Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.
To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.
But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).
That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).
Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).
And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?
According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.
Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.
And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.
Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.
1. Fred Cohen on July 31, 2008 8:49 AM writes...
Out of curiousity, I took a look at the granted US patent covering the method and compositions for treating Alzheimer's via tau aggregation disruption (the 695 patent).
What I found interesting is that Methylene Blue wasn't the best tau aggregation disruptor in vitro. The patent doesn't make it clear why Methylene Blue was preferred as a lead by TauRx, but it does imply that there was at least as strong a rationale for selecting carbemazepine, pyridoxine (B6), or cobalamine (B12), among other comnpounds tested.
As you might know, there has been a single RCT looking at supplementation that included 5 mg daily of pyridoxine and 500 mg of oral B12 (mecobalamin) plus 1 mg folate in mild/mod AD (Sun et al 2007, PMID: 18042476). The vitamins were studied under a different hypothesis of action: the homocysteine hypothesis. There was no benefit of the vitamins on top of ACHase inhibition. Observational data have been mixed, but there's little evidence of a correlation between AD progression and intake or serum levels of pyridoxine or B12 (see for example Luchsinger 2007, PMID: 17210813).
I couldn't find any studies with carbemazepine specifically looking at cognition in AD.
Although the results of the TauRx Phase 2 study appear promising at face value, I'd want to understand why MB was chosen over these other tau aggregation disruptors (just commercial considerations?) and why other compunds with the same tau MOA, namely pyridoxine and B12, appear to offer little or no benefit clinically before loosening the reins on my enthusiasm.
Permalink to Comment2. from_sgc on July 31, 2008 9:27 AM writes...
But apparently methylene blue also inhibits the aggregation of amyloid with the same IC50 ~2uM:
http://www.ncbi.nlm.nih.gov/pubmed/15611092?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
There might be no contradiction with amyloid hypothesis.
Permalink to Comment3. pcr on July 31, 2008 9:39 AM writes...
Assuming they generate sufficient efficacy and safety data to warrant approval, would FDA accept Rember as the brand name? Isn't it too similar to "Remember"?
Permalink to Comment4. satan on July 31, 2008 9:55 AM writes...
One of the problems with companies based outside N. America is that those environments have no accountability (legal or otherwise).
For all the problems with pharma companies here, reality ultimately triumphs. Asian cultures are often driven by names, personalities and "legends" as opposed to reality. Even japan is still stuck in modes of thinking that would not have been acceptable here in the 1950s.
Permalink to Comment5. seth on July 31, 2008 10:22 AM writes...
Best description I've seen is here..
http://www.alz.org/icad/_release_icad_072908_130pm_trials.asp
Permalink to Comment6. john.spevacek@aspenresearch.com on July 31, 2008 10:53 AM writes...
Just the fact that you can buy methylene blue off the shelf will make it difficult to maximize profits, even with US and EPO patents. I can easily imagine clinics in third world countries running the treatment themselves, even with the modifications that you suggest are needed.
Permalink to Comment7. from_sgc on July 31, 2008 11:08 AM writes...
The trial is claimed to be double-blinded.
Permalink to CommentBUT the obvious sign of methylene blue in the body is a blue urine. It should immediately become obvious to doctor/patient who is on placebo and who is treated. Unless of course there is a blue-urine placebo pill.
8. processchemist on July 31, 2008 11:13 AM writes...
#6
But if they patent a formulation for parenteral use and this one has the best effect, things should be different, I suppose
Permalink to Comment9. Still Scared of Dinosaurs on July 31, 2008 12:10 PM writes...
#7 is a good point. It's hard to imagine a way to measure cognition that wouldn't be susceptible to bias.
Maybe they need to test the drug in patients with porphyria.
Permalink to Comment10. natas on July 31, 2008 5:16 PM writes...
#4 that's an... interesting view. Perhaps you could back it up with something more than anecdote and spittle?
Permalink to Comment11. anon on July 31, 2008 5:42 PM writes...
#7, #9 - Nahh, one of the conditions of the trial was that you can only go to the bathroom blindfolded...with a nurse to make sure there's no peeking!
Permalink to Comment12. CMC guy on July 31, 2008 6:11 PM writes...
I thought there were some drugs that caused "blue urine" and heard story of one drug development was halted becasue of this side effect. Google search hit two and suggested some foods. (I assume there is no Methylene Blue in the formulations).
Triamterene – a mild diuretic and can cause a blue urine color.
