Potential COVID-19 remedies from repurposed drugs and herbal small RNAs.

To date, SARS-CoV-2 has caused millions of deaths, but the choice of treatment is limited. We previously established a platform for identifying Food and Drug Administration (FDA)-approved repurposed drugs for avian influenza A virus infections that could be used for coronavirus disease 2019 (COVID-19) treatment. In this study, we analyzed blood samples from two cohorts of 63 COVID-19 patients, including 19 patients with severe disease. Among the 39 FDA-approved drugs we identified for COVID-19 therapy in both cohorts, 23 drugs were confirmed by literature mining data, including 14 drugs already under COVID-19 clinical trials and 9 drugs reported for COVID-19 treatments, suggesting the remaining 16 FDA-approved drugs may be candidates for COVID-19 therapy. Additionally, we previously reported that herbal small RNAs (sRNAs) could be effective components in traditional Chinese medicine (TCM) for treating COVID-19. Based on the abundance of sRNAs, we screened the 245 TCMs in the Bencao (herbal) sRNA Atlas that we had previously established, and we found that the top 12 TCMs for COVID-19 treatment was consistent across both cohorts. We validated the efficiency of the top 30 sRNAs from each of the top 3 TCMs for COVID-19 treatment in poly(I:C)-stimulated human non-small cell lung cancer cells (A549 cells). In conclusion, our study recommends potential COVID-19 remedies using FDA-approved repurposed drugs and herbal sRNAs from TCMs.

Repurposed drugs in combinations exert additive anti-chikungunya virus activity: an in-vitro study.

Chikungunya virus (CHIKV) infection causes chikungunya, a viral disease that currently has no specific antiviral treatment. Several repurposed drug candidates have been investigated for the treatment of the disease. In order to improve the efficacy of the known drugs, combining drugs for treatment is a promising approach. The current study was undertaken to explore the antiviral activity of a combination of repurposed drugs that were reported to have anti-CHIKV activity. We explored the effect of different combinations of six effective drugs (2-fluoroadenine, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol) at their non-toxic concentrations against CHIKV under post infection treatment conditions in Vero cells. Focus-forming unit assay, real time RT-PCR, immunofluorescence assay, and western blot were used to determine the virus titre. The results revealed that the combination of 2-fluoroadenine with either metyrapone or emetine or enalaprilat exerted inhibitory activity against CHIKV under post-infection treatment conditions. The effect of these drug combinations was additive in nature compared to the effect of the individual drugs. The results suggest an additive anti-viral effect of these drug combinations against CHIKV. The findings could serve as an outline for the development of an innovative therapeutic approach in the future to treat CHIKV-infected patients.

Role of blood-brain barrier dysfunction in the development of poststroke epilepsy.

Stroke is a major contributor to mortality and morbidity worldwide and the most common cause of epilepsy in the elderly in high income nations. In recent years, it has become increasingly evident that both ischemic and hemorrhagic strokes induce dysfunction of the blood-brain barrier (BBB), and that this impairment can contribute to epileptogenesis. Nevertheless, studies directly comparing BBB dysfunction and poststroke epilepsy (PSE) are largely absent. Therefore, this review summarizes the role of BBB dysfunction in the development of PSE in animal models and clinical studies. There are multiple mechanisms whereby stroke induces BBB dysfunction, including increased transcytosis, tight junction dysfunction, spreading depolarizations, astrocyte and pericyte loss, reactive astrocytosis, angiogenesis, matrix metalloproteinase activation, neuroinflammation, adenosine triphosphate depletion, oxidative stress, and finally cell death. The degree to which these effects occur is dependent on the severity of the ischemia, whereby cell death is a more prominent mechanism of BBB disruption in regions of critical ischemia. BBB dysfunction can contribute to epileptogenesis by increasing the risk of hemorrhagic transformation, increasing stroke size and the amount of cerebral vasogenic edema, extravasation of excitatory compounds, and increasing neuroinflammation. Furthermore, albumin extravasation after BBB dysfunction contributes to epileptogenesis primarily via increased transforming growth factor ß signaling. Finally, seizures themselves induce BBB dysfunction, thereby contributing to epileptogenesis in a cyclical manner. In repairing this BBB dysfunction, pericyte migration via platelet-derived growth factor ß signaling is indispensable and required for reconstruction of the BBB, whereby astrocytes also play a role. Although animal stroke models have their limitations, they provide valuable insights into the development of potential therapeutics designed to restore the BBB after stroke, with the ultimate goal of improving outcomes and minimizing the occurrence of PSE. In pursuit of this goal, rapamycin, statins, losartan, semaglutide, and metformin show promise, whereby modulation of pericyte migration could also be beneficial.

