scholarly journals Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Sean Ekins ◽  
Mary A. Lingerfelt ◽  
Jason E. Comer ◽  
Alexander N. Freiberg ◽  
Jon C. Mirsalis ◽  
...  
Keyword(s):  
Half Life ◽  
Ebola Virus ◽  
Virus Disease ◽  
Dose Range ◽  
The United States ◽  
Time Curve ◽  
Lethal Challenge ◽  
Range Finding ◽  
Orally Bioavailable

ABSTRACTTilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine-learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potentin vitroEBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series ofin vitroADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2- and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ∼2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.

scholarly journals Repurposing Quinacrine against Ebola Virus Infection In Vivo

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Thomas R. Lane ◽  
Jason E. Comer ◽  
Alexander N. Freiberg ◽  
Peter B. Madrid ◽  
Sean Ekins
Keyword(s):  
Machine Learning ◽  
Virus Infection ◽  
Ebola Virus ◽  
Lethal Challenge ◽  
Once Daily ◽  
Machine Learning Model ◽  
Orally Bioavailable ◽  
Ebola Virus Infection

ABSTRACT Quinacrine hydrochloride is a small-molecule, orally bioavailable drug that has been used clinically as an antimalarial and for many other applications. A machine learning model trained on Ebola virus (EBOV) screening data identified quinacrine as a potent (nanomolar) in vitro inhibitor. In the current study, quinacrine 25 mg/kg was shown to protect 70% of mice (statistically significant) from a lethal challenge with mouse-adapted EBOV with once-daily intraperitoneal dosing for 8 days.

scholarly journals Equine-Origin Immunoglobulin Fragments Protect Nonhuman Primates from Ebola Virus Disease

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Hualei Wang ◽  
Gary Wong ◽  
Wenjun Zhu ◽  
Shihua He ◽  
Yongkun Zhao ◽  
...  
Keyword(s):  
Large Scale ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
West African ◽  
Clinical Testing ◽  
The Past ◽  
Over 40 Years

ABSTRACT Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans, with fatality rates reaching 90% and with no licensed specific therapeutics to treat ill patients. Advances over the past 5 years have firmly established monoclonal antibody (MAb)-based products as the most promising therapeutics for treating EBOV infections, but production is costly and quantities are limited; therefore, MAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal F(ab′)2 fragments from horses hyperimmunized with an EBOV vaccine. The F(ab′)2 was found to potently neutralize West African and Central African EBOV in vitro. Treatment of nonhuman primates (NHPs) with seven doses of 100 mg/kg F(ab′)2 beginning 3 or 5 days postinfection (dpi) resulted in a 100% survival rate. Notably, NHPs for which treatment was initiated at 5 dpi were already highly viremic, with observable signs of EBOV disease, which demonstrated that F(ab′)2 was still effective as a therapeutic agent even in symptomatic subjects. These results show that F(ab′)2 should be advanced for clinical testing in preparation for future EBOV outbreaks and epidemics. IMPORTANCE EBOV is one of the deadliest viruses to humans. It has been over 40 years since EBOV was first reported, but no cure is available. Research breakthroughs over the past 5 years have shown that MAbs constitute an effective therapy for EBOV infections. However, MAbs are expensive and difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since EBOV is endemic in several third world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antiserum F(ab′)2 fragments from horses vaccinated with an EBOV vaccine, and we tested the protectiveness in monkeys. We showed that F(ab′)2 was effective in 100% of monkeys even after the animals were visibly ill with EBOV disease. Thus, F(ab′)2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

scholarly journals Ebola virus disease: Case management in the Institute of Infectious Diseases, University Hospital of Sassari, Sardinia, Italy

2016 ◽  
Vol 10 (05) ◽  
pp. 537-543 ◽  
Author(s):  
Giulia Bertoli ◽  
Marco Mannazzu ◽  
Giordano Madeddu ◽  
Riccardo Are ◽  
Alberto Muredda ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Ebola Virus ◽  
Virus Disease ◽  
Developed Countries ◽  
The United States ◽  
Ebola Virus Disease ◽  
University Hospital ◽  
Governmental Organization ◽  
Medical Division ◽  
Disease Case

Since the onset of the worst epidemic of Ebola virus disease in December 2013, 28,637 cases were reported as confirmed, probable, or suspected. Since the week of 3 January 2016, no more cases have been reported. The total number of deaths have amounted to 11,315 (39.5%). In developed countries, seven cases have been diagnosed: four in the United States, one in Spain, one in the United Kingdom, and one in Italy. On 20 July 2015, Italy was declared Ebola-free. On 9 May 2015, an Italian health worker came back to Italy after a long stay in Sierra Leone working for a non-governmental organization. Forty-eight hours after his arrival, he noticed headache, weakness, muscle pains, and slight fever. The following day, he was safely transported to the Infectious Diseases Unit of University Hospital of Sassari. The patient was hospitalized for 19 hours until an Italian Air Force medical division transferred him to Rome, to the Lazzaro Spallanzani Institute. Nineteen people who had contacts with the patient were monitored daily for 21 days by the Public Health Office of Sassari and none presented any symptoms. So far, neither vaccine nor treatment is available to be proposed on an international scale. Ebola is considered a re-emerging infectious disease which, unlike in the past, has been a worldwide emergency. This case study aimed to establish a discussion about the operative and logistic difficulties to be faced and about the discrepancy arising when protocols clash with the reality of facts.

