The study is a follow-up to a successful Phase 2a study (the RASMET study) completed last year. ENT-01 is an orally administered, synthetic derivative of squalamine that acts locally on the enteric nerve cells of the gut, stimulating gut motility and altering afferent neural signaling from gut to brain. Based on results from the RASMET study, ENT-01 has the potential to ameliorate some or all of the non-motor and motor symptoms of Parkinson's disease, including constipation, motor dysfunction, hallucinations, memory, depression, fragmented sleep and REM-behavior disorder.
KARMET Study Begins Enrollment: The study... - Cure Parkinson's
KARMET Study Begins Enrollment
Written by
Farooqji
To view profiles and participate in discussions please or .
Read more about...
118 Replies
•
Pretty amazing.
Very intriguing. Thanks for sharing!
Very promising, just like so many other discoveries. Just wait for another several years!
I can't tell if the stuff is a steroid or antibiotic. I think it's an antibiotic?
I wish the guy in the video, i.e. the founder and CEO of Enterin would have used precise language.
It's coming back to me. Now I remember. I think about 6 months ago park_bear explained it was antibiotic?
it's a protein called squalamine
I meant Trodusquemine, the stuff that passes the BBB. Simon says only that it's an aminosterol. Can that be an antibiotic?
Wiki says, "an amino derivative of a sterol, especially any of a group of such antibiotics obtained from sharks"
Turns out, there's a trial an hour away and I have an appointment for an evaluation this Thursday. Never seriously considered participating in a trial, but their claim of stopping a/syn from even aggregating is pretty unequivocal.
Are they still recruiting? The KARMET study says that it was to start last month. They also seem to limit participants to those who have had severe constipation for quite some time.
Unfortunately (or fortunately) for me, that problem went away when I began eating much better, exercising, and taking B1.
Still, this is exciting because the video explains how their ENT-01 molecule can (hopefully) get all of the αS off of the neurons, possibly bringing them back to health.
Did anyone else have trouble understanding his music metaphor? Is he saying that ENT-01 does 2 things: remove the αS and also play this 'music' for the brain? I'm a bit skeptical that this simple molecule from sharks would do both. Or is he projecting ahead to a future advance? Does ENT-01 just remove the αS (which would be huge) or does it also make pretty calming "music"? Or, maybe, the αS itself is causing an alarm to go off, triggering even more αS? So if the αS goes away, the calming "music" will return? So many questions.
But the hypothesis that the brain's αS problem begins due to a real or perceived attack on the brain has been around for several years and makes sense to me. I (and many others) had an encounter with tick-borne Lyme disease several months before noticing the first PD symptoms. If correct, then the gut noticed and responded to the threat and sent αS to the brain, the αS (hopefully) dealt with the problem (go team!) but then the brain failed to remove the αS and (I guess) might still be getting more from the gut?
Yes, there are many locations and many of them are recruiting. A few have not started yet.
I'm not usually excited by trials, but the claim is that it stops a/syn from aggregating and reduces some that's already present.
The music for the brain kind of descriptions is what I was referring to when I said I wished you would've used precise language. I know the interview was in the context of a audience of know nothing peons like us, but I'd like to try to figure it out.
I thought what he meant by calming music was a layman's description of various molecular configurations, but I need to go back and look at that again.
He did say the excess of a/syn is an overreaction.
Yes, the claim is it does 2 things. The derivative blocks and enzyme (PTP1B) that facilitates aggregating, and secondly, it reduces a/syn from partially damaged cells.
SoPD in his May or June issue was impressed with ENT-01.
They're unequivocal that PD starts in the gut, which as you point out is not a new theory and then moves throughout ENS and up the vagus nerve. (I think it's at least 15 years old, but gaining more traction now.) I don't doubt it.
So do you know if ENT-01 is an antibiotic. The statement on wiki aminosterol refers to a group of antibiotics, but it isn't clear to me.
From what I've been able to piece together it's an antimicrobial peptide, which can act as an antibiotic (I could definitely be wrong about that). I found an old and crappy video on Youtube of Dr Zasloff's work then. At time 10:47 there's a chart showing the "secreted anti-infective protein/peptide arsenal": youtu.be/fIHa-9ArQZY
from iqbaliqbal's link,
"Based on results from the RASMET study, ENT-01 has the potential to ameliorate some or all of the non-motor and motor symptoms of Parkinson's disease, including constipation, motor dysfunction, hallucinations, memory, depression, fragmented sleep and REM-behavior disorder. "
Isn't there an old cliché that says something like, "If it sounds too good to be true..."
I forget the rest.
Maybe it'll help with memory too (that was a joke; I couldn't remember long enough... sigh).
I think the hypothesis is an infection which occurs 1st in the gut triggers production of a/syn which then travels and triggers the production of a/syn throughout the ENS and up the vagus nerve which triggers the production of more aS in the brain.
I'm now pretty enthused about getting in this trial.
It is pretty exciting. I'm in Calfornia, and the closest is Tulsa, 1600 miles away. But I'll keep checking!
Fresno is a trial site.
Really? That's not very far. But when I go to their site here: enterininc.com/karmet/ and enter my zip code, Fresno doesn't show up. It doesn't even show up when I enter a Fresno zip code (93650 or 93726). Are you looking somewhere else?
1st 1.
clinicaltrials.gov/ct2/show...
