scholarly journals Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

2021 ◽  
Author(s):  
Courtney L. Finch ◽  
Julie Dyall ◽  
Shuang Xu ◽  
Elizabeth A. Nelson ◽  
Elena Postnikova ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Delivery ◽  
Ebola Virus ◽  
Cost Effective ◽  
High Morbidity ◽  
Strong Activity ◽  
Approved Drugs ◽  
Formulation Stability ◽  
Synergistic Combinations

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

scholarly journals Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo

2021 ◽  
Vol 9 (3) ◽  
pp. 566
Author(s):  
Courtney L. Finch ◽  
Julie Dyall ◽  
Shuang Xu ◽  
Elizabeth A. Nelson ◽  
Elena Postnikova ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Delivery ◽  
Ebola Virus ◽  
Cost Effective ◽  
High Morbidity ◽  
Strong Activity ◽  
Approved Drugs ◽  
Formulation Stability ◽  
Synergistic Combinations

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

scholarly journals Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine

2021 ◽  
Author(s):  
Yuan Liu ◽  
Ziwen Tong ◽  
Jingru Shi ◽  
Tian Deng ◽  
Ruichao Li ◽  
...  
Keyword(s):  
Cost Effective ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Inflammatory Drug ◽  
Development Of Resistance ◽  
Drug Resistant Bacteria ◽  
Metabolic States ◽  
Anti Inflammatory ◽  
Approved Drugs

Antimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimen. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing previously approved drugs as potent antibiotic adjuvants offers a cost effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non-steroidal anti-inflammatory drug in clinic, remarkably potentiated broad spectrum antibiotic tetracyclines activity against a panel of clinical important resistant pathogens, including MRSA, VRE, MCRPEC and tet (X)-positive Gram negative bacteria. Further mechanistically experiments showed that benzydamine dissipated membrane potential (ΔΨ) in both Gram positive and negative bacteria, which in turn upregulated the transmembrane proton gradient (ΔpH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline benzydamine combination against different metabolic states of bacteria including persister cells. As a proof of concept, the in vivo efficacy of this combination therapy was evidenced in multiple animal infection models. These findings revealed that benzydamine is a promising tetracycline antibiotics adjuvant and has the potential to address life threatening infections by MDR bacteria.

A screen of approved drugs and molecular probes identifies therapeutics with anti–Ebola virus activity

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra89-290ra89 ◽  
Author(s):  
Lisa M. Johansen ◽  
Lisa Evans DeWald ◽  
Charles J. Shoemaker ◽  
Benjamin G. Hoffstrom ◽  
Calli M. Lear-Rooney ◽  
...  
Keyword(s):  
Viral Entry ◽  
Ebola Virus ◽  
Molecular Probes ◽  
Infection Model ◽  
Channel Blockers ◽  
Emerging Infections ◽  
Virus Infections ◽  
Approved Drugs

Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration–approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

scholarly journals Déjà vu: Stimulating Open Drug Discovery for SARS-CoV-2

2020 ◽  
Author(s):  
Sean Ekins ◽  
Melina Mottin ◽  
Paulo R. P. S. Ramos ◽  
Bruna K. P. Sousa ◽  
Bruno Junior Neves ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Ebola Virus ◽  
Antiviral Drug ◽  
Open Science ◽  
Virus Rna ◽  
Deja Vu ◽  
Déjà Vu ◽  
Approved Drugs

In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the current outbreak of coronavirus disease which has been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). There is a strong sense of Déjà vu as the world is caught flat footed without effective treatments to administer to patients. Our team has been actively involved in several small molecule drug discovery efforts for the preceding virus outbreaks. In 2014 we used machine learning to identify 3 new molecules to test for the Ebola virus and these were subsequently shown to be active in vitro and in vivo. We have also been involved in open science approaches that leverage the community to help. In 2016 we launched the OpenZika project as an IBM World Community Grid Project that used distributed computing power of volunteers to dock large numbers of compounds into Zika and related flavivirus targets. This led us into several collaborations in which we validated computational predictions in vitro. With both of these initiatives there was some knowledge of the virus, many compounds had already been tested in the case of Ebola, whereas for Zika initially all we had was the virus RNA sequence. In the current SARS-CoV-2 outbreak, this was a completely new virus and the scientists in China and elsewhere have started from scratch. In the space of a few weeks since the outbreak is acknowledged to have started, there are now compounds suggested as active in vitro and molecules repurposed in clinical trials. While this has been impressive, we propose there may still be gaps in our approach to drug discovery for such outbreaks. There is an opportunity to repurpose additional approved drugs for this virus and we now suggest how these might be identified leveraging prior work on MERS-CoV, SARS-CoV and other viruses. We also describe some of the immense challenges and limitations of the open antiviral drug discovery approaches we have been involved in.