Rinsapin ...antibiotic sometimes used to treat a staph infection and can cause you to see a blue or green urine color
http://www.urinecolors.com/blue_urine_color.php
Don't know how could use as Placebo but in addition to #11 anon suggestion could always make them wiz in the dark...
Permalink to Comment13. Jose on July 31, 2008 6:25 PM writes...
A web site for "urinecolors.com?" I think I see the horsemen of the Apocalypse headed this way....
Permalink to Comment14. Retread on July 31, 2008 9:15 PM writes...
"It’s hard to show decent efficacy in an Alzheimer’s trial" -- not so at all -- if the drug reversed the disability, we'd know in a flash. This just shows how low our expectations of this class of drugs has become.
In 9/70 two great things happened: I finished my two years as a doc in the Air Force, and L-DOPA was released in the USA (having been used in Europe for years). The chief assigned me to run the L-DOPA clinic (set up because we had zero experience with the drug) in our residency program and I watched people get out of wheelchairs. Interestingly, just like the anti-depressants (which we thought and probably still think muck around with catecholamine neurotransmitters and serotonin) L-DOPA doesn't work right away, the effects build over several weeks.
While Aricept may be the standard of care -- it is a lousy drug. I never saw significant improvement (this was how this class of drugs was initially touted), nor did any clinical neurologist I knew. We clearly need something better.
Assuming Rember does help, the next thing would be to combine it with a drug in the Aricept class. Few, if any, cancers are beaten with a single drug.
#9 -- amusing idea, but porphyrics when not in an attack have normal looking urine. When they're in an attack, they are very, very sick.
As a clinician, I was exposed to some nasty bugs and once had to take prophylactic rifampicin for a while -- which turns the urine orange. Unfortunately I went to a college football game while taking it and got some very strange looks in the john -- which consisted of several 40 foot long urinals.
Permalink to Comment15. Morten on August 1, 2008 3:33 AM writes...
@#4 Um... wow. "One of the problems with companies based outside N. America is that those environments have no accountability (legal or otherwise)."
@#7&9 I'm assuming that the placebo was just straight-up methylene blue since TauRX wanted to show efficacy for their formulation... or is that dumb?
@Derek It's called a Swiss-type claim when you use a known substance for new indications. Rather than those patent links you might want to just link here: http://en.wikipedia.org/wiki/Claim_(patent)#Swiss-type_claim
Permalink to Comment16. Alan Hochberg on August 1, 2008 9:57 AM writes...
The efficacy might be modest rather than stellar, but still it's nice to see a drug on which there is decades of safety data, and that is benign enough for college students to slip into to their friends' drinks as a joke without getting arrested. Let the formulation and derivatization begin.
Permalink to Comment17. Still Scared of Dinosaurs on August 1, 2008 10:48 AM writes...
"which turns the urine orange. Unfortunately I went to a college football game while taking it and got some very strange looks in the john -- which consisted of several 40 foot long urinals."
Lemme guess - the 'bama fans thought there was something seriously wrong with you and the Clemson fans wanted to know where they could get some.
Permalink to Comment18. retread on August 1, 2008 12:56 PM writes...
Nope -- it was a Syracuse game. They are known as the Orangemen, whence I gave new meaning to their cheer "Go Orange"
Permalink to Comment19. Still Scared of Dinosaurs on August 1, 2008 1:41 PM writes...
I almost, ALMOST went with 'cuse, but the last game I attended was Clemson at BC so I went with that. Dohhh!
I guess people taking Rember can go to Giants games and shout "Go Big Blue!" Just trying to return the thread to the original topic.
Permalink to Comment20. John Bosnitch on August 2, 2008 2:38 AM writes...
The author and many posters on this topic seem to be professionals in this field.
So here's my question #1: With a family history of Alzheimer's, an aged (89) father who is starting to become noticeably forgetful, and 'rember' promising to slow but NOT reverse the disease... why should I wait for further trials before getting my father on this apparently non-threatening drug by simply buying Methylene Blue.
And the inevitable question #2: Where can I buy it and how should I administer the 60mg "effective" dose?
I would appreciate any advice you have... either here in these postings or directly to me: john.b@imcnews.com
Thanks!
John Bosnitch
Permalink to Comment21. Spottymaldoon on August 2, 2008 8:15 AM writes...
In terms of general import to humanity, this announcement is reminiscent of 1989 claim to have produced 'cold fusion' of deuterium using a palladium electrode! Quite on the same scale if it proves to be valid and, of course, it's inevitable that many people are going to jump the gun and start dosing themselves well ahead of any clinical trials.
