Animals (Basel). 2021 Dec 23;12(1):29. doi: 10.3390/ani12010029.

ABSTRACT

Mastitis, a disease with high incidence worldwide, is the most prevalent and costly disease in the dairy industry. Gram-negative bacteria such as Escherichia coli (E. coli) are assumed to be among the leading agents causing acute severe infection with clinical signs. E. Coli, environmental mastitis pathogens, are the primary etiological agents of bovine mastitis in well-managed dairy farms. Response to E. Coli infection has a complex pattern affected by genetic and environmental parameters. On the other hand, the efficacy of antibiotics and/or anti-inflammatory treatment in E. coli mastitis is still a topic of scientific debate, and studies on the treatment of clinical cases show conflicting results. Unraveling the bio-signature of mastitis in dairy cattle can open new avenues for drug repurposing. In the current research, a novel, semi-supervised heterogeneous label propagation algorithm named Heter-LP, which applies both local and global network features for data integration, was used to potentially identify novel therapeutic avenues for the treatment of E. coli mastitis. Online data repositories relevant to known diseases, drugs, and gene targets, along with other specialized biological information for E. coli mastitis, including critical genes with robust bio-signatures, drugs, and related disorders, were used as input data for analysis with the Heter-LP algorithm. Our research identified novel drugs such as Glibenclamide, Ipratropium, Salbutamol, and Carbidopa as possible therapeutics that could be used against E. coli mastitis. Predicted relationships can be used by pharmaceutical scientists or veterinarians to find commercially efficacious medicines or a combination of two or more active compounds to treat this infectious disease.

PMID:35011134 | DOI:10.3390/ani12010029

Int J Mol Sci. 2021 Dec 27;23(1):262. doi: 10.3390/ijms23010262.

ABSTRACT

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.

PMID:35008687 | DOI:10.3390/ijms23010262

Cancers (Basel). 2021 Dec 26;14(1):99. doi: 10.3390/cancers14010099.

ABSTRACT

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction in the HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction in clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of H2AX indicated NFV-mediated DNA damage, which was associated with decreased survival and proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho-eIF2α, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.

PMID:35008264 | DOI:10.3390/cancers14010099

Gene. 2022 Jan 7:146137. doi: 10.1016/j.gene.2021.146137. Online ahead of print.

ABSTRACT

The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.

PMID:35007686 | DOI:10.1016/j.gene.2021.146137

Mol Biomed. 2021 Sep 20;2(1):28. doi: 10.1186/s43556-021-00050-3.

ABSTRACT

Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.

PMID:35006427 | DOI:10.1186/s43556-021-00050-3

Front Cell Infect Microbiol. 2021 Dec 24;11:797509. doi: 10.3389/fcimb.2021.797509. eCollection 2021.

ABSTRACT

Malaria, a disease caused by the protozoan parasites Plasmodium spp., is still causing serious problems in endemic regions in the world. Although the WHO recommends artemisinin combination therapies for the treatment of malaria patients, the emergence of artemisinin-resistant parasites has become a serious issue and underscores the need for the development of new antimalarial drugs. On the other hand, new and re-emergences of infectious diseases, such as the influenza pandemic, Ebola virus disease, and COVID-19, are urging the world to develop effective chemotherapeutic agents against the causative viruses, which are not achieved to the desired level yet. In this review article, we describe existing drugs which are active against both Plasmodium spp. and microorganisms including viruses, bacteria, and fungi. We also focus on the current knowledge about the mechanism of actions of these drugs. Our major aims of this article are to describe examples of drugs that kill both Plasmodium parasites and other microbes and to provide valuable information to help find new ideas for developing novel drugs, rather than merely augmenting already existing drug repurposing efforts.

PMID:35004357 | PMC:PMC8740689 | DOI:10.3389/fcimb.2021.797509

Mol Divers. 2022 Jan 10. doi: 10.1007/s11030-021-10355-8. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Its main protease, 3C-like protease (3CLpro), is an attractive target for drug design, due to its importance in virus replication. The analysis of the radial distribution function of 159 3CLpro structures reveals a high similarity index. A study of the catalytic pocket of 3CLpro with bound inhibitors reveals that the influence of the inhibitors is local, perturbing dominantly only residues in the active pocket. A machine learning based model with high predictive ability against SARS-CoV-2 3CLpro is designed and validated. The model is used to perform a drug-repurposing study, with the main aim to identify existing drugs with the highest 3CLpro inhibition power. Among antiviral agents, lopinavir, idoxuridine, paritaprevir, and favipiravir showed the highest inhibition potential. Enzyme - ligand interactions as a key ingredient for successful drug design.

PMID:35001230 | DOI:10.1007/s11030-021-10355-8

FASEB J. 2022 Feb;36(2):e22148. doi: 10.1096/fj.202101447R.