Thanks! Well then, Enterin's web site hasn't been kept up to date with all of the centers. Interesting.
How far away from Fresno are you? How interested are you in this trial?
ENT-01 may be most promising thing in the pipeline along with PRX002.
There ought to be a law requiring pharmaceutical companies to continue providing the trial therapy to anyone benefited from it and wants to continue. A tax on the pharmaceutical industry of .0001% would cover the cost.
Otherwise, I imagine, being relieved of PD only to be revisited some months later.
How should we feel about a company who is able to take a drug to market, make $1,000,000,000 in part because we participated in a trial, but where they declined to spend a few hundred or a few thousand continuing the therapy?
Turns out that my neurologist is the one running the study in Fresno. I'm only about 50 miles from his office. He'd sent me a letter last month asking if I was interested in a trial, but it wasn't this one. I knew he was big on running trials but he must've decided to do this one very recently or I think he would've mentioned it to me. I'm calling his office in a few minutes and I'll let you know how it goes.
I'm very interested and I agree that this could really be something that could work, which is way better than the usual chances on these things. I also agree that they should give the drug for free or their cost of making it to anyone in the study who wants it afterward. It seems to me that they could get more data if they did that and required continued journal entries. Anyone who randomly gets selected for the placebo should have a chance to see if it works for them.
How should we feel about it if they don't? Not happy of course. Have you asked them about it? I will if you don't want to.
That's a bit of great luck having your neurologist run the trial. That'll come in handy.
If the stuff meets the expectations they've created, I'll not only ask, I'll plead, cajole, cry and throw myself on the floor and have a hissy fit, if I think that will help.
If the stuff meets expectations, we should start (sooner than later) figuring out how to have it made. If one lab can make it, another lab can make it, too. I mean, they are claiming the stuff prevents the aggregation of aS. What else do we want?
What more do we want? Not dying from a fake drug from a lab in China would be nice. 
If they don't give it to us after the trial, we should all throw hissy fits and report them as side-effects. (Just kidding, thought police).
Well, I left a voice msg with my neurologist. I've also sent him an email. And I've reported the problem on Enterin's site to them. Now I wait.
Your concern about fake drugs can be covered.
When I participated in a cooperative drug buy from a compounding pharmacy in China, the pharmacy agreed to send the entire batch to an independent lab in the US and further agreed that a finance company (like PayPal) would hold payment until they got a certificate of authentication from the lab in the US that the product was molecularly identical.
True, I'm getting ahead of myself.
Well this is somewhat encouraging. Yesterday, I sent a message (via Enterin's 'Contact' page) asking a question. Today, I get this:
"The answer is yes, makes sense and worked in the last trial, brilliantly!
I’m the founder/ president of the company and a professor of neurology by background. Please feel free to ask me more questions.
My very best,
Denise"
The only problem? I forget what I asked her. I do have PD after all. And since I sent the msg from their site, my question isn't attached as it would be with email.
Some days I just have to shake my head and laugh.
I'll go ahead and ask my question, "if the trial works well for some patients, is there a mechanism in place for them to continue the therapy?"
Don't forget those who get a placebo.
My correspondence.
Ms. Daggerhart,
I have 2 questions I'm hoping you or someone on your team will try to answer for me.
Whether or not your company proceeds to a phase lll trial, is there a mechanism in place for those patients for whom the therapy was beneficial to continue the therapy if they want?
I know you cannot answer this definitively, but once the administration of Trodusquemine ends and is no longer inhibiting PTP1B, does your team expect a residual benefit (to last awhile) or do they expect a/syn to resume aggregating right away?
For the first visit, you can expect the following.
•Informed consent
•Demographics/Medical & Medication History
•Complete Physical Exam
•Height/Weight
•Vital Signs (BP, HR, RR and Temp)
•12-lead ECG
•Labs and urinalysis
•Diary instructions
•Questionnaires
Hi Marc,
I’m the President and CMO of Enterin and a neurologist. In answer to your question, no, you would not be allowed to continue after the ongoing study. However the answer is YES after the pivotal study which will begin in October. You would stay on medicine for a year or two if you responded. The advantage of participating now might be that you would get priority to participate in the pivotal study but it will be a large study so its not that important.
All best,
Denise
Sent from my iPhone
Well, she did answer some of your questions at least. Whether or not they expect a-S to start clumping again right away after stopping treatment is a good one, but I can see why they wouldn't want to say yet. I would like to know more about what happened during the first trial, but they will make that public only when they're ready to. I have enough info to sign up, and I've already contacted my neurologist about it.
I wish they would've published their studies, too. I'll try and find out some of that information during my evaluation tomorrow. I think the reason they, and other pharmaceutical companies, don't publish studies is because it would reveal proprietary information. Other companies might make an insignificant adjustment and patent that.
You've probably already seen this, but in case you haven't: enterininc.com/Perni-et-al-...
I thought this was interesting:
"In the present context, our choice of studying squalamine was prompted by the observation that this molecule is able to enter eukaryotic cells and displace proteins that are bound to the cytoplasmic face of plasma membranes (17–19), suggesting that it may influence the initiation of the aggregation of α-synuclein (12). Indeed qualamine has been referred to as a “cationic lipid” (18) as it carries a net positive charge and shows a high affinity for anionic phospholipids (20) of the type that nucleates the aggregation of α-synuclein, thereby reducing the negative charge of the membrane surface to which it is bound (18, 21) without significantly disrupting the integrity of lipid surfaces (18). In analogy, it has recently been shown that a homologous protein, β-synuclein, can inhibit α-synuclein lipid-induced aggregation via a competitive binding at the surface of lipid vesicles."
