Thursday, November 6, 2014

What About Testing Already-Licensed Drugs Against Ebola? Here are some that may be promising

I will elaborate on this important subject as I learn more.  And what more has been learned about the benefits of lamivudine, an antiviral used by a Liberian doctor with reported high survival in a small number of patients?  UPDATE Nov 14:  A WHO committee says it does not work.  MSF will test 2 antiviral drugs (brincidofovir and favipiravir) and convalescent serum in its treatment centers soon.

But for now, here are 4 papers that suggest licensed drug candidates (in red) that may have efficacy against Ebola.  And why not give chloroquine (an anti-malarial with anti-viral effects in mice) to patients, at least before one knows the cause of the fever?:

1.   2014 Aug;69(8):2123-31. doi: 10.1093/jac/dku091. Epub 2014 Apr 7.The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. Gehring G1Rohrmann K2Atenchong N1Mittler E3Becker S3Dahlmann F4Pöhlmann S4Vondran FW5David S6Manns MP7Ciesek S7von Hahn T8. OBJECTIVES:

Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors, we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. METHODS:
We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds.RESULTS:
We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant.CONCLUSIONS:
The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.

2.  ScienceVol. 345 no. 6198 pp. 718-719 DOI: 10.1126/science.345.6198.718  Martin Enserink
Debate erupts on ‘repurposed’ drugs for EbolaWith the outbreak of Ebola in West Africa escalating, some scientists think they can save lives by using existing, approved drugs that weren't developed for Ebola but that might nonetheless help patients. Among the proposals being floated are interferon α and statins. The advantage of such existing drugs is that they have been tested for safety, and they are cheap and widely available. 
3.  S 2013 Jun 19;5(190):190ra79. doi: 10.1126/scitranslmed.3005471.
FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection.Johansen LM1Brannan JMDelos SEShoemaker CJStossel ALear CHoffstrom BGDewald LESchornberg KL,Scully CLehár JHensley LEWhite JMOlinger GG.
Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)- and ex-US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.PMID:
Free PMC Article

4.   2013;8(4):e60579. doi: 10.1371/journal.pone.0060579. Epub 2013 Apr 5.A systematic screen of FDA-approved drugs for inhibitors of biological threat agents.Madrid PB1Chopra SManger IDGilfillan LKeepers TRShurtleff ACGreen CEIyer LVDilks HHDavey RA,Kolokoltsov AACarrion R JrPatterson JLBavari SPanchal RGWarren TKWells JBMoos WHBurke RLTanga MJ.Author information
  • 1Center for Infectious Disease and Biodefense Research, SRI International, Menlo Park, California, USA. rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. METHODOLOGY/PRINCIPAL FINDINGS:A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. CONCLUSIONS/SIGNIFICANCE:The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.PMC3618516 Free PMC Article PMID:23577127
UPDATE Nov 7 from the Guardian:  FDA demands randomised, placebo-controlled clinical trials, while WHO and experts elsewhere do not think that will work in Africa, where trust in the healthcare system is, at best, tenuous. IMHO, FDA is required to license drugs that meet a high bar, to avoid legal and regulatory problems. But FDA is not responsible for licensing drugs for use outside the US. What is appropriate in the African setting, when 70% of patients are dying despite medical care, is an entirely different matter than what is appropriate in the US. Trials with many arms are used for cancer, and are entirely appropriate for Africa.

And there is another kind of drug assessment, in which you look carefully at each treated patient, and how they respond from hour to hour. This is a very different design than just looking at survival vs death, and can yield much more specific information about drugs.


Anonymous said...

Listen to the Alex Jones show.
I managed to get through and get Steven Hatfill to admit he was in North Carolina during November 2001. This is the month I caught him walking down my street.


Anonymous said...

Link to Alex Jones hour 2 Nov 6th 2014