Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease.

MBio. 2018 12 18;9(6):

Authors: Montoya MC, Krysan DJ

Abstract
The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. From these efforts, the triphenylethylene class of selective estrogen receptor modulators related to tamoxifen has shown activity against a wide range of medically important human pathogens, including bacteria, fungi, parasites, and viruses. Because it has activity against many pathogens affecting people in resource-limited areas of the world, TAM and related drugs may be particularly useful. Here, we review the in vitro, in vivo, and mechanistic studies of the anti-infective activity of tamoxifen, toremifene, clomiphene, and their analogs. We also discuss the pharmacologic properties of this privileged scaffold and its potential utility in treating infectious diseases.

PMID: 30563895 [PubMed - indexed for MEDLINE]

Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition.

Pharmacol Res. 2018 11;137:89-103

Authors: Tomilov A, Allen S, Hui CK, Bettaieb A, Cortopassi G

Abstract
When insulin binds insulin receptor, IRS1 signaling is stimulated to trigger the maximal insulin response. p52Shc protein competes directly with IRS1, thus damping and diverting maximal insulin response. Genetic reduction of p52Shc minimizes competition with IRS1, and improves insulin signaling and glucose control in mice, and improves pathophysiological consequences of hyperglycemia. Given the multiple benefits of Shc reduction in vivo, we investigated whether any of 1680 drugs used in humans may function as Shc inhibitors, and thus potentially serve as novel anti-diabetics. Of the 1680, 30 insulin sensitizers were identified by screening in vitro, and of these 30 we demonstrated that 7 bound Shc protein. Of the 7 drugs, idebenone dose-dependently bound Shc protein in the 50-100 nM range, and induced insulin sensitivity and cytoprotection in this same 100 nM range that clinically dosed idebenone reaches in human plasma. By contrast we observe mitochondrial effects of idebenone in the 5,000 nM range that are not reached in human dosing. Multiple assays of target engagement demonstrate that idebenone physically interacts with Shc protein. Idebenone sensitizes mice to insulin in two different mouse models of prediabetes. Genetic depletion of idebenone's target eliminates idebenone's ability to insulin-sensitize in vivo. Thus, idebenone is the first-in-class member of a novel category of insulin-sensitizing and cytoprotective agents, the Shc inhibitors. Idebenone is an approved drug and could be considered for other indications such as type 2 diabetes and fatty liver disease, in which insulin resistance occurs.

PMID: 30290222 [PubMed - indexed for MEDLINE]

Antileishmanial activity of H1-antihistamine drugs and cellular alterations in Leishmania (L.) infantum.

Acta Trop. 2019 Apr 16;:

Authors: de Melo Mendes V, Tempone AG, Treiger Borborema SE

Abstract
Leishmaniases are infectious diseases caused by protozoan parasites Leishmania and transmitted by sand flies. Drug repurposing is a therapeutic approach that has shown satisfactory results in their treatment. Analyses of antihistaminic drugs have revealed their in vitro and in vivo activity against trypanosomatids. In this way, this study evaluated the antileishmanial activity of H1-antihistamines and identified the cellular alterations in Leishmania (L.) infantum. Cinnarizine, cyproheptadine, and meclizine showed activity against promastigotes with 50% inhibitory concentration (IC50) values between 10 - 29 μM. These drugs also demonstrated activity and selectivity against intracellular amastigotes, with IC50 values between 20 - 35 μM. Fexofenadine and cetirizine lacked antileishmanial activity against both forms. Mammalian cytotoxicity studies revealed 50% cytotoxic concentration values between 52 - >200 μM. These drugs depolarized the mitochondria membrane of parasites and caused morphological alterations, including mitochondrial damage, disorganization of the intracellular content, and nuclear membrane detachment. In conclusion, the L. infantum death may be ascribed by the subcellular alterations followed by a pronounced decrease in the mitochondrial membrane potential, indicating dysfunction in the respiratory chain upon H1-antihistamine treatment. These H1-antihistamines could be used to explore new routes of cellular death in the parasite and the determination of the targets at a molecular level, would contribute to understanding the potential of these drugs as antileishmanial.

PMID: 31002807 [PubMed - as supplied by publisher]

Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells.