If Enterin is correct about a-S blocking the pathway from the ENS to the brain, then a lot of things other people are trying are sort of doomed to fail until a-S is cleared and (hopefully) communication is restored. Even then, the damage to the nerve and neuron cells has to heal or dead ones replaced. A lot of ifs but this seems like the right first step. My gut tells me it's right. Or it would if it could.
Of all the studies I've all read, I don't recall any talking about aS clinging to membrane services or the relevance of positive or negative charge.
I had my evaluation today. Enterin doesn't do it. They subcontracted to a company who apparently runs trials for several different illnesses.
It took 5 hours. Took all my vital signs, EKG twice. Probably 20 pages of questions regarding health history. The will let me know in 2 weeks if I'm in. During that 2 weeks I have to keep up precise log of the frequency, time a day, consistency, i.e., everything I didn't want to know about my poop. I guess I have to get used to taking stool samples. Ugh.
The good news is, you have a 75% chance of getting the therapy and if you get admitted to this trial, you can be automatically admitted to the next trial which will begin in October.
Here is your math puzzle for the day. One cohort get 75 mg, one cohort gets 150 mg, and one cohort gets the placebo. Why are the odds 75% and not 66%?
Ha. Do cohorts have to have the same number of people? My guess is they're doubling either the 75 or 150 mg cohorts or increasing both by 50%.
I don't suppose they answered any questions. I see they mention staying on a diet and I'm curious about that.
The charge thing makes sense because although I don't think I've seen it mentioned for PD, that is how a lot of things cling to each other in cellular biology in general.
But something else does concern me: what if all they're doing is detaching a-S from dead neurons so the a-S molecules move on to attach to live neurons? My remaining neurons want to know!
Also curious: how often do they want stool samples?
You got the math puzzle right.
They're doing two sub studies and 1 of them they collect four stool samples. I volunteered because they indicated they would share my data with me and as I am obsessing about my microbiota, I thought that be interesting. (Generous of them.) Otherwise, they want two samples.
Since they were subcontractors, they were mostly technicians and clinical practitioners following a protocol from binders so they didn't have answers to all my questions. I knew more about it than most of them. That's pretty sad.
I didn't have the impression the aS was only removed from dead neurons. I believe it's from from living neurons where aS is aggregating but hasn't reached the toxic level yet. If neurons are dead, do they even have the ability to move material in and out?
A doctor did the UPDRS exam. He indicated to me, in a way that I felt he was talking out of school, that the therapy is beneficial to a wide variety of symptoms beyond constipation.
The therapy is only administered for 30 days, so if there is to be a response, it would be pretty quick.
Nothing ventured, nothing gained.
Your aS theory seems sound. My neurons rejoice!
I remember that constipation is often the first symptom, often starting years before the more obvious symptoms. Maybe they expect the gut to respond first, especially since ENT-01 is to be swallowed. I suppose the theory is that whatever attacked the gut has been defeated long ago, but the aS continues to be produced as a continuing "overreaction" (to use Zasloff's word)?
Constipation is probably due to the brain-gut communication being cut off. That makes sense, based on what we know about circadian rhythms (mentioned by Zasloff). So for constipation to go away, the vagus nerve must be cleared of aS, not just the gut.
Maybe aS is being produced to fight misfolded aS? Detach all of the aS and let the brain's cleaning system clear it out and then maybe no more aS will be made? That would be nice. Fascinating to think about it that way.
My neurologist's office called and set my appointment to be interviewed/evaluated. I go in on the 31st.
Good for you. I begin getting the pills on the 31st -- either the real thing or placebo.
They will have you keep a log of your sleep and poop for 2 weeks before you start on the pills.
If we don't get the placebo, I think the stuff is supposed to work within a few days.
This and FUS are the only trials I've been interested in.
Have you gotten your pills? My neurologist has rescheduled me twice because he's waiting to receive some sort of equipment before he's able to do the evaluation. My new date for that is the 12th, next Tuesday.
I got my 1st dose Wednesday the 30th. 6 pills for 3 days, then 7 pills for 3 days, then 8 pills for 3 days, the 1st of which was today. They cautioned me to call them if I got diarrhea which means they thought that might happen from 8 pills, but I got nothing, so apparently I got the placebo. Boo-hoo. I had a 75% chance of getting the real thing and let that get my hopes up -- only to be dashed.
PS. I don't know what kind of equipment he could be talking about. They didn't use any. Except maybe an EKG, but every doctor's office as 1 of those.
Well, maybe you'll still get lucky and have diarrhea soon! (A sentence I had never thought I'd tell someone.)
PS. I don't know either. Now I wish that I'd asked what she was talking about. Now my imagination is running wild. Some sort of probe to measure constipation?
• in reply toJAS9
New doggie? Looks very young.
Art
JAS9• in reply to
Shes new to us, but old for a dog. We got her recently from a friend who couldn't keep her anymore. Nola is a very smart 11-year old German Shepard.