I understand that methylene blue prices have already shot up - as did palladium in 1989.
Permalink to Comment22. sharon on August 2, 2008 9:52 AM writes...
Hi Satan,
I'll have you know that Singapore is near the very top of the world's economic league and have zero debt as opposed to Mr. Bush's sorry economic legacy so make you criticism of Asian countries carefully in the future. And by the way, the science of the rember™drug could well have been formulated in a world class university in Singapore but, as it is, the research was done mainly out of the University of Aberdeen in Scotland where Prof. Wischik is based.
Permalink to Comment23. bobtaylor8@hotmail.co.uk on August 2, 2008 11:54 AM writes...
As an apprentice pharmacist in 1954 I dispensed many a bottle of 'magic' medicine for one of our local doctors in Durban South Africa. Apart form a 'mess' of ingredients, he used to include metylene blue and liquor sact (burnt sugar or dark caramel) so that the patient would swallow black medicine and pee blue. This was the magic, which probably did the patient as much good as the other ingredients!!
Permalink to Comment24. bobtaylor8@hotmail.co.uk on August 2, 2008 11:55 AM writes...
As an apprentice pharmacist in 1954 I dispensed many a bottle of 'magic' medicine for one of our local doctors in Durban South Africa. Apart form a 'mess' of ingredients, he used to include metylene blue and liquor sact (burnt sugar or dark caramel) so that the patient would swallow black medicine and pee blue. This was the magic, which probably did the patient as much good as the other ingredients!!
Permalink to Comment25. losingit2 on August 2, 2008 6:00 PM writes...
All,
Interesting discussion as I am a 58 year old early onset patient. I was diagnosed about 2 years ago and am currently on Aricept and Namemda.
I appreciate the gallows humor, but I think this is a hoax.
Based on what I see, I am amazed that he was allowed to present at ICAD
Permalink to Comment26. EISERMANNS on August 3, 2008 8:53 PM writes...
INDIGO CARMINE WOULD BE A PERFECT PLACEBO - URINE DISCOLORING AGENT !
Permalink to Comment27. EISERMANNS on August 3, 2008 8:53 PM writes...
INDIGO CARMINE WOULD BE A PERFECT PLACEBO - URINE DISCOLORING AGENT !
Permalink to Comment28. Petros on August 4, 2008 5:25 AM writes...
The patent position of Rember is discussed in this wek's Current Patents GAzette. The author suggests that the filings published to date, assigned to WISTA LABORATORIES (now TauRx), offer little, if any, effective protection to Rember.
Permalink to Comment29. bets on August 5, 2008 12:42 PM writes...
Like a previous contributor I notice there are a few folks of a scientific 'bent' posting on this site. I wish to God this disease was only of academic interest to me. My father is 77 and was diagnosed a year ago ( there were some delays in getting specialist help) . To be honest I would give him dynamite if I thought it would blow this 'worm' out of his brain. ( I exaggerate but I really wouldn't care what colour his pee was if this helped him.) He is on Arricept which helped initially but the effect has tailed off and the worm continues eating ... Any advice gratefully received. Four years is too long to wait and watch a person revert to toddlerhood.
Permalink to Comment30. eugene on August 5, 2008 2:57 PM writes...
Even though most of us are of a scientific bent, most of us are chemists and not physicians, so we can't give you any useful advice. Our choice on what to do by reading the info would be just as good as yours (with the difference that if I decided to dose myself, I'd read up on the formulation details used in the study or ask an insider if that was unavailable).
And even if we were physicians, no physician who is not involved in this study would urge you to take a drug that hasn't been fully tested or that at the end of the day could prove to offer no benefit. There is just no possible value to possibly misleading strangers over the internet no matter how bad their circumstances are. And I sympathize of course.
Now if you put up an online poll of this blog's readership asking: "If you had early Alzheimer's yourself and knew the formulation details of Rember, would you dose yourself based on these perliminary results?", the percentages who vote 'yes' or 'no' would serve as guidance for you. But giving advice from a single scientist (not a physician) to a single person with a devastating problem concerning an experimental drug over the internet? That is going to be very difficult here.
Permalink to Comment31. dorothy on August 8, 2008 7:32 PM writes...
#30 I am an R.N.,and yes, I would self administer. My Mother was diagnosed 10 yrs. ago and I would try rat shit if I thought it could stop her horrendous suffering. Thank you all for the work that you do .Please pray for those who are dying endlessly.
Permalink to Comment32. Terence on August 13, 2008 8:36 AM writes...