Serosurvey on healthcare personnel caring for patients with Ebola virus disease and Lassa virus in the United States

2020 ◽  
Vol 41 (4) ◽  
pp. 385-390
Author(s):  
Colleen S. Kraft ◽  
Aneesh K. Mehta ◽  
Jay B. Varkey ◽  
G. Marshall Lyon ◽  
Sharon Vanairsdale ◽  
...  
Keyword(s):  
Infection Control ◽  
Ebola Virus ◽  
Virus Disease ◽  
Adenovirus Type ◽  
The United States ◽  
Ebola Virus Disease ◽  
University Hospital ◽  
Healthcare Personnel ◽  
Lassa Virus ◽  
Serum Samples

AbstractObjective:Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion.Setting:From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP.Participants:All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible.Results:No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens.Conclusions:Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.

scholarly journals Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

2008 ◽  
Vol 53 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Fenglei Huang ◽  
Kristin Drda ◽  
Thomas R. MacGregor ◽  
Joseph Scherer ◽  
Lois Rowland ◽  
...  
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Dose Range ◽  
Dose Interval ◽  
Phase Ii Trials ◽  
Time Curve ◽  
Minimum Concentration ◽  
Oral Dosing ◽  
Repeated Dosing

ABSTRACT The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

scholarly journals Ebola Virus: a Clear and Present Danger

2014 ◽  
Vol 53 (1) ◽  
pp. 4-8 ◽  
Author(s):  
Eileen M. Burd
Keyword(s):  
United States ◽  
Ebola Virus ◽  
Virus Disease ◽  
The United States ◽  
Ebola Virus Disease ◽  
Burial Practices ◽  
Western Africa ◽  
Medical Facilities ◽  
Risk Patients ◽  
Clear And Present Danger

An epidemic of Ebola virus disease is occurring in Western Africa on a scale not seen before, particularly in the countries of Guinea, Liberia, and Sierra Leone. The continued spread is facilitated by insufficient medical facilities, poor sanitation, travel, and unsafe burial practices. Several patients diagnosed with Ebola virus disease in Africa have been evacuated to the United States for treatment, and several other patients have been diagnosed in the United States. It is important for laboratories to be aware of available tests, especially those granted emergency use authorization, as hospitals prepare protocols for the diagnosis and management of high-risk patients.

scholarly journals Infectious Disease Physician Assessment of Hospital Preparedness for Ebola Virus Disease

2015 ◽  
Vol 2 (3) ◽  
Author(s):  
Philip M. Polgreen ◽  
Scott Santibanez ◽  
Lisa M. Koonin ◽  
Mark E. Rupp ◽  
Susan E. Beekmann ◽  
...  
Keyword(s):  
Infectious Disease ◽  
United States ◽  
Ebola Virus ◽  
Virus Disease ◽  
The United States ◽  
Ebola Virus Disease ◽  
Teaching Hospitals ◽  
Emerging Infections ◽  
First Case ◽  
Hospital Preparedness

Abstract Background.  The first case of Ebola diagnosed in the United States and subsequent cases among 2 healthcare workers caring for that patient highlighted the importance of hospital preparedness in caring for Ebola patients. Methods.  From October 21, 2014 to November 11, 2014, infectious disease physicians who are part of the Emerging Infections Network (EIN) were surveyed about current Ebola preparedness at their institutions. Results.  Of 1566 EIN physician members, 869 (55.5%) responded to this survey. Almost all institutions represented in this survey showed a substantial degree of preparation for the management of patients with suspected and confirmed Ebola virus disease. Despite concerns regarding shortages of personal protective equipment, approximately two thirds of all respondents reported that their facilities had sufficient and ready availability of hoods, full body coveralls, and fluid-resistant or impermeable aprons. The majority of respondents indicated preference for transfer of Ebola patients to specialized treatment centers rather than caring for them locally. In general, we found that larger hospitals and teaching hospitals reported higher levels of preparedness. Conclusions.  Prior to the Centers for Disease Control and Prevention's plan for a tiered approach that identified specific roles for frontline, assessment, and designated treatment facilities, our query of infectious disease physicians suggested that healthcare facilities across the United States were making preparations for screening, diagnosis, and treatment of Ebola patients. Nevertheless, respondents from some hospitals indicated that they were relatively unprepared.

scholarly journals IN VITRO DIAGNOSIS FOR EBOLA VIRUS DISEASE. A COMPARISON OF CURRENT TECHNIQUES AND DIAGNOSTIC ASSAYS

2019 ◽  
Vol 1 (3) ◽  
pp. 105-116
Author(s):  
A. O. Sementsova ◽  
V. G. Dedkov ◽  
V. A. Ternovoy ◽  
E. V. Chub ◽  
S. A. Pyankov ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Clinical Symptoms ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
Multiple Organ ◽  
Ebola Virus Disease ◽  
Diagnostic Assays ◽  
Natural Foci ◽  
Forested Areas

Ebola virus disease is dangerous viral infection, occurring in the form of hemorrhagic fever, characterized by acute clinical symptoms and high mortality rate due to multiple organ failure. Ebola virus natural foci are located in forested areas of the central and western parts of Africa. It was believed for many years, the incidence of Ebola virus disease has been sporadic and the burden of it is true only in endemic areas. However, the unprecedented Ebola epidemic caused by Zaire virus in 2013 — 2016, has significantly changed our understanding of this disease and the patterns of its distribution. We have also identified weaknesses in the organization of anti-epidemic measures, the effectiveness of which was not very effective at the onset of the epidemic, in particular due to weak development of in vitro diagnostics (IVD). However, during the elimination of the epidemic in West Africa, anti-epidemic system has been modified substantially, largely due to quickly developed IVD kits. This review is devoted to analysis of trends in IVD for Ebola virus disease based on the experience obtained in the course of the West-African epidemic in 2013 — 2016.

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