Turns out, I did get lucky. Now, I think I have the real thing. They worked me up to 9 pills a day and when I got there, I started having BMs a half-hour later. I have also commented to my wife on 2 occasions that I've been feeling better the last week, nothing dramatic, just better.
Since there is not anything about it that is a laxative, I wonder how can work that fast?
I hope that the good progress continues
Thank you, iqbaliqbal. God, would that be wonderful or what?
If this drug (ENT-01) is clearing aS from partially compromised dopaminergic neurons in the G.I. and ENS, then it is triggering the mechanisms for normal motility immediately.
I'm always ambivalent about whether or not I'm getting worse or getting better and I've been racking my brain trying to figure out if I done anything differently this week and I haven't except for this trial drug.
They have another pilot study scheduled to begin in October in many locations. Might be worth watching.
I thought about this a little more, and we might have one more clue as to what's going on. Do you remember when Dr Zasloff said that the brain had to hear a certain "tune" from the gut to know that everything's OK with it? And you say that you've been feeling "just better" over the last week. Now, that could be the placebo effect or it could be the first indication (even before BM) that the gut and brain are communicating again. I'm a retired engineer and programmer, and I worked on the avionics software for a few large airplanes and other software systems, so I recognize distributed systems interacting with each other in order to make decisions. This helps me to understand this and to make a few guesses.
The brain needs all the input that it can get in order to move the body safely; it needs to know the status of all of its sub-systems, including the gut. The brain uses input from the gut, along with the eyes, ears, skin, etc. to determine when it's safe to rest. If any of those systems raises a red flag (or can't be reached), it defaults to the safest mode; the fight or flight mode.
Now, it could be that the a-S was cleared out of the ENS/vagus nerve first, allowing it to communicate to the brain and finally tell it that it's OK - not under attack. Of course, this is just a theory, but it fits the clues that I know of so far.
That's great!! I do know that bowel movements are normally triggered by the circadian rhythm, and if the brain-gut axis is free to communicate, they should just happen on time every day. For example, you should not have one at night while you're sleeping, but you should get one after getting up around 9 am or so, and another just before bedtime.
What I'm getting at is, besides the a-S you shouldn't have any physical impairment that needs fixing before the bowels begin to work; not like a broken leg. Like you said, it might've cleared away the a-S from partially clogged neurons.
Of course, this might not be the case with some of the other symptoms having to do with brain cell death, which is why they're looking for bowel movements first. What we're all holding our breath for is to find out if this will work to stop or reverse that by letting more of the neurons recover or be repaired or even replaced, but this is a great first step!
It's been about 10 days now with 20 days to go?? If this stuff works that fast to clear out the a-S then I'm really impressed and encouraged. This is fantastic news - so far so good.
My appointment to be evaluated is on the 14th. If I'm accepted into the study and if they give me the real thing too, I'll be another data point. Exciting!
I like your theory. Makes sense.
I was commenting to my wife about feeling better during the period when I believed I was getting the placebo.
I hesitate to get too excited at this time because I don't want to jinx it.
If I continue to have regular BMs at the same time every morning, then It appears they have found a compound that can begin to clear out years of accumulating gunk within a few weeks (at least in me.)
Let's hope you get the real thing, too. If you do and if your experience is Similar to mine, then this may be a big deal.
It could be big, but you're right not to get too excited about it just yet. So what happens now? Do you stay on 9 pills for the rest of the time?
Took 9 pills again this morning. It triggered both diarrhea and throwing up. Ugh. I don't think throwing up comes with the placebo effect, so clearly I have the real thing. I haven't thrown up in 50 years, so this morning was a refresher course on how unpleasant it is.
It's the weekend, so I can't get official permission to downgrade the dose tomorrow, but I'm going down the 6 pills.
Isn't throwing up our body's way of saying, "Whatever it was you just took -- don't do it again."
This means we should expect there to be 2 sides to this coin.
As they had cautioned about the same thing while upping your dose, this was very much expected. May be they bring your dose down.
on clinicaltrials website they have mentioned following as the primary outcome measure
"Specific treatment related events of recurrent vomiting, recurrent diarrhea, abdominal pain, and hypotension will be assessed with respect to grade and frequency of occurrence.
"
clinicaltrials.gov/ct2/show...
Thank you, again.
I'm going to email the medical director and explain that I'm not inclined to spend the 1st few hours of every day with diarrhea and vomiting, so I assume they have to bring it down?
Well, I guess they're pushing the boundaries. That's part of the study after all. Since they had been increasing the dose by 3 pills every 3 days, it's not a coincidence that this time they increased it by only 1. It likely means that they've seen this threshold before and they're verifying it. I'm sure they'd want you to cut back. It's a little shoddy to not have a 24/7 number to call though. I hope you're feeling better soon if you aren't already.
They were increasing by one pill every 3 days. (6 pills for 3 days, then 7 pills for 3 days, then 8 pills for 3 days, etc.)
In fairness to them, they do have a clinical practitioner Assigned to me who I can contact at any time And who, as it turns out, I end up speaking with every day. I just got off the phone with her and she wanted me to go down to 8 pills/day and when I was resistant, she suggested 7 and we compromised at 6.
I Asked her if she didn't agree that stomach pain, vomiting, and diarrhea is the body's way of telling us I'm overdosed.
I wish I didn't feel like cannon fodder.