I feel so sad for the shareholders of TauRx and Prof wischik. He has spent more than 20 years of research and who knows how much money. Yet there are people in this blog that are suggesting using generics or breaking the patent. These same people insult Asians in the same breath. Shame on you.
Permalink to Comment33. MICHAEL HAMILTON on August 13, 2008 2:56 PM writes...
So methylene blue turns urine blue? Okay - beetroot turns urine purple. If this drug helps dementia sufferers those of us who care 7/24 for relatives who are becoming totally helpless and dependent would gladly accept the medicine for their suffering loved ones even if it caused striped urine with rainbow spots.
Permalink to Comment34. sb2 on August 14, 2008 3:50 PM writes...
Wow - speaking on behalf of Alzheimer's patients who need your help and help you by donating to research - many of you should be ashamed of yourselves. Call me naive, but when is a patent worth more than a human life? When is blue urine a reason to halt a clinical trial? I'll take blue urine over memory loss any day. I don't know when the industry took this turn and I hope that your comments don't reflect the true feelings of pharma and the researchers in the field.
Permalink to Comment35. metame on August 14, 2008 7:57 PM writes...
A couple questions for anyone who is game:
1) When dealing with a disease that has essentially zero rate of spontaneous recovery, why bother with a placebo control group? Can't we just take it as read that the disease would otherwise progress?
2) I can't tell from reading the patent what exactly they did to methylene blue to merit a new patent. And--the more urgent question for many--how is it any different from the stuff that's been with us for years?
My mother has corticobasal degeneration--another tauopathy that, briefly stated, does horrific things and nothing yet has been found to stop it.
Permalink to Comment36. linda on August 20, 2008 3:23 AM writes...
my mother has alzheimers....
we tried all the medications
namenda aricept excelon
none of them work.........
i wish i could get some of
this medicine right now to try
i hate to see her regressing to
a two year old...for thirty five
years she was a business manager
now she cant even make out a
personal check.........
thanks to anyone researching this disease
Permalink to Commenthope it wont be too late for mom.......
37. Denise on August 20, 2008 10:04 AM writes...
For those caring for loved ones with AD and other dementias, think about trying a more comprehensive approach. There is no "magic bullet" for these conditions. Current research suggests that AD involves inflammation and an underactive immune system. The best approach should include the current rx's, treatment for nutritional deficiencies such as Bcomplex, B12, Vit D, Fish Oil, etc., and support for the immune system. Not to mention lifestyle changes; especially those that reduce stress for the patient. Good luck!
Permalink to Comment38. MTK on August 20, 2008 10:42 AM writes...
sb2 and M. Hamilton,
You two are misunderstanding the significance of the blue urine. No one is saying this should stop an effective medication being used. what they are saying is that it is a potential complication in designing a clinical trial and getting meaningful results.
So the comments which you interpret as callous disregard for human suffering are anything but that. What they are saying is "How can we make sure that this works?" "How can we ensure that we are providing patients and their relatives real effective medicines and not false hopes?" "How can we assess this potential drug properly, so we can either make it better or move on to other leads with a real chance of making a difference?"
I hope this helps you understand and appreciate what researchers and the pharma industry does.
Believe it or not, everyone in the industry wants to help. We all have or have had family members afflicted with cancer, Alzheimer's, heart disease, etc. That's why many of us got in the business in the first place.
Permalink to Comment39. Shawn on August 20, 2008 11:50 AM writes...
My understanding is that the current treatment plan using methylene blue for Alzheimer's and Parkinson's, is that very small doses would be used, a la, "a few raindrops in four Olympic-sized swimming pools" (ref. http://www.world-science.net/othernews/080818_blue)
In fact, high doses of the drug can cause brain damage over time.
Permalink to CommentIf this is the case, the "blue urine" issue would probably be irrelevant as the doses are so low. As Derek pointed out, the dosing may be the critical potentially valuable/patentable aspect in addressing mitochondrial dysfunction in Alzheimer's. Delivery of the drug is another issue, but many new and existing drug delivery mechanisms avoid ingestion and therefore the diarrhea issue.
40. Jiff on August 20, 2008 5:26 PM writes...
For those dealing with loved ones with this illness hang in there. Taking it one moment at a time works for me.
Permalink to Comment#37 We have been doing all this and Mom's progessive slide has been very slow (about one stage per year) No longer using Aricept (leg cramps) just namenda, B6, B12, vitamins and calm surrounding.