Repurposed pharmacotherapy: targeting cathepsin L with repurposed drugs in virtual screening.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.

An in-depth analysis of COVID-19 treatment: Present situation and prospects.

Coronavirus disease 2019 (COVID-19) the most contagious infection caused by the unique type of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), produced a global pandemic that wreaked havoc on the health-care system, resulting in high morbidity and mortality. Several methods were implemented to tackle the virus, including the repurposing of existing medications and the development of vaccinations. The purpose of this article is to provide a complete summary of the current state and future possibilities for COVID-19 therapies. We describe the many treatment classes, such as antivirals, immunomodulators, and monoclonal antibodies, that have been repurposed or developed to treat COVID-19. We also looked at the clinical evidence for these treatments, including findings from observational studies and randomized-controlled clinical trials, and highlighted the problems and limitations of the available evidence. Furthermore, we reviewed existing clinical trials and prospective COVID-19 therapeutic options, such as novel medication candidates and combination therapies. Finally, we discussed the long-term consequences of COVID-19 and the importance of ongoing research into the development of viable treatments. This review will help physicians, researchers, and policymakers to understand the prevention and mitigation of COVID-19.

Pyrvinium doubles against WNT-driven cancer.

The WNT-ß-catenin signaling pathway has a major role in regulating cell proliferation and differentiation. Aberrant activation of the pathway contributes to various human cancer types. Because casein kinase CK1α-initiated phosphorylation of ß-catenin is a key first step to restrain WNT signaling, effective restoration of CK1α activity represents an innovative strategy to combat WNT-driven cancer. A recent study in JBC reveals the anthelmintic pyrvinium directly binds to CK1α as an activator and also stabilizes CK1α protein, doubling against WNT-driven cancer activity.

Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations.

Long coronavirus disease (COVID) has emerged as a global health issue, affecting a substantial number of people worldwide. However, the underlying mechanisms that contribute to the persistence of symptoms in long COVID remain obscure, impeding the development of effective diagnostic and therapeutic interventions. In this study, we utilized computational methods to examine the gene expression profiles of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their associations with the wide range of symptoms observed in long COVID patients. Using a comprehensive data set comprising over 255 symptoms affecting multiple organ systems, we identified differentially expressed genes and investigated their functional similarity, leading to the identification of key genes with the potential to serve as biomarkers for long COVID. We identified the participation of hub genes associated with G-protein-coupled receptors (GPCRs), which are essential regulators of T-cell immunity and viral infection responses. Among the identified common genes were CTLA4, PTPN22, KIT, KRAS, NF1, RET, and CTNNB1, which play a crucial role in modulating T-cell immunity via GPCR and contribute to a variety of symptoms, including autoimmunity, cardiovascular disorders, dermatological manifestations, gastrointestinal complications, pulmonary impairments, reproductive and genitourinary dysfunctions, and endocrine abnormalities. GPCRs and associated genes are pivotal in immune regulation and cellular functions, and their dysregulation may contribute to the persistent immune responses, chronic inflammation, and tissue abnormalities observed in long COVID. Targeting GPCRs and their associated pathways could offer promising therapeutic strategies to manage symptoms and improve outcomes for those experiencing long COVID. However, the complex mechanisms underlying the condition require continued study to develop effective treatments. Our study has significant implications for understanding the molecular mechanisms underlying long COVID and for identifying potential therapeutic targets. In addition, we have developed a comprehensive website (https://longcovid.omicstutorials.com/) that provides a curated list of biomarker-identified genes and treatment recommendations for each specific disease, thereby facilitating informed clinical decision-making and improved patient management. Our study contributes to the understanding of this debilitating disease, paving the way for improved diagnostic precision, and individualized therapeutic interventions.