Yes, I agree they should be more concerned about your wellbeing. If the reactions continue after reducing the pills to 6, I would counsel you to stop, or at least try to "compromise" to a lower dose again. This makes me a little less enthusiastic, but I'll do it anyway.
I just got home from my 1st follow-up/2 week evaluation and they did drop my dose to 6 pills/day, but want me to go to 7 tomorrow, which I'm not inclined to do. I just took my 6 for today so we will see what happens.
Interesting. Yes, I think that I would go slow as well. I've always been sensitive to medicines in general, so I'm curious to see how I respond to it. I suppose meds are different though, so who knows?
So you took 6 on Sat and 6 on Sunday and 6 today? And you feel well enough on 6? Did they explain what they think is causing your bad reaction?
I'm wondering what their plan is if this stuff really works well; would we see an immediate increase in dopamine? Wouldn't we have to reduce any meds we're on or feel sick? Overdosing on dopamine isn't fun. I've experienced it and don't care to again. But that's putting the cart waaaay ahead of the horse. Or is it? I'd still like to know, so I guess I'll just ask them.
I was a little disappointed when my neurologist postponed my appointment once, then twice. But if he hadn't, I'm not sure I could've gotten there anyway. I live in the foothills near Yosemite and we've been mostly snowed in for about a week. It should be ok for this Thursday though.
Yes! I did indeed make it to the evaluation, but just minutes after getting home we were hit with a huge amount of hail and wind, plus a lot of thunder that scared the dogs.
I think it went well. They've given me lots to read and I'm supposed to register online. But when I go to register it tells me that my email address has already been taken, so clearly someone has already registered for me. When I click on "Forgot Password" it displays evil red letters that tell me that not all of the required secret challenge questions have been entered, and doesn't send me the temp password that it promised. So I will contact my contact. But hopefully, I will get started soon!
How are you doing? Any more trouble?
their stool & sleep logs don't work either.
9 pills/day = vomiting & diarrhea
8 pills/day = nausea & diarrhea
7 pills/day = slight nausea & loose stool
can't say any other improvements
Wow. This is the first study that I've participated in and it surprises me that they're having so much trouble with the online logging. It's quite a bit confusing. They have me filling out "stool" and "rescue med" logs but I haven't seen a sleep log. I'll have to ask about that. They told me that they had all the poop they needed, so they didn't take a sample, nor do they need any from me. Do they have you filling out any other logs besides stool, rescue meds, and sleep?
I have my second appointment on the 28th, where, if I'm lucky, they'll give me pills that will make me nauseated and vomit. Can't wait! There was one funny thing that happened at my appointment. The assistant and I were waiting for a decision on whether they would need me to send them a stool sample. I'm afraid that I was wearing a geeky 'Star Trek' shirt and we started talking about the future of medicine. The conversation went something like this:
Sally: "In the future, doctors might take stool samples the way they take blood and pee samples now."
Me: "Have you ever noticed that there are never any toilets on Star Trek? Maybe they don't poo anymore?"
Sally: "I don't think that'll ever change."
Me: "Maybe Scotty transports all the poo out of people so they don't have to bother."
Sally: "McCoy could freeze it in case anybody needs a fecal transplant."
Me: "There is a lot of radiation in space that could mess up gut biomes."
Without missing a beat, Sally said: "Ooh, so that's what 'captain's log' means!"
That's the funniest thing I've read in a long time. You should be a comedian. Other than MJF, you'd be the first PWP standup (fall down?) comedian. You'd shake things up. Ok, ok, you do the comedy! Thanks for the laugh, though, much appreciated.
Ha.
I have the same logs you.
It is somewhat disconcerting that a company that is using a person ia a guinea pig for experimental drug can't provide a competent report form.
The other piece of questionable competence is even taking a sleep log because IMHO a person doesn't know what time they fall asleep. I got a fitness tracker and before my wife would read me the data, I would try and guess what it would say, and the only consistency is that I was never accurate. There's good sleep trackers for $39 which they ought of provide the trial participants even if only during the trial because otherwise, sleep data is worthless. I sent them a politely worded email pointing this out and never heard back from them.
Be careful of what you wish for. I'm not big on diarrhea and vomiting, myself. I find that it worsens all my other symptoms.
Marc
I just figured out the sleep log. When I log in just after getting up, the sleep log shows up. Then, just before I go to bed I log in and the stool and rescue medicine logs show up. So it was my error, not theirs, except that I don't think they told me about logging in twice a day. Are the logs not showing up for you, or do they show up but don't work?
They are showing up, one at 5 AM, one at 6 PM, but after I input the data, it is not recognized and says I didn't complete the form.
So what results have you got so far?
Strange it thinks you haven't completed the form. I suppose you've thought of this, but sometimes the data input fields extend out of view to the right. I have to scroll over to see them.
I haven't gotten the pills yet. They delayed my initial appointment so many times I wasn't sure if it would ever happen. I go back on the 28th, hopefully (I guess), to get the pills. So I'm just enjoying the experience of not being able to take a laxative whenever I want to.
Yeah, I've examined the log thoroughly many times and it just does not work. They could have just used Excel. The nurse I talk to every day created an "enable editing" log in Word, so I fill that out now.
I did get permission from them to take my dose with yogurt and oatmeal to deal with the nausea. Today's the 1st day of that. We'll see how it works.
I must be a prima donna because I find being nauseated pretty distracting.