41. Jiff on August 20, 2008 5:26 PM writes...
For those dealing with loved ones with this illness hang in there. Taking it one moment at a time works for me.
Permalink to Comment#37 We have been doing all this and Mom's progessive slide has been very slow (about one stage per year) No longer using Aricept (leg cramps) just namenda, B6, B12, vitamins and calm surrounding.
42. mike on August 27, 2008 11:00 PM writes...
Another product claiming similar effects:
Permalink to CommentProfessor Kruzel (Regen Therapeutics)
'In this presentation I will explain how such a low dose of Colostrinin™ can produce significant medical benefits in AD patients. I will focus on our findings from recent genomic microarray work, which shows that Colostrinin™ can favourably modulate the expression of several molecules involved in the pathology of Alzheimer's disease (upregulation of bleomycin hydrolase, downregulation of APP and effect on Tau phosphorylation). This enables the body's own multiple responses to reduce neuronal pathology and achieve homeostasis. The effect on Tau is said to be the reason for the response witnessed by the patients taking the drug Rember*. This data suggests that Colostrinin™, may be one of the first compounds with the potential to impact both Tau tangles and beta amyloid plaques, the two key pathologies of Alzheimer's disease.'
43. Alexandra Brown on August 30, 2008 6:36 AM writes...
Thank you for all of the interesting articles you have written on Alzheimer's.
Permalink to Comment44. jtwiz7 on August 31, 2008 7:40 AM writes...
After Dorothy and Denise's comments, I discussed it with wife and after ten days,there's a new person in our house.
Permalink to Comment45. kathy phillips on September 3, 2008 9:50 PM writes...
Why didn't you post my commentsof France being able to come up with cures for certaind diseases as Cancer and Alzheimers diseases but the USA hasn't approved them, are you afraid to post this, it's a money making business, and I believe, the government has more to do in hiding the cures for these diseases, so they can pocket money. I want answers.
Permalink to Comment46. Derek Lowe on September 4, 2008 8:15 AM writes...
Your comment showed up about nine times, actually. Could you provide any examples at all of a French cancer or Alzheimer's cure? Name, company, when it was approved by the EU regulatory authorities - any of those? I'm not aware of a single one, and I've worked in both areas.
Drug discovery is indeed a money making business, both here and in Europe. But how the government is pocketing money by "hiding cures" is a mystery to me. Believe me, drug companies would love to find some of these, because they'd make a mint.
Permalink to Comment47. lisa on September 9, 2008 12:43 AM writes...
Seem to recall methylene blue being used to treat bipolar disorder. Interesting that Lithium also seems to interfere with tau formation (GSK inhibition) and is currently being tested in ALzheimer's. If lithium prevents phosphorylation and methylene blue breaks down tangles, the combo should be especially effective...assuming tau is the culprit.
Permalink to Comment48. Damitha Edirisinghe on September 9, 2008 4:22 AM writes...
It is very exiting to know that there is hope for alzheimer sufferers. A cure or something that improves memory matters immencely to me for personal reasons and hence would like to know when these trial drugs would be available ? and if there are any clinical trials going on at the moment where patients can obtain these on trial basis?
Permalink to Comment49. ltdem on September 21, 2008 12:23 PM writes...
To #44. jtwiz7. When you say theirs a new person in the house, are you saying that you tried the methelyne blue (Rember)? If so, what dosage? How much improvement? How was it administered?
Permalink to Comment50. Daniel Crespin on September 23, 2008 7:08 AM writes...
A molecular weight of 320 for MB suggested, after some estimations, to interpret the "few raindrops in four Olympic-sized swimming pools" metaphor as one part per billion (ppb) or 10^(-9) order of magnitude.
Since a close relative has been ravaged by Alzheimer for several years, I diluted and administered the usual 2% commercial MB. It was hard to measure the possible mild improvement in the patient.
More recently I had access to one of the original articles on MB and found their most effective concentration was actually 100 ppb. With this datum, some Web search on MB pharmacokinetics/ pharmacodynamics and given that the volume of blood plasma in adults is about three liters, I arrived at the following practical dose formulation:
Dilute twenty-fold commercial 2% MB in water.
For example, add water to 25 ml of 2% MB to complete 500 ml, or half liter. At 20 drops per ml this contains 10000 drops at 0.1% dilution.
This MB at 0.1% is given one drop three times a day, preferably in half glass of water (to avoid blue tongue). I am trying this on myself as well.
I am 62. Assuming no placebo effects, and not being ---as far as I know--- an Alzheimer person, the following seem to take place:
1.-Skin become smooth
2.- Nails grow faster
3.-Physical activity goes on rather well.