scholarly journals Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1

2012 ◽  
Vol 56 (4) ◽  
pp. 1942-1948 ◽  
Author(s):  
Christine L. Clouser ◽  
Colleen M. Holtz ◽  
Mary Mullett ◽  
Daune L. Crankshaw ◽  
Jacquie E. Briggs ◽  
...  
Keyword(s):  
Cell Culture ◽  
Mouse Model ◽  
Drug Combination ◽  
Leukemia Virus ◽  
Treatment Options ◽  
Murine Aids ◽  
Approved Drugs ◽  
Number Of Treatment ◽  
Hiv 1

ABSTRACTThe emergence of drug resistance threatens to limit the use of current anti-HIV-1 drugs and highlights the need to expand the number of treatment options available for HIV-1-infected individuals. Our previous studies demonstrated that two clinically approved drugs, decitabine and gemcitabine, potently inhibited HIV-1 replication in cell culture through a mechanism that is distinct from the mechanisms for the drugs currently used to treat HIV-1 infection. We further demonstrated that gemcitabine inhibited replication of a related retrovirus, murine leukemia virus (MuLV),in vivousing the MuLV-based LP-BM5/murine AIDS (MAIDS) mouse model at doses that were not toxic. Since decitabine and gemcitabine inhibited MuLV and HIV-1 replication with similar potency in cell culture, the current study examined the efficacy and toxicity of the drug combination using the MAIDS model. The data demonstrate that the drug combination inhibited disease progression, as detected by histopathology, viral loads, and spleen weights, at doses lower than those that would be required if the drugs were used individually. The combination of decitabine and gemcitabine exerted antiviral activity at doses that were not toxic. These findings indicate that the combination of decitabine and gemcitabine shows potent antiretroviral activity at nontoxic doses and should be further investigated for clinical relevance.

scholarly journals Oral Insulin Delivery Using Poly (Styrene Co-Maleic Acid) Micelles in a Diabetic Mouse Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1026
Author(s):  
Fatemah Bahman ◽  
Sebastien Taurin ◽  
Diab Altayeb ◽  
Safa Taha ◽  
Moiz Bakhiet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Maleic Acid ◽  
Oral Delivery ◽  
Animal Studies ◽  
Ex Vivo ◽  
Insulin Delivery ◽  
Diabetic Mouse ◽  
Oral Insulin

The oral delivery of insulin is a convenient and safe physiological route of administration for management of diabetes mellitus. In this study, we developed a poly-(styrene-co-maleic acid) (SMA) micellar system for oral insulin delivery to overcome the rapid degradation of insulin in the stomach, improve its absorption in the intestine, and provide a physiologically-relevant method of insulin to reach portal circulation. The insulin was encapsulated into SMA micelles in a pH-dependent process. The charge and size of the nanoparticles were determined by dynamic light scattering. The insulin loading of the nanoparticles was measured by HPLC. The transport of the SMA-insulin through biological membranes was assessed in vitro using Caco-2 cells, ex vivo rat intestinal section, and in vivo in a streptozotocin-induced diabetes mouse model. SMA-insulin micelles were negatively charged and had a mean diameter of 179.7 nm. SMA-insulin efficiently stimulated glucose uptake in HepG-2 hepatic cells and was transported across the Caco-2 epithelial cells in vitro by 46% and ex vivo across intestinal epithelium by 22%. The animal studies demonstrated that orally-administered SMA-insulin can produce a hypoglycemic effect up to 3 h after administration of one dose. Overall, our results indicate that SMA micelles are capable of the oral delivery of bioactive compounds like insulin and can be effective tools in the management of diabetes.