J Immunol Res. 2019;2019:9678098

Authors: Soria-Castro R, Schcolnik-Cabrera A, Rodríguez-López G, Campillo-Navarro M, Puebla-Osorio N, Estrada-Parra S, Estrada-García I, Chacón-Salinas R, Chávez-Blanco AD

Abstract
Valproic acid (VPA) is widely recognized for its use in the control of epilepsy and other neurological disorders in the past 50 years. Recent evidence has shown the potential of VPA in the control of certain cancers, owed in part to its role in modulating epigenetic changes through the inhibition of histone deacetylases, affecting the expression of genes involved in the cell cycle, differentiation, and apoptosis. The direct impact of VPA in cells of the immune system has only been explored recently. In this review, we discuss the effects of VPA in the suppression of some activation mechanisms in several immune cells that lead to an anti-inflammatory response. As expected, immune cells are not exempt from the effect of VPA, as it also affects the expression of genes of the cell cycle and apoptosis through epigenetic modifications. In addition to inhibiting histone deacetylases, VPA promotes RNA interference, activates histone methyltransferases, or represses the activation of transcription factors. However, during the infectious process, the effectiveness of VPA is subject to the biological nature of the pathogen and the associated immune response; this is because VPA can promote the control or the progression of the infection. Due to its various effects, VPA is a promising alternative for the control of autoimmune diseases and hypersensitivity and needs to be further explored.

PMID: 31001564 [PubMed - in process]

Identification of Off-Patent Compounds That Present Antifungal Activity Against the Emerging Fungal Pathogen Candida auris.

Front Cell Infect Microbiol. 2019;9:83

Authors: de Oliveira HC, Monteiro MC, Rossi SA, Pemán J, Ruiz-Gaitán A, Mendes-Giannini MJS, Mellado E, Zaragoza O

Abstract
Candida auris is an emerging fungal pathogen of great concern among the scientific community because it is causing an increasing number of hospital outbreaks of difficult management worldwide. In addition, isolates from this species frequently present reduced susceptibility to azole and echinocandin drugs. For this reason, it is necessary to develop new antifungal strategies to better control the disease caused by this yeast. In this work, we screened drugs from the Prestwick chemical library, which contains 1,280 off-patent compounds that are already approved by the Food and Drug Administration, with the aim of identifying molecules with antifungal activity against C. auris. In an initial screening, we looked for drugs that inhibited the growth of three different C. auris strains and found 27 of them which it did so. Ten active compounds were selected to test the susceptibility profile by using the EUCAST protocol. Antifungal activity was confirmed for seven drugs with MICs ranging from 0.5 to 64 mg/L. Some of these drugs were also tested in combination with voriconazole and anidulafungin at sub-inhibitory concentrations. Our results suggest synergistic interactions between suloctidil and voriconazole with fractional inhibitory concentration index (FICI) values of 0.11 to 0.5 and between ebselen and anidulafungin (FICI, 0.12 to 0.44). Our findings indicate that drug repurposing could be a viable alternative to managing infections by C. auris.

PMID: 31001487 [PubMed - in process]

Drug prioritization using the semantic properties of a knowledge graph.

Sci Rep. 2019 Apr 18;9(1):6281

Authors: Malas TB, Vlietstra WJ, Kudrin R, Starikov S, Charrout M, Roos M, Peters DJM, Kors JA, Vos R, 't Hoen PAC, van Mulligen EM, Hettne KM

Abstract
Compounds that are candidates for drug repurposing can be ranked by leveraging knowledge available in the biomedical literature and databases. This knowledge, spread across a variety of sources, can be integrated within a knowledge graph, which thereby comprehensively describes known relationships between biomedical concepts, such as drugs, diseases, genes, etc. Our work uses the semantic information between drug and disease concepts as features, which are extracted from an existing knowledge graph that integrates 200 different biological knowledge sources. RepoDB, a standard drug repurposing database which describes drug-disease combinations that were approved or that failed in clinical trials, is used to train a random forest classifier. The 10-times repeated 10-fold cross-validation performance of the classifier achieves a mean area under the receiver operating characteristic curve (AUC) of 92.2%. We apply the classifier to prioritize 21 preclinical drug repurposing candidates that have been suggested for Autosomal Dominant Polycystic Kidney Disease (ADPKD). Mozavaptan, a vasopressin V2 receptor antagonist is predicted to be the drug most likely to be approved after a clinical trial, and belongs to the same drug class as tolvaptan, the only treatment for ADPKD that is currently approved. We conclude that semantic properties of concepts in a knowledge graph can be exploited to prioritize drug repurposing candidates for testing in clinical trials.

PMID: 31000794 [PubMed - in process]

Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease.

Antimicrob Agents Chemother. 2018 04;62(4):

Authors: Nixon GL, McEntee L, Johnson A, Farrington N, Whalley S, Livermore J, Natal C, Washbourn G, Bibby J, Berry N, Lestner J, Truong M, Owen A, Lalloo D, Charles I, Hope W

Abstract
Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

PMID: 29311092 [PubMed - indexed for MEDLINE]

Biological Hallmarks of Cancer in Alzheimer's Disease.