Was curious to know about the latest status, how much dose was finalized and how are the results so far
The primary measure is constipation which for me has been an issue. It completely eliminates that in about 2 hours.
No other clear benefit except I thought I felt a little better after a few days, but I don't know if that's still true.
I've been going between 7 & 8 pills/day of 25 mg per. 9 pills has me throwing up with the added bonus of diarrhea. 8 pills is diarrhea and nausea, 7 pills - for me - is normal bowel movements and little nausea.
hopefully the other benefits will appear in a few months as well. It will take some time due to the theoretical mechanism of action
How come/can it work for constipation in 2 hours? Do you know the half life of Trodusquemine?
Unfortunately the drug profile is asking for 47£
adisinsight.springer.com/dr...
$50 for information???
>> I've been going between 7 & 8 pills/day of 25 mg per...
The original idea was to have 2 non-placebo cohorts of 75 mg and 150 mg. 8x25=200, so they're exceeding what they told both of us? I just wanted to confirm that.
Also, I'll heartily agree that being nauseated sucks and I'm not looking forward to it at all! I've always had a sensitive stomach, so this should be fun. I may be lucky to get 1 pill to stay down.
Where did you read that? When you say, "the original idea..." do you mean that's what was anticipated they would do or do you mean that's what the claim is in the trial document or some other official pronouncement?
A month or so ago you wrote: "Here is your math puzzle for the day. One cohort get 75 mg, one cohort gets 150 mg, and one cohort gets the placebo. Why are the odds 75% and not 66%?"
So when I went for my initial visit I asked a few questions about what else was in the pill besides ENT-01 (they didn't know but would find out for me), how long the trial would last (69 days beginning on the 2nd visit), and what the odds were that I'd get the placebo (25%). So I guess I assumed that the 75 mg and 150 mg amounts were also correct.
I'm looking through the paperwork they gave me and I don't see anything about dosage, just that they will instruct you on how to find the right dose. But does that mean that the 75% getting the real deal will all be told how to find the right dose? If they give me the placebo will they pretend to help me find the right dose? It's not making a lot of sense yet.
Also, even though they told me that the study would last 69 days, the papers they gave me say: "... to study the effects of ENT-01 for up to 25 days..." Maybe the discrepancy has to do with the "follow up period".
I have Parkinson's. I cannot be expected to remember what I set a month ago. Ha.
I go back and find it and then raise it with them just in case an administrative person has made a mistake and is overdosing me.
If you get the placebo, I don't believe they will go through the charade of trying to adjust the dose because -- based on what? Placebo people won't have complaints to raise.
I wish somebody would invent a reliable method for us to figure out what our progression status is instead of just guessing from one day to the next. I suppose the UPDRS does that, but I only see my neurologist twice a year and I want to know if Trodusquemine is doing anything. Not knowing where I am is an ongoing frustration.
That "hope springs eternal..." interferes with my objectivity.
Their PK sub-study is meant to "... evaluate the effect of ENT-01 on the blood levels of levodopa..." So if that goes up, it's telling them that the gut is producing more? But does the gut produce levodopa or dopamine which is also used by the body? I've had PD for over 10 years and I still don't know exactly what's going on. It's not measuring the level in the brain, obviously. I do know that dopamine can't cross the blood-brain barrier, while levodopa can.
I think there's a lot of dopaminergic neurons throughout the intestines and the enteric nervous system. We produce levodopa and dopamine, but I don't know if levodopa is produced in the intestine. It's bio synthesized from L tyrosine.
I believe if you're going to do the PK sub study, you'll be submitting several stool samples. Oh fun. I signed up for it, but they wouldn't let me mail in the samples and the trial location is 75 minutes from me so I dropped out of that study. I didn't want to spend 2 1/2 hours driving a gram of poop somewhere. I was afraid somebody might find out.
Plus, there will be times when you have to keep your sample in your refrigerator. Hopefully your wife is not a real creative cook who likes to mix a lot of new ingredients.
Ha! Yummy! My wife bought me a box of oatmeal for valentine's day. That's the extent of her creative cooking. I got her a card. Both the oatmeal and card were mushy, so we're even.
They have two sub-studies; stool and PK. I was told that the stool study had enough volunteers (because who wouldn't?), but I've tentatively signed up for PK. For this pharmacokinetics study, they'll draw my blood 4 more times. They'll analyze the blood samples and test for the level of levodopa.
I think you should not pull out of the study. It will definitely benefit you
Yes, I will probably see it through. But I just realized as I was re-reading their description; they'll take four samples during each of the next three visits! That's a lot of poking! Fortunately, they told me that I have easy to poke veins, so they shouldn't have to keep trying like some horror movie.
They don't want me to take any levodopa until I get to the visit, then they'll draw my blood just after I take my levodopa and just before taking ENT-01, then 20, 40, and 60 minutes after that.
iqbaliqbal,
You've indicated a couple of times that this trial will be beneficial to us. Why do you think that?
I am quite hopeful for the effectiveness of this drug , as the theory behind it's expected mechanism of action is quite convincing. As per ENTERNIN website
"Kenterin has the remarkable property of entering the nerve cell, attaching itself to the nerve’s membrane, and dislodging αS. If αS can’t bind to a membrane, it can’t form aggregates. It’s that simple. There are no other known drugs on market or in development that act via this mechanism of action."
