Review of drugs used in humans with prion disease
After reviewing tens of candidate antiprion drugs and treatment approaches on this blog, I thought I had at least exhausted all of the compounds that had been tested in humans. It turns out I was wrong: Stewart 2008 provides an astonishingly thorough review of every drug that had been attempted for therapeutic use in humans with prion disease up to that time. I can’t even believe how much work this paper must have been – adding up the numbers mentioned in the paper, it appears that the authors read almost 5,000 abstracts and 400 full text papers in order to cull the 53 studies that they ultimately cite.
Their thoroughness paid off: they identified 14 drugs that have been attempted for therapeutic use in humans with prion disease. Since I’d only been aware of 5 of these, this inspired me to go search for the others in PubMed and do some reading.
I compiled this table of the drugs that have been tried and the citations I found for them. This isn’t a perfect duplicate, subset nor superset of Stewart’s list – I didn’t bother to track down things that aren’t in PubMed, and I did include other stuff that has come out since 2008. If you want a more exhaustive list of citations (at least up to 2008), please see Stewart’s bibliography. Most of these are just case reports or one or two individuals; I’ve bolded the more comprehensive studies.
Not surprisingly, the three antiviral drugs and interferon (which also has antiviral properties) were all used long ago when many people still thought CJD was a virus. Some of the more recent applications of other drugs surprised me, especially since (to my knowledge) some of these (clomipramine, venlafaxine, topiramate, phenytoin, levetiracetam) were never tested in prion-infected mice.
Indeed, the biggest surprise is flupirtine [Otto 2004], for which a randomized trial of 28 patients was undertaken based purely on results from cell culture experiments. In fact, there hadn’t even been cell culture experiments with actual prions. Otto cites two experiments in cell culture models of other diseases (Batten and Alzheimer’s) suggesting that flupirtine inhibited apoptosis [Dahr 2002, Muller 1997] and one experiment with the synthetic peptide PrP 106-126 [Perovic 1997]. That’s it. As far as I can tell, no animal work on flupirtine for prion diseases either preceded or followed Otto’s work.
Otto reports that flupirtine did not extend survival but did significantly improve mental function according to a battery of cognitive tests.
Though a handful of case reports claimed positive results, Stewart concludes that Otto’s work represents the only positive result ever reported in any sort of systematic study. Even if Otto’s result is real, a mild improvement in cognitive function without any extension of survival does not seem all that promising. The results of systematic trials on quinacrine and pentosan polysulfate have come out since Stewart’s review and aren’t more positive either.
So I didn’t learn anything promising or exciting from this exercise, but it’s always good to know what’s out there and what’s been tried. Thanks to Stewart for an exquisitely thorough review.
About Eric Vallabh Minikel
Eric Vallabh Minikel is on a lifelong quest to prevent prion disease. He is a scientist based at the Broad Institute of MIT and Harvard.