Of course, I have not subjected myself to any sophisticated cognitive or clinical tests.
My Alzheimer relative, an extremely fragile a 93 years old person, seems to be improving as well.
Regards,
Permalink to CommentDaniel
51. Daniel Crespin on September 23, 2008 8:03 AM writes...
Sorry, in my previous comment, where it says 100 ppb it should say 100 nanomol. The final 0.1 % dilution is OK.
Permalink to Comment52. Ken Gillman on October 5, 2008 6:37 AM writes...
Methylthioninium chloride (methylene blue) is an monoamine oxidase inhibitor (MAOI), see my web site for details, and paper in Brit J Pharmacol.
Permalink to Comment53. Ken Gillman on October 5, 2008 5:03 PM writes...
Daniel, can you send me the references you refer to. Basically its very uncertain trying to extrapolate from such information to what an effective human dose might be at the effector site: a CNS enzyme, receptor etc. In the end analysis its clinical effects that are the proof of pudding. MB definitely causes serotonin toxicity ( serotonin syndrome) if mixed w serotonin reuptake inhibitors. The earlier work re depression / MDP averred to isnt good enough to say much, but of course MAO-A inhib like moclobemide are thought by some to be mild antidepressants. Youdims 2006 review is useful re MAOIs which may indeed be helpful for dementia.
Permalink to Commenthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16552415
54. Barbarawanda on October 6, 2008 8:51 AM writes...
Where are folks sourcing methylene blue? Chemical companies (eg Sigma Aldrich) only sell "GPR" grade - which is likely to have heavy metal contamination.
Permalink to Comment55. Barbara on October 7, 2008 4:22 AM writes...
Sourcing MB
http://www.anaspec.com/products/product.asp?id=29652
Anaspec claims to produce "ultrapure" MB. I don't know what criteria they use - insufficient info on website. Hopefully may be better than the GPR grade which is certain to have significant heavy metal contamination.
Here's another one:-
http://www.bioexpress.com/index.html?wscdet_show=000000000200212000212260
If anyone tries to find out more about the quality of their MB from these websites, please post.
Permalink to Comment56. rina on October 8, 2008 11:29 AM writes...
I have been using MB from American Regent, but the urine is not turning blue.?wrong dose or wrong MB, I diluted it according to your instructions to .1%.
Permalink to Commentplease, respond, thank you.
57. b.w.durkacz@ncl.ac.uk on October 9, 2008 8:51 AM writes...
Rina and Daniel - I don't know where you are getting your figures from, but MB was used at 60 mg per day in the clinical trial. A 0.1% (weight/volume) solution will only contain 100 mg in 100 ml by definition - you would need to drink 60 ml of this to get the therapeutic dose. A few drops would be not much more than homeopathic! Also see my suggestion for sourcing MB if you are intent on self-dosing - most MB suppliers are selling stuff that is likely to be contaminated with heavy metals.
Permalink to Comment58. Daniel Crespin on October 15, 2008 8:03 PM writes...
Answers below for several persons
----------------
For Ken Gillman
I wanted to attach the article to this message but neither this web page, nor yours, seem to give me the option. The article is:
Atamna et al. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. The FASEB Journal, 2007; 22 (3)
and is quoted in
http://www.sciencedaily.com/releases/2008/08/080818101335.htm
Extrapolating clinical doses from in vitro experiments is not the most scientifically sound procedure nor a clinically strict method, but MB has a long story of folk use since its discovery. Accordind to the FDA ---I checked a few weeks ago--- there has not been any report on MB toxicity.
As you certainly know soldiers during WWII used it as antimalarial in doses high enough to give then blue urine, feces and sclerotic tissue. No toxicity report ever surfaced. Also, during my childhood ---1950's--- it was used as topic for tonsillitis, we swallowed it and it produced similar effect. The risk/benefit rate for Alzheimer and Parkinson patients is therefore rather small. The few I know take it seem to be improving.
Had Jenner or Pasteur been restricted by today pharmaceutical standards they would have not benefited humanity the way they did. Such standards, useful as they are, are also enforced by the big pharmaceutical companies to corner the market. If MB is really effective, a strong attack from the companies against OTC MB can be expected.
A friend with advanced type 1 diabetes had a persistent infection in a foot for longer than one year. He decided to take MB three weeks ago and today informed me over the phone that his foot is cured, with only a scar left. Was it MB or some other cause?