Therefore I would suggest you as well not to give it up so early. They have the most logical explanation of Gut - Brain axis
Thank you. Your confidence and opinion means a lot to me. This is the only trial I've been excited about (that is close enough to participate) in 5 years. I have another appointment tomorrow at 9 AM. I will explore trying to get in one or both of the sub studies. After all, driving for 2 1/2 hours several times to deliver my poop is a small price to pay for some relief.
What I find remarkable is that this drug causes a bowel movement usually within 2 hours of administration. We expect that from a laxative, but not from a pharmaceutical unrelated to laxatives.
PS. You can confide in me. I won't tell anyone else. How many staff do you have working for you to read and understand all the reports you post?
Marc
Ah. Thanks. I apparently mixed up the 2 sub studies. I have another visit Thursday, so I'll ask her about it. Having more levodopa in your blood can only be good.
Has anyone determined if ENT-01 is an antibiotic or something else? If not I will ask.
JAS9, Looks like only you, me and iqbaliqbal are interested in ENT-01. He/she probably knows. He/she knows everything.
Both the Sci of PD and Wiki use identical language, so they got up from the same place. They say, "an amino derivative of a sterol, especially any of a group of such antibiotics obtained from sharks"
What does that even mean?
I looked for that answer last month and could not find it definitively. I don't think it is, but that it mimics the action of an antibiotic, that it is a peptide and some peptides can be antimicrobial.
Why do you ask?
I had my 3rd evaluation yesterday. My next is March 8 which will be the last day I take the drug. They did reaffirm that I will be invited into their one-year or two-year long study that begins in October.
All of a sudden everything stopped happening. No more bowel movements. They said I could take the drug with a small amount of food because I was getting nauseated. Perhaps that made a difference. Tomorrow I'll take my dose on an empty stomach.
I asked because many antibiotics can kill off gut bacteria. I've been working to improve my digestion and losing a few billion of my new friends would make me sad. My 2nd visit is in 6 days and I should get my 1st pills.
They told me on Monday to stay on 8 pills the rest of my trial. I'm anxious to see how it affects you.
Yes, "anxious" covers it. Good luck to both of us!
Today I went to my second visit. They gave me some pills and lots of instructions on how to use them. I believe that they are applying what they've learned from your experience, MBAnderson. I'm taking 6 pills for 3 days. If in that time I have 2 complete BMs in a row, I just keep taking 6 and that is my dose for the remainder of the trial. Otherwise, I go to 7 pills, repeat, etc. until I eventually have 2 BMs and find my dose.
I did ask them if this is an antibiotic, and she said 'no, it's a laxative'. Well, I guess they don't want to raise expectations, but I think we're all hoping for more than that.
The 6 pills that I took today had a nearly immediate effect. Things are churning away a little already! The hardest part for me was having them draw my blood; she had to poke me 3 times. Fingers crossed.
If it is a laxative, I'm seriously disappointed, but since it's working immediately on you too perhaps it is? What happened to all that complex explanation about displacing a/syn from synapse membranes?
It does sound like they're more flexible with you.
Things have settled down in my gut this morning, even after I took my second dose of 6 pills (yesterday at their office and this morning). My 4th day w/o a BM. Yay! She told me that I should no longer use the rescue meds, and to rely only on the pills. Can't say I'm happy about this yet, but we'll see.
I suspect that they learned something in the previous trial; the first marker that shows that it's present in the gut is that it restarts BM, so that's what they're looking for first. This trial is to test to see how well it's tolerated, at least in part. Just some thoughts.
Ha, speak of the devil. As I was writing this, my gut started rumbling again and... BM, my old friend, paid me a visit. If I have one tomorrow, I guess my dose will stay at 6.
You do know, of course, you can't not take the rescue medicine (on the 4th day?)
I have heard that impaction surgery is no fun -- could be wrong.
HAha, no I think you're right that impaction surgery is no fun. Fortunately, I don't have that problem today. If I get to day 4 again, I'll go ahead with the rescue meds no matter what they say.
Here's something that I find interesting: my neurologist evidently runs quite a few of these trials, and he has a small staff that helps him. They don't have anyone else come in as a consultant or contractor or anything like that. From what you said, that's different than what you've experienced. It makes me wonder if my support team here even understands what's going on, or if they're just telling me what they've been told to tell me.
I know that the placebo effect can be a big factor with PD, so I guess they're doing whatever they can to keep us from expecting a lot right now.
Lyme patients almost always have serious gut problems due to LD attacking it, so my theory might still be valid. Many Lyme patients also develop "Neurological Lyme Disease", so it's not a stretch that the gut notices LD attacking it, creates a-S to protect itself, and sends more a-S to the brain to help it fight off LD (which can get through the blood-brain-barrier). In my case, that might've actually been a "better of 2 evils" decision since I don't seem to have symptoms of neurological Lyme.
Good luck tomorrow at your evaluation!
PS. Plus, they claim to restore dying, dormant and damaged neurons throughout the ENS and the vagus nerve.
That this company or its predecessor tried out perhaps this drug for obesity and diabetes without going to market, concerns me.
Thank you. What is file bin? How do you find all this stuff ? There were no identifying marks on the paper.
How do you go about making the connection between a molecule in the cartilage of the dogfish shark and Parkinson's?