Mol Neurobiol. 2019 Apr 16;:

Authors: Nudelman KNH, McDonald BC, Lahiri DK, Saykin AJ

Abstract
Although Alzheimer's disease (AD) is an international health research priority for our aging population, little therapeutic progress has been made. This lack of progress may be partially attributable to disease heterogeneity. Previous studies have identified an inverse association of cancer and AD, suggesting that cancer history may be one source of AD heterogeneity. These findings are particularly interesting in light of the number of common risk factors and two-hit models hypothesized to commonly drive both diseases. We reviewed the ten hallmark biological alterations of cancer cells to investigate overlap with the AD literature and identified overlap of all ten hallmarks in AD, including (1) potentially common underlying risk factors, such as increased inflammation, deregulated cellular energetics, and genome instability; (2) inversely regulated mechanisms, including cell death and evading growth suppressors; and (3) functions with more complex, pleiotropic mechanisms, some of which may be stage-dependent in AD, such as cell adhesion/contact inhibition and angiogenesis. Additionally, we discuss the recent observation of a biological link between cancer and AD neuropathology. Finally, we address the therapeutic implications of this topic. The significant overlap of functional pathways and molecules between these diseases, some similarly and some oppositely regulated or functioning in each disease, supports the need for more research to elucidate cancer-related AD genetic and functional heterogeneity, with the aims of better understanding AD risk mediators, as well as further exploring the potential for some types of drug repurposing towards AD therapeutic development.

PMID: 30993533 [PubMed - as supplied by publisher]

Pulmonary Arterial Hypertension: A Case Study in FDA Expedited Program Designations.

Ther Innov Regul Sci. 2019 03;53(2):264-269

Authors: Daizadeh I

Abstract
BACKGROUND: FDA expedited program designations (EPDs) are intended to facilitate drug development for serious conditions with an unmet medical need. There are over 10 FDA-approved therapies for the rare disease pulmonary arterial hypertension (PAH). This work investigates the landscape of EPDs in the context of FDA-approved PAH therapies in order to inform on future drug development.
METHODS: The publicly available FDA Action Package (AP) was manually culled for information related to EPDs for 10 FDA-approved treatments for PAH. Documentation supporting the EPD request and/or its review (including potential rejection) was not found during the data cull.
RESULTS: This investigation finds that (1) only ambrisentan received the Fast Track Designation; (2) no Breakthrough Designations were elucidated; (3) bosentan and treprostinil received Accelerated Approval Designations, and (4) ambrisentan, sildenafil, riociguat, epoprostenol, iloprost, and treprostinil received Priority Review Designations. All therapies (except sildenafil) received an Orphan Drug Designation.
CONCLUSION: Based on these results, it is recommended that drug developers be encouraged to revisit traditional endpoint measures, explore novel biological mechanisms, and/or effectively differentiate in other dimensions (eg, safety). Developers should also consider engaging the FDA early in development (ideally prior to first-in-human) to agree on the kind and amount of data to meet the statutory bar with the intention of increasing the probability of securing a Fast Track or Breakthrough Designation.

PMID: 29874936 [PubMed - indexed for MEDLINE]

Discovering proteasomal deubiquitinating enzyme inhibitors for cancer therapy: lessons from rational design, nature and old drug reposition.

Future Med Chem. 2018 09 01;10(17):2087-2108

Authors: Patel K, Ahmed ZS, Huang X, Yang Q, Ekinci E, Neslund-Dudas CM, Mitra B, Elnady FA, Ahn YH, Yang H, Liu J, Dou QP

Abstract
The ubiquitin proteasome system has been validated as a target of cancer therapies evident by the US FDA approval of anticancer 20S proteasome inhibitors. Deubiquitinating enzymes (DUBs), an essential component of the ubiquitin proteasome system, regulate cellular processes through the removal of ubiquitin from ubiquitinated-tagged proteins. The deubiquitination process has been linked with cancer and other pathologies. As such, the study of proteasomal DUBs and their inhibitors has garnered interest as a novel strategy to improve current cancer therapies, especially for cancers resistant to 20S proteasome inhibitors. This article reviews proteasomal DUB inhibitors in the context of: discovery through rational design approach, discovery from searching natural products and discovery from repurposing old drugs, and offers a future perspective.

PMID: 30066579 [PubMed - indexed for MEDLINE]

The potential of dopamine receptor 2 (DRD2) as a therapeutic target for tackling pancreatic cancer.

Expert Opin Ther Targets. 2019 Apr 15;:

Authors: Bakadlag R, Jandaghi P, Hoheisel JD, Riazalhosseini Y

PMID: 30986128 [PubMed - as supplied by publisher]

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer.