As for serotonin toxicity, is it true that even aged cheese has such effect?
Perhaps the FDA does not consider serotonin toxicity to be a relevant form of toxicity. After all common salt is so toxic that Romans often used it to commit suicide. In large enough doses Yellow number 5 ---tartrazine--- has a behavioral effect in children, probably mediated via neural mechanism, hence could be considered neurotoxic but is still found in many foods. Alcohol is a commonly used toxic substance, and is not, apparently, a cure for Alzheimer, Parkinson, etc.
Please let us know your opinion.
-----------------
For Barbarawanda and Barbara:
I use standard 2% MB as sold over the counter in many pharmacies (like Walgreen's) in South Florida. It is usually found in the "Hispanic Medicines" stand.
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For Rina:
At such low concentration no coloring effect will appear in urine/stools or sclerotic tissue.
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For b.w.durkacz@ncl.ac.uk:
A 60 mg dose is too large to conform the Olympic pool methaphor. For the moment I will stay with the "one drop of .1% dilution three times a day".
Since MB is often used to add to aquariums as a cure for some diseases of fish and fish are very susceptible to heavy metals I would expect these chemicals to be very-very low in MB.
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Regards to all,
Daniel
Permalink to Comment59. Scott on November 30, 2008 11:20 AM writes...
After viewing all the comments: (1) it is still not clear what the commonded dosage is for improved mental acuity, (2) is this number greater or smaller than the amoung that will cause discolored urine, (3) where can I buy it (I tried a CVS and they never heard of it), (4) how can TauRx get a patent on a drug that is available over the counter (it's like getting a patent on electricity)? Whenever TauRx gets this approved by the FDA (they tell me at the earliest by 2012), will doctors then start writing prescriptions for it? Why do they need to write a prescription for a drug that is available over the counter?
Permalink to Comment60. Ken Gillman on December 10, 2008 5:18 AM writes...
This discussion will benefit from a bit more understanding of the interface of science with clinical medicine. No-one seems to have noted that, apart from having nano-mol potency as an MAOI (ie like moclobemide, which has also been claimed to help dementia) it is also a potent NO synthase inhibitor.
Permalink to CommentIf anyone wishes to contact me thro' my website I will explain it, pref via skype.
Also fairly comprehensive refs are in my 'paper' about MB, pdf on website.
NB I have no commercial interested of any sort
61. John Bosnitch on December 19, 2008 8:29 PM writes...
I am returning to this list after being contacted by quite a few readers who asked me whether I had found any more information about dosing and administration of MB.
I discovered what appears to be a good estimate of what needs to be prepared in the form of instructions that almost anyone could prepare. Here is the source, which also includes other good advice:
http://geddarkstorm.livejournal.com/188959.html
If you are not in Florida (where you can buy Methylene Blue over the counter, I have a friend there who can send it out at cost.
I have one other suggestion. Since there is not supposed to be any negative effect whatsoever from taking MB, I suggest that if you are planning to give it to an older relative who is in serious need, you should still administer it to yourself at the same time so that you don't need to do any guessing about side effects on a person who might not be a cognant as you are about what they are experiencing.
I give this advice not as a professional and I welcome any and all comments here by scientists/doctors who might have better ideas. No matter what though, we need to assemble reports on all results and or side effects and publish them on the Net to get around the system's embargo on this very needed therapy...
I look forward to hearing of your results, as well as any better advice... please keep in touch with me directly as well...
Sincerely,
John Bosnitch
Permalink to Commentjohn.b@imcnews.com
62. Joe Pesec on December 29, 2008 11:58 AM writes...
Hello
I am trying to get in on a clinical trial of Rember. Could anyone suggest the fastest way to do this? 216-481-0787
Thank you and Happy Holidays
Permalink to CommentJoe Pesec
63. Scott on January 3, 2009 8:16 PM writes...
In response to Joe's desire to get in on a clinical trial for Rember, I sent and email to TauRx on this subject. They responded that you cannot get on a clinical trial by applying. The system is that they will contact neurologists and the neurologists will recommend subjects for such trials. You can get their email on their web site which is www.taurx.com.
Permalink to Comment64. Zarabeth on January 3, 2009 10:06 PM writes...
@John Bosnitch:
1) My understanding is that the effective dose is approximately 60mg three times per day, not the microscopic quantities listed in that article.
2) Methylene Blue is a powerful MAOI and thus should not be taken along with any SRI (which includes the SSRIs such as Celexa, Prozac, etc.) - doing so could very well be fatal upon the first dose.
