I know no one knows the definitive answers for what I'm about to ask, but I'm hoping those with a science background can give me some reassurance about putting my Dad on the Dimebon trial. This issue with the drug raising the amyloid levels vs. decreasing it is nagging at me. What if I'm making my Dad worse by making him take Dimebon? Is this recent unexpected finding unsettling to anyone else? Anyone out there that can offer some reassurance that this unexpected finding is not necessarily a bad thing? Anyone else out there second guessing putting their LO on the trial?

PatiR

Pati---I don't have any medical background... so...I won't begin to attempt to reassure you. What I will do is suggest that you read page 8 of the Dimebon thread (specifically JAB's Oct 5, 9:17 AM post). Hopefully, she will find the time to share her current thoughts.

Forget to say...I'm not worried about something that scientists apparently cannot figure out the implications of (amyloid levels in laboratory mice). Charlie is still participating in the trial.

Skiricheri,

Don't you have a LO on the Dimebon? What are your observations?

PatiR

Pati, hi.

(a) Mice are a notoriously poor model for studying AD. Not one of the AD treatments originally developed with mice has proven out in clinical trials.

(b) We still do not know the role that Abeta plays in AD -- if any -- and if Abeta is "toxic", whether it is the soluble form or the aggregated form that is "toxic". Note that all drugs designed to clear or prevent amyloid accumulation have so far failed to show efficacy in large-scale clinical trials.

(c) The mouse study showed that the interstitial (i.e., in the fluids in between cells) levels of soluble Abeta went up in "freely moving mice". This could be interpreted to mean that dimebon may be effective by dissolving plaques, so that the Abeta can be removed from the body.

(d) This was an "acute" study, i.e., analyses were done within the first few hours after a single dose. The picture might be quite different if chronic use were to be studied.

(e) Dimebon had no effect on interstitial Abeta levels in studies done with mouse brain cell cultures.

(f) And in just now poking around on this subject, I found a paper which reported that acute stress increases interstitial fluid Abeta levels in "freely moving mice". So maybe the Abeta went up in the mice because of the stress of the test, not because of the med.

http://ukpmc.ac.uk/articlerender.cgi?artid=1165319

Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and nuronal activity. Proc Nat Acad Sci USA 2007; 104:10673-10678.


I'd believe what is seen in people long before I'd believe a single, simple study on mice. Russians used dimebon as an antihistamine for a long time, and showed no ill effects from it. Pfizer must be seeing good initial results in the many ongoing clinical trials now, since they keep pouring more and more money into dimebon. They've just announced two large Phase III trials for treating moderate-to-severe AD.

JAB, thanks so much for your thorough response. You guys are far beyond me in your research of all of these meds & I knew someone had some information that would be of comfort to me. I agree that Pfizer must feel optimistic about this drug. Surely they would've pulled the plug if they thought it was doing something bad.

My Dad has only been on the real thing (for sure) 15 days, so I know I need to be patient.

PatiR

We met with the neurologist (who is also a professor of Neurology at Northwestern University's Feinberg School of Medicine) Monday, and I told him I was trying to get access to Dimebon for Steve. He said that Dimebon was the only drug presented at this year's Alzheimer's conference that he thought was at all promising.

Although he said he could not help us acquire the drug, he would be willing to oversee its administration to Steve and to write a letter to that effect if it would help us get access.

I also reviewed the improvements to Steve's visual symptoms since beginning the CO/MCT oil therapy. Throughout that discussion, he took copious notes, asking clarifying questions and asking me several times to slow down or repeat something so he could get it down.

Steve tested twice this week at 18 on the MMSE with different doctors, the same score he got two months ago when he was diagnosed. I was disappointed, but the neurologist was impressed that Steve "has stabilized".

What I find most interesting is that Steve tested 18 at a time of extreme stress. Our 5-year-old dog, who had been his constant companion since he had to quit teaching three years ago, had to be put down last Friday due to kidney failure. Steve has been very upset and had literally not been to bed the entire night before the second MMSE. (In fact, he was in the middle of what turned out to be a 42-hour period when he never went to bed and spent much of the time pacing. I had to take him to the Emergency Room night before last at midnight, where they finally got him knocked out around 3:00 a.m. with a large dose of Ativan.)

Hmp10:

Thanks for the update from your Neurologist.

What are the visual problems Steve is experiencing in connection with his AD? I think my Dad might have something gonig on visually too,

PatiR

Steve has posterior cortical atrophy, which is the visual variant of Alzheimer's and differs from the conventional disease in affecting visuo-spatial perception more than general cognition in the early stages of the disease. However, it eventually progresses to full-blown Alzheimer's, which is beginning to happen with Steve.

Steve had developed problems with reading text, spelling, seeing icons on computer screens, finding buttons on remotes, judging distances when driving, seeing clearly when shaving, etc. long before he began to experience memory deficits and difficulty finding words.

While the memory deficits, verbalization, and general cognition seem to be both improving in some respects and worsening in others, his visual problems are noticeably improved, as are his motor skills. (He is scraping his feet less when he walks, following my lead in making up a bed more easily, fastening seatbelts again with no problem, and spilling and dropping things less. More significantly, he has recovered the ability he lost many months ago to use his computer on his own, including finding icons, reading text, finding and using drop-down menus, sending print commands.)