Comb Chem High Throughput Screen. 2018;21(2):74-83

Authors: Hsiao TH, Chiu YC, Chen YH, Hsu YC, Chen HH, Chuang EY, Chen Y

Abstract
AIM AND OBJECTIVE: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, "repositioning" of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures.
MATERIALS AND METHODS: First, a "gene set-compound" network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A "cancer-functional gene set- compound" network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained.
RESULTS: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment.
CONCLUSION: Our method can effectively identify compounds with a potential to be "repositioned" for cancer treatment according to their active mechanisms and their association with patients' survival time.

PMID: 29303076 [PubMed - indexed for MEDLINE]

Use of metformin and outcome of patients with newly diagnosed glioblastoma - pooled analysis.

Int J Cancer. 2019 Apr 13;:

Authors: Seliger C, Genbrugge E, Gorlia T, Chinot O, Stupp R, Nabors B, Weller M, Hau P, EORTC Brain Tumor Group

Abstract
Metformin has been linked to improved survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAGlio, CENTRIC and CORE trials. We performed multivariate COX-analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radio-chemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and non-fasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, HR for OS=0.87; 95%CI=0.65-1.16; HR for PFS=0.84; 95%CI=0.64-1.10; during TMZ/RT HR for OS=0.97; 95%CI=0.68-1.38; HR for PFS=1.02; 95%CI=0.74-1.41). We found a statistically non-significant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS =0.68; 95%CI=0.42-1.10; HR for PFS=0.57; 95%CI=0.36-0.91), but not during the TMZ/RT period (HR for OS=0.90; 95%CI=0.51-1.56; HR for PFS=1.05; 95%CI=0.64-1.73). Diabetes mellitus or increased non-fasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumour characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities. This article is protected by copyright. All rights reserved.

PMID: 30980539 [PubMed - as supplied by publisher]

The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

Clin Pharmacol Ther. 2018 03;103(3):409-418

Authors: Denny JC, Van Driest SL, Wei WQ, Roden DM

Abstract
Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine.

PMID: 29171014 [PubMed - indexed for MEDLINE]

Repurposing natural products as novel HDAC inhibitors by comparative analysis of gene expression profiles.

Phytomedicine. 2019 Mar 22;59:152900

Authors: Byun MR, Lee DH, Jang YP, Lee HS, Choi JW, Lee SK

Abstract
BACKGROUND: Extracts derived from natural products have been used to produce health supplements or therapeutic agents in oriental medicine. Although these extracts contain various bioactive compounds, their applications are generally limited to a few previously known diseases. To effectively expand their use for the treatment of other conditions, systematic analysis should be conducted for repurposing.
PURPOSE: The purpose of the present study was to investigate the new therapeutic efficacies of the Platycodon grandiflorum and ginseng extract using the CMAP-based gene expression analysis.
METHODS: In the present study, we analyzed the expression patterns of differentially expressed genes (DEGs) from extracts as the basis for drug repurposing. Cells were treated with extracts or single compounds derived from nine natural products. DEG analysis indicated that the gene expression patterns of cells treated with P. grandiflorum and ginseng extracts were highly similar to those of cells treated with different types of Histone deacetylase (HDAC) inhibitors. To identify the new mechanism of these extracts, we carried out cell viability assay, TUNEL assay, HDAC enzyme activity assay and immunoblot analysis.
RESULTS: In vitro experiments at the dose of 50 µg/ml of each extract did not affect cell death rate but significantly inhibited HDAC activity. Each extract was found to inhibit HDAC enzymatic activity and induce the expression of the p21. Furthermore, our results revealed that each extract stimulated cell death and inhibited cell proliferation.
CONCLUSION: These findings demonstrate the HDAC-inhibiting activity of P. grandiflorum and ginseng extracts and further validate the effectiveness of DEG similarity-based repurposing of natural products.

PMID: 30974310 [PubMed - as supplied by publisher]

Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors.

Front Cell Infect Microbiol. 2019;9:67

Authors: Radosevic D, Sencanski M, Perovic V, Veljkovic N, Prljic J, Veljkovic V, Mantlo E, Bukreyeva N, Paessler S, Glisic S

Abstract
Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, and therefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers, are one of the two classes of Food and Drug Administration-approved anti-influenza drugs, although their use was discontinued due to prevalent drug resistance. Fast emergence of resistance to current anti-influenza drugs have raised an urgent need for developing new anti-influenza drugs against resistant forms of circulating viruses. Here we propose a simple theoretical criterion for fast virtual screening of molecular libraries for candidate anti-influenza ion channel inhibitors both for wild type and adamantane-resistant influenza A viruses. After in silico screening of drug space using the EIIP/AQVN filter and further filtering of drugs by ligand based virtual screening and molecular docking we propose the best candidate drugs as potential dual inhibitors of wild type and adamantane-resistant influenza A viruses. Finally, guanethidine, the best ranked drug selected from ligand-based virtual screening, was experimentally tested. The experimental results show measurable anti-influenza activity of guanethidine in cell culture.

