness in predicting the complex relationships occurring in a whole context. Each contributing source contains information on each element in a specific field of knowledge but there is a lack of inter-disciplinary insight in combining them.

METHODS: In this study, we propose the RWD Integrated platform for Discovering Associations in Biomedical research (RIDAB) to predict interactions between biomedical entities. RIDAB is established as a graph network to construct a platform that predicts the interactions of target entities. Biomedical open database is combined with EMRs each representing a biomedical network and a real-world data. To integrate databases from different domains to build the platform, mapping of the vocabularies was required. In addition, the appropriate structure of the network and the graph embedding method to be used were needed to be selected to fit the tasks.

RESULTS: The feasibility of the platform was evaluated using node similarity and link prediction for drug repositioning task, a commonly used task for biomedical network. In addition, we compared the US Food and Drug Administration (FDA)-approved repositioned drugs with the predicted result. By integrating EMR database with biomedical networks, the platform showed increased f1 score in predicting repositioned drugs, from 45.62% to 57.26%, compared to platforms based on biomedical networks alone.

CONCLUSIONS: This study demonstrates that the elements of biomedical research findings can be reflected by integrating EMR data with open-source biomedical networks. In addition, showed the feasibility of using the established platform to represent the integration of biomedical networks and reflected the relationship between real world networks.

PMID:35594580 | DOI:10.1016/j.cmpb.2022.106866

Med Res Rev. 2022 May 20. doi: 10.1002/med.21891. Online ahead of print.

ABSTRACT

Zika virus (ZIKV) is an arbovirus belonging to the flavivirus genus and is transmitted in Aedes mosquito vectors. Since its discovery in humans in 1952 in Uganda, ZIKV has been responsible for many outbreaks in South America, Africa, and Asia. Patients infected with ZIKV are usually asymptomatic; mild symptoms include fever, joint and muscle pain, and fatigue. However, severe infections may have neurological implications, such as Guillain-Barré syndrome and fetal microcephaly. To date, there are no existing approved therapeutic drugs or vaccines against ZIKV infections; treatments mainly target the symptoms of infection. Preventive measures against mosquito breeding are the main strategy for limiting the spread of the virus. Antiviral drug research for the treatment of ZIKV infection has been rapidly developing, with many drug candidates emerging from drug repurposing studies, and compound screening. In particular, several studies have demonstrated the potential of natural products as antivirals for ZIKV infection. Hence, this paper will review recent advances in natural products in ZIKV antiviral drug discovery.

PMID:35593443 | DOI:10.1002/med.21891

Cell Genom. 2022 Apr 13;2(4):None. doi: 10.1016/j.xgen.2022.100117.

ABSTRACT

Identifying cellular functions dysregulated by disease-associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. However, follow-up studies can be challenging if disease-relevant cell types are difficult to sample. Variants associated with immune diseases point toward the role of CD4+ regulatory T cells (Treg cells). We mapped genetic regulation (quantitative trait loci [QTL]) of gene expression and chromatin activity in Treg cells, and we identified 133 colocalizing loci with immune disease variants. Colocalizations of immune disease genome-wide association study (GWAS) variants with expression QTLs (eQTLs) controlling the expression of CD28 and STAT5A, involved in Treg cell activation and interleukin-2 (IL-2) signaling, support the contribution of Treg cells to the pathobiology of immune diseases. Finally, we identified seven known drug targets suitable for drug repurposing and suggested 63 targets with drug tractability evidence among the GWAS signals that colocalized with Treg cell QTLs. Our study is the first in-depth characterization of immune disease variant effects on Treg cell gene expression modulation and dysregulation of Treg cell function.

PMID:35591976 | PMC:PMC9010307 | DOI:10.1016/j.xgen.2022.100117

Sci Rep. 2022 May 19;12(1):8434. doi: 10.1038/s41598-022-12180-x.

ABSTRACT

Drug Discovery is an active research area that demands great investments and generates low returns due to its inherent complexity and great costs. To identify potential therapeutic candidates more effectively, we propose protein-ligand with adversarial augmentations network (PLA-Net), a deep learning-based approach to predict target-ligand interactions. PLA-Net consists of a two-module deep graph convolutional network that considers ligands' and targets' most relevant chemical information, successfully combining them to find their binding capability. Moreover, we generate adversarial data augmentations that preserve relevant biological backgrounds and improve the interpretability of our model, highlighting the relevant substructures of the ligands reported to interact with the protein targets. Our experiments demonstrate that the joint ligand-target information and the adversarial augmentations significantly increase the interaction prediction performance. PLA-Net achieves 86.52% in mean average precision for 102 target proteins with perfect performance for 30 of them, in a curated version of actives as decoys dataset. Lastly, we accurately predict pharmacologically-relevant molecules when screening the ligands of ChEMBL and drug repurposing Hub datasets with the perfect-scoring targets.