Literature-Based Discovery Predicts Antihistamines Are a Promising Repurposed Adjuvant Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a movement disorder caused by a dopamine deficit in the brain. Current therapies primarily focus on dopamine modulators or replacements, such as levodopa. Although dopamine replacement can help alleviate PD symptoms, therapies targeting the underlying neurodegenerative process are limited. The study objective was to use artificial intelligence to rank the most promising repurposed drug candidates for PD. Natural language processing (NLP) techniques were used to extract text relationships from 33+ million biomedical journal articles from PubMed and map relationships between genes, proteins, drugs, diseases, etc., into a knowledge graph. Cross-domain text mining, hub network analysis, and unsupervised learning rank aggregation were performed in SemNet 2.0 to predict the most relevant drug candidates to levodopa and PD using relevance-based HeteSim scores. The top predicted adjuvant PD therapies included ebastine, an antihistamine for perennial allergic rhinitis; levocetirizine, another antihistamine; vancomycin, a powerful antibiotic; captopril, an angiotensin-converting enzyme (ACE) inhibitor; and neramexane, an N-methyl-D-aspartate (NMDA) receptor agonist. Cross-domain text mining predicted that antihistamines exhibit the capacity to synergistically alleviate Parkinsonian symptoms when used with dopamine modulators like levodopa or levodopa-carbidopa. The relationship patterns among the identified adjuvant candidates suggest that the likely therapeutic mechanism(s) of action of antihistamines for combatting the multi-factorial PD pathology include counteracting oxidative stress, amending the balance of neurotransmitters, and decreasing the proliferation of inflammatory mediators. Finally, cross-domain text mining interestingly predicted a strong relationship between PD and liver disease.

Structure-based drug repositioning: Potential and limits.

Drug repositioning, the assignment of new therapeutic purposes to known drugs, is an established strategy with many repurposed drugs on the market and many more at experimental stage. We review three use cases, a herpes drug with benefits in cancer, a cancer drug with potential in autoimmune disease, and a selective and an unspecific drug binding the same target (GPCR). We explore these use cases from a structural point of view focusing on a deep understanding of the underlying drug-target interactions. We review tools and data needed for such a drug-centric structural repositioning approach. Finally, we show that the availability of data on targets is an important limiting factor to realize the full potential of structural drug-repositioning.

Statins as Repurposed Drugs in Gynecological Cancer: A Review.

Discovering new drugs is an expensive and time-consuming process, including target identification, bioavailability, pharmacokinetic (PK) tests, pharmacodynamic (PD) tests, toxicity profiles, recommended dosage test, and observation of the side effects, etc. Repurposed drugs could bypass some steps, starting from phase II trials, and shorten the processes. Statins, also known as HMG-CoA inhibitors (HMGCR), are commonly used to manage and prevent various cardiovascular diseases and have been shown to improve the morbidity and mortality of patients. In addition to the inhibitory effects on the production of cholesterol, the beneficial effects of statins on the prognosis and risk of various cancers are also shown. Statins not only inhibited cell proliferation, metastasis, and chemoresistance but affected the tumor microenvironment (TME). Thus, statins have great potential to be repurposed in oncology. Hence, we review the meta-analysis, cohort, and case-control studies of statins in gynecological cancers, and elucidate how statins regulate cell proliferation, apoptosis, tumor growth, and metastasis. Although the results in gynecological cancers remain controversial and the effects of different statins in different histotypes of gynecological cancers and TME are needed to elucidate further, statins are excellent candidates and worthy of being repurposed drugs in treating gynecological cancers.

Drug Repurposing in Cancer Therapy: Influence of Patient's Genetic Background in Breast Cancer Treatment.

Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients' characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients' genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.

Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells.

With increasing global health threats has come an urgent need to rapidly develop and deploy safe and effective therapies. A common practice to fast track clinical adoption of compounds for new indications is to repurpose already approved therapeutics; however, many compounds considered safe to a specific application or population may elicit undesirable side effects when the dosage, usage directives, and/or clinical context are changed. For example, progenitor and developing cells may have different susceptibilities than mature dormant cells, which may yet be different than mature active cells. Thus, in vitro test systems should reflect the cellular context of the native cell: developing, nascent, or functionally active. To that end, we have developed high-throughput, two- and three-dimensional human induced pluripotent stem cell (hiPSC)-derived neural screening platforms that reflect different neurodevelopmental stages. As a proof of concept, we implemented this in vitro human system to swiftly identify the potential neurotoxicity profiles of 29 therapeutic compounds that could be repurposed as anti-virals. Interestingly, many compounds displayed high toxicity on early-stage neural tissues but not on later stages. Compounds with the safest overall viability profiles were further evaluated for functional assessment in a high-throughput calcium flux assay. Of the 29 drugs tested, only four did not modulate or have other potentially toxic effects on the developing or mature neurospheroids across all the tested dosages. These results highlight the importance of employing human neural cultures at different stages of development to fully understand the neurotoxicity profile of potential therapeutics across normal ontogeny.

Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment.

Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID.

Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.

COVID-19 therapy: What weapons do we bring into battle?

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents.

Promising treatment strategies to combat Staphylococcus aureus biofilm infections: an updated review.

Staphylococcus aureus is a leading cause of nosocomial and community-acquired infections. The formation of biofilm by this pathogen renders it resilient to antimicrobial agents, which complicates the treatment of such infections. S. aureus can form biofilms with other pathogens and cause polymicrobial infections recalcitrant to antimicrobial agents. Therefore, anti-biofilm agents against which this bacterium cannot develop resistance are a highly desirable treatment strategy. Nanoparticles and some non-antimicrobial drugs proposed for various clinical purposes have proven to be excellent antibacterial and anti-biofilm agents to control S. aureus biofilm infections. A variety of chemically distinct compounds capable of acting as anti-biofilm agents against S. aureus have been extracted from microbial sources. This review explains the characteristics of S. aureus biofilms, emphasizing the therapeutic potential of nanoparticles, repurposed drugs, and anti-biofilm agents from microbial sources to combat S. aureus biofilm infections.

FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failure and death. BMPR2 (bone morphogenetic protein receptor type 2) mutations account for most familial PAH forms whereas reduced BMPR2 is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear. OBJECTIVES: We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH. METHODS: We combined siRNA high-throughput screening of >20,000 genes with a multicohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2 modifiers. After confirming gene dysregulation in tissue from patients with PAH, we determined the functional roles of BMPR2 modifiers in vitro and tested the repurposed drug enzastaurin for its propensity to improve experimental pulmonary hypertension (PH). MEASUREMENTS AND MAIN RESULTS: We discovered FHIT (fragile histidine triad) as a novel BMPR2 modifier. BMPR2 and FHIT expression were reduced in patients with PAH. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit-/- mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/hypoxia/normoxia rat model, by improving right ventricular systolic pressure, right ventricular hypertrophy, cardiac fibrosis, and vascular remodeling. CONCLUSIONS: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug enzastaurin as a potential novel therapeutic strategy to improve PAH.

Targeting the pH Paradigm at the Bedside: A Practical Approach.

The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the "cancer problem"? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article's goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

Three-dimensional models of Mycobacterium tuberculosis proteins Rv1555, Rv1554 and their docking analyses with sildenafil, tadalafil, vardenafil drugs, suggest interference with quinol binding likely to affect protein's function.

BACKGROUND: Earlier based on bioinformatics analyses, we had predicted the Mycobacterium tuberculosis (M.tb) proteins; Rv1555 and Rv1554, among the potential new tuberculosis drug targets. According to the 'TB-drugome' the Rv1555 protein is 'druggable' with sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) drugs. In the present work, we intended to understand via computer modeling studies, how the above drugs are likely to inhibit the M.tb protein's function. RESULTS: The three-dimensional computer models for M.tb proteins; Rv1555 and Rv1554 constructed on the template of equivalent membrane anchor subunits of the homologous E.coli quinol fumarate reductase respiratory protein complex, followed by drug docking analyses, suggested that the binding of above drugs interferes with quinol binding sites. Also, we experimentally observed the in-vitro growth inhibition of E.coli bacteria containing the homologous M.tb protein sequences with sildenafil and tadalafil drugs. CONCLUSIONS: The predicted binding sites of the drugs is likely to affect the above M.tb proteins function as quinol binding is known to be essential for electron transfer function during anaerobic respiration in the homologous E.coli protein complex. Therefore, sildenafil and related drugs currently used in the treatment of male erectile dysfunction targeting the human phosphodiesterase 5 enzyme may be evaluated for their plausible role as repurposed drugs to treat human tuberculosis.

Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation.

BACKGROUND: Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. METHODS: We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18-75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. RESULTS: One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. CONCLUSIONS: Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. TRIAL REGISTRATION: This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.