PMID: 30972303 [PubMed - in process]

A Computational Model of Tumor Growth and Anakoinosis.

Front Pharmacol. 2019;10:287

Authors: Pantziarka P, Ghibelli L, Reichle A

Abstract
Anakoinosis is a new cancer treatment paradigm that posits a key role for communicative reprogramming within tumor systems. To date no mathematical or computational models of anakoinosis have been developed. Here we outline the NEATG_A system, a first computational model of communicative reprogramming. The model recapitulates key features of real tumor systems and responses to both traditional cytotoxic treatments and biomodulatory/anakoinotic treatments. Results are presented and discussed, particularly with respect to the implications for future cancer treatment protocols.

PMID: 30971926 [PubMed]

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review.

Front Neurosci. 2019;13:236

Authors: Yimer EM, Hishe HZ, Tuem KB

Abstract
To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional de novo drug discovery technique is more challenging, particularly for neurological disorders. Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies.

PMID: 30971875 [PubMed]

Repurposing azole antifungals into antileishmanials: Novel 3-triazolylflavanones with promising in vitro antileishmanial activity against Leishmania major.

Parasitol Int. 2019 Apr;69:103-109

Authors: Keighobadi M, Emami S, Fakhar M, Shokri A, Mirzaei H, Hosseini Teshnizi S

Abstract
Previously, we have described a series of azole antifungals namely 3-(1,2,4-triazol-1-yl)flavanones (TFs) containing an N-(phenethyl)azole framework required for sterol 14α-demethylase (CYP51) inhibitory activity. Similar mechanism of action of azoles in fungi and protozoan parasites prompted us to investigate the potential effects of TFs against promastigote and amastigote forms of Leishmania major (L. major), as well as their toxicity against macrophages, apoptosis induction and in silico interactions with the target enzyme. All compounds showed more potent anti-parasitic activity against L. major in comparison with reference azole drug fluconazole and standard antileishmanial agent glucantime. Among the tested compounds, the 4-chloro derivative (TF-2) was found to be the most potent one, being about 13 times more potent than fluconazole against promastigotes. TF-2 decreased both mean infection rate of macrophages (MIR) and mean number of amastigotes per macrophages (MNAPM), significantly more than fluconazole (P < .001). Furthermore, the cytotoxicity assay against J774.A.1 macrophages revealed that this compound displays high selectivity against amastigotes over macrophages (SI = 30.21). The in silico study showed that TF-2 can properly accommodated in the active site of parasitic CYP51 and coordinated to the heme. The SAR analysis showed that the introduction of 4-chloro on 2-phenyl moiety results in the best profile of activity and selectivity. Accordingly, the compound TF-2 prototype can be considered as promising candidate for development of new antileishmanial agents.

PMID: 30582997 [PubMed - indexed for MEDLINE]

Repurposing Pharmaceuticals as Neuroprotective Agents for Cerebral Malaria.

Curr Clin Pharmacol. 2017;12(2):62-72

Authors: Brooks HM, Hawkes MT

Abstract
BACKGROUND: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection which may result in death or developmental disability. The pathologic processes leading to CM are not fully elucidated; however, widely accepted mechanisms include parasite sequestration, release of infected red blood cell contents, activation of endothelial cells, increased inflammatory responses, and ultimately dysfunction of the neurovascular unit (NVU). The endothelium plays a central role in these processes as the site of parasitized erythrocyte sequestration and as the regulator of fluid extravasation into the central nervous system. Modulating endothelial barrier function at the NVU may provide new therapeutic approaches to improve outcomes in CM.
METHODS: Here we provide a narrative review of the literature of peer-reviewed research relating to adjunctive therapies for CM. We discuss regulatory pathways of the NVU, with a focus on the potential for pharmacologic modulation of the NVU to improve CM outcomes.
RESULTS: Recently licensed pharmaceuticals, developed as therapies for cancer or neurologic disease, could be re-purposed for use as host-directed therapies in CM to target pathways involved in endothelial stability and activation.
CONCLUSION: The findings of this review highlight recently licensed pharmaceuticals that may be developed as future adjunctive therapies for CM.

PMID: 28676008 [PubMed - indexed for MEDLINE]