scholarly journals Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis

2000 ◽  
Vol 44 (9) ◽  
pp. 2356-2360 ◽  
Author(s):  
Rosaria Santangelo ◽  
Padmaja Paderu ◽  
Guillaume Delmas ◽  
Zi-Wei Chen ◽  
Raphael Mannino ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amphotericin B ◽  
Delivery System ◽  
Oral Delivery ◽  
Experimental Period ◽  
Oral Formulation ◽  
Systemic Candidiasis ◽  
Log Reduction ◽  
Cell Counts

ABSTRACT Amphotericin B (AMB) remains the principal therapeutic choice for deep mycoses. However, its application is limited by toxicity and a route of administration requiring slow intravenous injection. An oral formulation of this drug is desirable to treat acute infections and provide prophylactic therapy for high-risk patients. Cochleates are a novel lipid-based delivery system that have the potential for oral administration of hydrophobic drugs. They are stable phospholipid-cation crystalline structures consisting of a spiral lipid bilayer sheet with no internal aqueous space. Cochleates containing AMB (CAMB) inhibit the growth of Candida albicans, and the in vivo therapeutic efficacy of CAMB administered orally was evaluated in a mouse model of systemic candidiasis. The results indicate that 100% of the mice treated at all CAMB doses, including a low dosage of 0.5 mg/kg of body weight/day, survived the experimental period (16 days). In contrast, 100% mortality was observed with untreated mice by day 12. The fungal tissue burden in kidneys and lungs was assessed in parallel, and a dose-dependent reduction in C. albicansfrom the kidneys was observed, with a maximum 3.5-log reduction in total cell counts at 2.5 mg/kg/day. However, complete clearance of the organism from the lungs, resulting in more than a 4-log reduction, was observed at the same dose. These results were comparable to a deoxycholate AMB formulation administered intraperitoneally at 2 mg/kg/day (P < 0.05). Overall, these data demonstrate that cochleates are an effective oral delivery system for AMB in a model of systemic candidiasis.

scholarly journals Repurposing Licensed Drugs for Use Against Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Leslie C. Norins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Life Expectancy ◽  
Cost Effective ◽  
Epidemiological Data ◽  
Health Concern ◽  
Effective Manner ◽  
In Vivo Testing ◽  
Approved Drugs

Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics.

scholarly journals Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xufeng Cen ◽  
Yanying Chen ◽  
Xiaoyan Xu ◽  
Ronghai Wu ◽  
Fusheng He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Therapeutic Intervention ◽  
Drug Candidates ◽  
Model Of Alzheimer’S Disease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Shed Light

AbstractThere is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer’s disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer’s disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer’s disease.

scholarly journals Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma

Foods ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1195
Author(s):  
Jingjing Zhang ◽  
Xiaoxuan Ma ◽  
Daidi Fan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Oral Delivery ◽  
Metastatic Potential ◽  
High Morbidity ◽  
Hypoxic Conditions ◽  
Mesenchymal Transformation ◽  
Related Proteins ◽  
Feedback Pathway

Hepatocellular carcinoma (HCC) is a kind of malignant tumor with high morbidity and mortality rates worldwide. Epithelial–mesenchymal transformation (EMT) is crucial for HCC progression and prognosis. Characteristics of the tumor microenvironment, such as hypoxia, and excessive activation of the NF-κB signaling pathway have been identified as the key inducers of EMT in HCC. In our study, we verified the crosstalk between HIF-1α signaling and NF-κB pathway and their effects on EMT in HCC cells. The results show that CoCl2-induced hypoxia could promote IκB phosphorylation to activate NF-κB signaling and vice versa. Moreover, we found that ginsenoside CK, a metabolite of protopanaxadiol saponins, could inhibit the proliferation and colony formation of different HCC cell lines. Furthermore, ginsenoside CK could impair the metastatic potential of HCC cell lines under hypoxic conditions. Mechanistically, ginsenoside CK suppressed HIF-1α/NF-κB signaling and expression level of EMT-related proteins and cytokines in hypoxia-induced or TNFα-stimulated HCC cell lines. An in vivo study revealed that the oral delivery of ginsenoside CK could inhibit the growth of xenograft tumors and block HIF-1α and NF-κB signaling as well as EMT marker expression. Our study suggests that ginsenoside CK is a potential therapy for HCC patients that functions by targeting the HIF-1α/NF-κB crosstalk.

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