ABSTRACT

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

PMID:34997949 | DOI:10.1096/fj.202101447R

Mol Psychiatry. 2022 Jan 7. doi: 10.1038/s41380-021-01432-3. Online ahead of print.

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accelerates the discovery of prophylactic and therapeutic drugs for persons infected with the virus. Drug repurposing for the COVID-19 pandemic has received particular attention. Increasing clinical data suggest that antidepressant use in early-stage subjects with COVID-19 might be associated with a reduced risk of intubation or death. Among the antidepressants, fluvoxamine is the most attractive drug for mild to moderate subjects with COVID-19. In this article, we review the mechanisms of action (i.e., serotonin transporter, sigma-1 receptor, and acid sphingomyelinase) of fluvoxamine for COVID-19. Furthermore, we discuss a possible link between maternal COVID-19 infection and a risk for neuropsychiatric disorders (i.e., autism spectrum disorder and schizophrenia) in offspring.

PMID:34997196 | DOI:10.1038/s41380-021-01432-3

Precis Clin Med. 2021 Aug 28;4(4):215-230. doi: 10.1093/pcmedi/pbab022. eCollection 2021 Dec.

ABSTRACT

Coronavirus disease 2019 (COVID-19) has impacted almost every part of human life worldwide, posing a massive threat to human health. The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics, for example drug repurposing. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients with mild and severe COVID-19 (GEO: GSE145926, public data available and accessed on 22 April 2020). We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).

PMID:34993416 | PMC:PMC8694063 | DOI:10.1093/pcmedi/pbab022

Front Pharmacol. 2021 Dec 21;12:768023. doi: 10.3389/fphar.2021.768023. eCollection 2021.

ABSTRACT

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

PMID:34992533 | PMC:PMC8724568 | DOI:10.3389/fphar.2021.768023

Infect Drug Resist. 2021 Dec 21;14:5575-5593. doi: 10.2147/IDR.S338987. eCollection 2021.

ABSTRACT

Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health and attracted the attention of the World Health Organization (WHO) and the governments of various countries. Therefore, the establishment of measures against bacterial resistance and the discovery of new antibacterial drugs are increasingly urgent to better contain the emergence of bacterial resistance and provide a reference for the development of new antibacterial drugs. In this review, we discuss some antibiotic drugs that have been approved for clinical use and a partial summary of the meaningful research results of anti-drug resistant bacterial drugs in different fields, including the antibiotic drugs approved by the FDA from 2015 to 2020, the potential drugs against drug-resistant bacteria, the new molecules synthesized by chemical modification, combination therapy, drug repurposing, immunotherapy and other therapies.

PMID:34992385 | PMC:PMC8711564 | DOI:10.2147/IDR.S338987

Parasit Vectors. 2022 Jan 7;15(1):10. doi: 10.1186/s13071-021-05127-0.

ABSTRACT

BACKGROUND: Drug resistance and toxic side effects are major challenges in the treatment of babesiosis. As such, new drugs are needed to combat the emergence of drug resistance in Babesia parasites and to develop alternative treatment strategies. A combination of naphthoquine (NQ) and artemisinin is an antimalarial therapy in pharmaceutical markets. The present study repurposed NQ as a drug for the treatment of babesiosis by evaluating the anti-Babesia activity of naphthoquine phosphate (NQP) alone.

METHODS: An in vitro growth inhibition assay of NQP was tested on Babesia gibsoni cultures using a SYBR Green I-based fluorescence assay. In addition, the in vivo growth inhibitory effect of NQP was evaluated using BALB/c mice infected with Babesia rodhaini. The parasitemia level and hematocrit values were monitored to determine the therapeutic efficacy of NQP and the clinical improvements in NQP-treated mice.

RESULTS: The half maximal inhibitory concentration of NQP against B. gibsoni in vitro was 3.3 ± 0.5 μM. Oral administration of NQP for 5 consecutive days at a dose of 40 mg/kg of body weight resulted in significant inhibition of B. rodhaini growth in mice as compared with that of the control group. All NQP-treated mice survived, whereas the mice in the control group died between days 6 and 9 post-infection.

CONCLUSION: This is the first study to evaluate the anti-Babesia activity of NQP in vitro and in vivo. Our findings suggest that NQP is a promising drug for treating Babesia infections, and drug repurposing may provide new treatment strategies for babesiosis.

PMID:34991686 | DOI:10.1186/s13071-021-05127-0

Pharmacol Res. 2022 Jan 3:106055. doi: 10.1016/j.phrs.2021.106055. Online ahead of print.