PMID:35589824 | DOI:10.1038/s41598-022-12180-x

PLoS Pathog. 2022 May 19;18(5):e1010498. doi: 10.1371/journal.ppat.1010498. eCollection 2022 May.

ABSTRACT

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.

PMID:35587469 | DOI:10.1371/journal.ppat.1010498

Biosci Rep. 2022 May 18:BSR20220040. doi: 10.1042/BSR20220040. Online ahead of print.

ABSTRACT

In the last couple of decades, biomarkers have been on the rise for diagnostic and predictive value. There has been a rush to identify new markers using new technologies and drug repurposing approaches. SMARCB1 acronym arises from the SWI/SNF (SWItch/Sucrose Non-Fermentable) related Matrix-associated Actin-dependent Regulator of Chromatin subfamily B member 1 (SMARCB1). It is a molecule, whose role is associated with the sucrose metabolism. SMARCB1 is also called INI1 (Integrase Interactor 1). The molecule was discovered in the mid-1990s. Its role as a loss-of-function marker for malignant rhabdoid tumors (MRT) of renal and extra-renal origin has enormously expanded the spectrum of involved neoplasms since that time. Several tumors have been characterized by genetic aberrations in the SMARCB1 gene. They include reduction of expression, loss of expression, and mosaic expression. Most of the tumors are sarcomas, but a variegated group of tumors with mixed phenotypes has also been delineated. It is well known that the outcome of patients harboring genetic aberrations in the SMARCB1 gene has been poor. Guo et al. reported that reduced SMARCB1 expression occurred in 70% of osteosarcomas. Their data significantly correlated with poor neo-adjuvant response. These authors emphasize a shorter progression-free and overall survival of the patients demonstrating an altered expression of this gene. Interestingly, mRNA in-silico analysis established that SMARCB1 expression correlates with the response to chemotherapy of osteosarcoma patients, but there was no reliable correlation between SMARCB1 expression level and metastasis, response to neoadjuvant therapy, overall survival, and progression-free survival. The study involved a tissue microarray (TMA) on bone tumors that may limit the full evaluation of the gene expression. Nevertheless, Guo et al.'s study is remarkable. It expands the list of the tumors harboring an altered SMARCB1 gene expression and suggests that this marker should be investigated in every pathology workup for potential predictive value. On the other side, much work needs to be done if we hope that we strive to provide additional therapeutic strategies for osteosarcoma patients with altered SMARCB1 gene expression.

PMID:35583077 | DOI:10.1042/BSR20220040

Epilepsia. 2022 May 17. doi: 10.1111/epi.17303. Online ahead of print.

ABSTRACT

Many brain insults and injuries are 'epileptogenic': they increase the risk of developing epilepsy. It is desirable to identify treatments that are 'antiepileptogenic': treatments that prevent the development of epilepsy, if administered after the occurrence of an epileptogenic insult. Current antiepileptic drugs are not antiepileptogenic, but evidence of antiepileptogenic efficacy is accumulating for a growing number of other compounds. From amongst these candidate compounds, statins are deserving of particular attention because statins are reported to be antiepileptogenic in more published studies and in a wider range of brain insults than any other individual or class of compounds. While many studies report the antiepileptogenic effect of statins, it is unclear how many studies provide evidence that statins exhibit the following two essential features of a clinically-viable antiepileptogenic drug: the drug must exert an antiepileptogenic effect even if it is initiated after the epileptogenic brain insult has already occurred, and the antiepileptogenic effect must endure even after the drug has been discontinued. In the current work, we interrogate published preclinical and clinical studies, to determine if statins fulfil these essential requirements. There are eight different statins in clinical use. To enable the clinical use of one of these statins for antiepileptogenesis, its antiepileptogenic effect will have to be established through future time- and resource-intensive clinical trials. Therefore, it is desirable to review published literature in order to determine which of the statins emerges as the most promising candidate for antiepileptogenic therapy. Hence, in the current work, we also collate and analyse published data-clinical and pre-clinical, direct and indirect-that helps answer the question: Which statin is the most promising candidate to take forward into an antiepileptogenesis clinical trial?

PMID:35582761 | DOI:10.1111/epi.17303