Permalink to Comment65. Ignacio on January 15, 2009 8:34 PM writes...
Herpes labial asociado a Altzheimer.
Permalink to CommentTratamiento herpes= Azul de metileno.
Tratamiento hongos= Azul de metileno
Tratamiento Altzeimer= !!!¿ Azul de metileno ?!!!
66. PV on January 16, 2009 8:17 PM writes...
Some people take a medication called Prosed/DS for urinary problems. It contains MB and it turns the urine blue but not right away. Even after you stop taking it the urine remains blue for a few days. I don't know why. There are people taking this drug for chronic urinary conditions such as interstitial cystitis even though the drug comes with the warning that it hasn't been tested long term. It is a compound drug with probably more dangerous ingredients than MB. I'd like to think that it helps AD as a side effect!
Permalink to Comment67. jtwiz7 on February 19, 2009 8:20 AM writes...
To #49, Itdem, and others; yes, after discussion we have been using MB since last August. Approximately 150mg twice/day with lots of tlc, very healthy diet, zero sugar and soda, lots of water and vitamins B3, B6, and B12, exercise and crossword puzzles. Filled empty #2 gelatin capsules with nettle-nose tweezers and rubber gloves. Amazing immediate improvement. Sorry for delay in responding. Hope this helps.
Permalink to CommentTo #44. jtwiz7. When you say theirs a new person in the house, are you saying that you tried the methelyne blue (Rember)? If so, what dosage? How much improvement? How was it administered?
68. Scott on February 26, 2009 3:08 PM writes...
There still seems to be a lot of discussion about dosages, etc. The big question remains: is MB the silver bullet or not?
Permalink to Comment69. chasmears on March 8, 2009 10:42 AM writes...
Where did you get the methylene blue? Is it in liquid form? Where did you get the capsules? How do you know that the dosage you are using is 150mg? How long ago was person diagnosed with altzheimer's?
Permalink to Comment70. Scott on March 11, 2009 10:54 PM writes...
In response to chasmears, I have not obtained any methylene blue. There has been a lot of chat saying that it was avaiable over the counter. I have not found that to be the case. My person was diagnosed with Alzheimer's about one year ago. The fundamental quations about methylene blue do not seem to be available. Dosage is not the top priority question. The top priority question is whether it will work or notl
Permalink to Comment71. Scott on March 11, 2009 10:55 PM writes...
In response to chasmears, I have not obtained any methylene blue. There has been a lot of chat saying that it was avaiable over the counter. I have not found that to be the case. My person was diagnosed with Alzheimer's about one year ago. The fundamental quations about methylene blue do not seem to be available. Dosage is not the top priority question. The top priority question is whether it will work or not.
Permalink to Comment72. Dan on March 29, 2009 10:13 PM writes...
My son is participating in an "unoffical" trial of MB for autism. Taking a daily dose of 1.0 ml per day. Although we were hoping for gains in speech - we primarilly have found less agitation, grimacing, muscle rigidity. We are going to cycle off and see if these return.
Permalink to Comment73. mike on May 1, 2009 4:58 PM writes...
Methylene blue kills fungus in fish tanks...maybe fungus has something to do with Alzheimers ? Fungus might be the "train " that the tangled tao rides on ??
Permalink to Comment74. mike on May 1, 2009 4:59 PM writes...
Methylene blue kills fungus in fish tanks...maybe fungus has something to do with Alzheimers ? Fungus might be the "train " that the tangled tao rides on ??
Permalink to Comment75. mike on May 1, 2009 4:59 PM writes...
Methylene blue kills fungus in fish tanks...maybe fungus has something to do with Alzheimers ? Fungus might be the "train " that the tangled tao rides on ??
Permalink to Comment76. agghouse on June 19, 2009 6:06 AM writes...
to 67. jtwiz7, I care for my precious mother who I have watched decline rapidly and significantly over the last couple of years. Exelon & Namenda are not working. She is healthy as an ox;take her to silversneakers @YMCA 3x/wk;yrs of taking fish oil, b complex, vitD etc. WHERE CAN I GET THE METHELYNE BLUE? & how did you know what dosage?
Permalink to Comment77. agghouse on June 19, 2009 6:14 AM writes...
tl 67. jtwiz7, I also give my mother a puzzle every day; find a word, simple math problems, mazes etc. she has been unofficially diagnosed with alzheimers since feb 09;started treatment for mild dementia w/exelon nov '07;started namenda 3 '09. decline, decline.pls respond.
Permalink to Comment