ABSTRACT

Polypharmacology is a concept where a molecule can interact with two or more targets simultaneously. It offers many advantages as compared to the conventional single targeting molecules. A multi-targeting drug is much more efficacious due to its cumulative efficacy at all of its individual targets making it much more effective in complex and multifactorial diseases like cancer, where multiple proteins and pathways are involved in the onset and development of the disease. For a molecule to be polypharmacologic in nature, it needs to possess promiscuity which is the ability to interact with multiple targets; and at the same time avoid binding to antitargets which would otherwise result in off-target adverse effects. There are certain structural features and physicochemical properties which when present would help researchers to predict if the designed molecule would possess promiscuity or not. Promiscuity canalso be identified via advanced state-of-the-art computational methods. In this review, we also elaborate on the methods by which one can intentionally incorporate promiscuity in their molecules and make them polypharmacologic. The polypharmacology paradigm of "one drug-multiple targets" has numerous applications especially in drug repurposing where an already established drug is redeveloped for a new indication. Though designing a polypharmacological drug is much more difficult than designing a single-targeting drug, with the current technologies and information regarding different diseases and chemical functional groups, it is plausible for researchers to intentionally design a polypharmacological drug and unlock its advantages.

PMID:34990865 | DOI:10.1016/j.phrs.2021.106055

Assay Drug Dev Technol. 2022 Jan 6. doi: 10.1089/adt.2021.090. Online ahead of print.

ABSTRACT

Cytokine release syndrome, a prominent mechanism of morbidity and mortality in patients with coronavirus disease 2019 (COVID-19), can cause multiple bodily reactions, including excessive release of proinflammatory mediators, with tumor necrosis factor-α (TNF-α) being the most prevalent cytokine combined with persistently elevated D-dimer levels that are indicative of potential thrombotic events, low levels of endogenous nitric oxide (NO) generation, and progressive decrease in hemoglobin production. In our argument, the conceptual repurposing of hydroxyurea (HU) for managing COVID-19 can provide a promising therapeutic option originating from a rich history of investigational antiviral activity. HU as a proposed supportive therapeutic agent for treating COVID-19 can exemplify a successful remedial choice through its anti-inflammatory activity along with an intrinsic propensity to control the circulatory levels of key cytokines including TNF-α. HU has the ability to undergo in vivo NO conversion acting as NO donor together with being a prominent inducer of fetal hemoglobin (HbF) production. The combination of the mentioned two properties allows HU to possess evident capability of protecting against thrombotic events by controlling D-dimer levels. The implication of our hypothetical argument sheds light on the curative potential of HU, which can be strategically harnessed against COVID-19.

PMID:34990284 | DOI:10.1089/adt.2021.090

Emerg Microbes Infect. 2022 Jan 6:1-29. doi: 10.1080/22221751.2022.2026739. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)-expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S-protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as clinical drug for the treatment of COVID-19.

PMID:34989664 | DOI:10.1080/22221751.2022.2026739

Artif Intell Life Sci. 2021 Dec;1:100020. doi: 10.1016/j.ailsci.2021.100020. Epub 2021 Dec 17.

ABSTRACT

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center 'Lean European Open Survey on SARS-CoV-2-infected patients' (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.

PMID:34988543 | PMC:PMC8677630 | DOI:10.1016/j.ailsci.2021.100020

Brain Commun. 2021 Dec 4;3(4):fcab287. doi: 10.1093/braincomms/fcab287. eCollection 2021.

ABSTRACT

Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs' activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs' effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins' dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases.

PMID:34988442 | PMC:PMC8710935 | DOI:10.1093/braincomms/fcab287

Open Forum Infect Dis. 2021 Dec 17;9(1):ofab581. doi: 10.1093/ofid/ofab581. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Currently, only dexamethasone, tocilizumab, and sarilumab have conclusively been shown to reduce mortality of coronavirus disease 2019 (COVID-19). Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programs. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices.

METHODS: We searched for repurposed drugs that have been approved by at least one of the World Health Organization, US Food and Drug Administration, or the United Kingdom National Institute of Health and Care Excellence organizations or at least given emergency use authorization or recommended for off-label prescription. Drug prices were searched for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab, and imdevimab, and sarilumab, using active pharmaceutical ingredients (APIs) data extracted from global shipping records. This was compared with national pricing data from a range of low-, medium-, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug.

RESULTS: Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from US $2.58 for intravenous (IV) dexamethasone (or US $0.19 orally) and US $4.34 for inhaled budesonide. No export price data were available for baricitinib, tocilizumab, casirivimab, and imdevimab, or sarilumab, but courses of these treatments have higher prices, ranging from US $6.67 for baricitinib to US $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries.

CONCLUSIONS: Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whereas monoclonal antibodies and IV treatment courses are more expensive.

PMID:34988252 | PMC:PMC8709896 | DOI:10.1093/ofid/ofab581

Front Oncol. 2021 Dec 20;11:822865. doi: 10.3389/fonc.2021.822865. eCollection 2021.

ABSTRACT

[This corrects the article DOI: 10.3389/fonc.2021.741326.].

PMID:34988031 | PMC:PMC8722216 | DOI:10.3389/fonc.2021.822865