The pre-clinical study results show that the synthesized steroid, squalamine, prevents and eliminates alpha-synuclein build-up inside neurons by unsticking the protein from the inner wall of nerve cells, where it clings and clusters into toxic clumps.
Source: gumc.georgetown.edu/magazin...
From their official webite:
"We are assessing ENT-01’s ability to deliver the following outcome in those with Parkinson’s Disease:
Correction of constipation
We will also be exploring ENT-01’s ability to deliver the following outcomes:
Improvement in sleep architecture
Improvement in temperature regulation
Improvement in mood, with reduced depression and anxiety
Improvement in cognition
Improvement in nocturnal visions/delusions/hallucinations"
OK, this trial is over and here's an update from my perspective as a participant. They were looking to see if constipation was relieved. In my case, it was improved to nearly 100% normal after the first week. In my case, constipation has remained 'cured' even after stopping the medication. It's been over 3 weeks, so I'm hoping it continues.
This trial also gathered data on sleep, but it seemed to be a secondary focus. Just before leaving my last office visit, they asked me if I would be interested in a follow-on study that would look more closely at sleep benefits. I probably will, but it starts in a few months (I believe).
At the end of each office visit, a neurologist always tested me (pull test, walking, etc.) At the last visit, he told me that, in his opinion, I was doing better than when the trial started. My opinion is that there are far too many triggers to be able to tell. He only saw me every 2 weeks or so and I'm not convinced that he could tell for sure.
Also, I'd stopped all of my suplements for the 2 month trial, including B1. Glad to get back on it.
Why not take the over the counter Squalamine?
That might be an option although I haven't tried to source it. But the answer to your question is risk. The natural form of squalamine is from sharks and has no equivalent in humans. In that form, it's only been tested on worms and such. Some of the researchers involved in those experiments have modified squalamine, giving it the catchy name "ENT-01". You could argue that the modifications might not be necessary and that natural squalamine might be just fine; evidently, some people take it as a supplement. The modifications might just be a way of making it patentable.
But, love it or hate it, this is how the system we have works (or doesn't). Someone has to come up with the money to test safety and efficacey. If they want to play, this is how it's done. There is a risk reguardless; it's unknown what might happen if ENT-01 succedes in "displacing all of the misfolded α-synuclein in the lipid vesicles, which are known to stimulate nucleation and find that this compound displaces α-synuclein from the surfaces of such vesicles. " In other words: Will replacing the α-synuclein in the lipid vesicles (a transport system) cause something else to 'break'?
parkinsonsnewstoday.com/201...
ENT-01 has at least gone through "two preclinical animal models of Parkinson’s Disease as well as a Phase 1/2a study completed in 2018." Plus, I guess, phase 2b was at least a partial success based on my experience. So, some formal human testing has been carried out using ENT-01, but not with natural squalamine.
prnewswire.com/news-release...
"The study evaluated the safety, tolerability and efficacy of an orally administered synthetic derivative of squalamine (ENT-01), which is not absorbed into the bloodstream. The compound acts locally on the enteric nerve cells of the gut, stimulating gut motility and altering afferent neural signaling from gut to brain. It has the potential to ameliorate some or all symptoms of Parkinson's disease, including constipation, disturbed sleep and hallucinations, and to modify disease progression.
"Synthetic squalamine was recently shown to prevent the buildup and reduce the toxicity of alpha-synuclein, implicated in the pathogenesis and progression of Parkinson's disease. The compound was shown to displace alpha-synuclein aggregates from the inner wall of nerve cells and to prevent the paralysis that develops in C. Elegans worms engineered to produce alpha-synuclein in its muscles. The results were published online in the Feb. 7 edition of the Proceedings of the National Academy of Sciences (Perni et al, PNAS Vol 114, no 6, 2017, doi: 10.1073/pnas.1610586114). Links to the article and to the press coverage can be found at the Enterin website, enterininc.com."
But then I found this: "Squalamine has been used in clinical trials for eye disorders and the treatment of cancer. Its safety profile is well established, meaning it could rapidly be tested as a new class of medications for the treatment of various viruses, such as hepatitis, dengue or yellow fever."
medicalnewstoday.com/articl...
And a source: positive-works.com/squalamax/
Ah, but wait just a minute, because then I found this: casewatch.net/fdawarning/pr...
Not what you're looking for?
You may also like...
Patient enrollment begins in study of novel light therapy for Parkinson’s disease
The first 100 patients have been enrolled in a clinical trial investigating a novel light therapy...
Gut bacteria could improve symptoms in Parkinson’s sufferers, study suggests
Gut bacteria could improve symptoms in Parkinson’s sufferers, study suggests...
Gut microbes may be the root cause for PD
Major new piece of research --
Short and sweet:...
LL-37, a natural antimicrobial molecule present in the brain and gut, Suppresses Alpha-synuclein Clumping in Parkinson’s
"LL-37, a natural antimicrobial molecule present in the brain and gut, selectively binds to harmful...
Another Study Suggests Taking Vitamin B2 and B7
A new study compared the gut microbiota of people with Parkinson’s disease in five countries....
Related Posts
Fecal Microbiota Transplantation (FMT), Is It A Nearer Term Future Treatment For People Living With Parkinson's Disease?
PS128 VS Bacillus Subtilis PXN21- Vitamin B12 Supplements May Help Slow Parkinson’s Progression, Study Finds
Fecal microbiota transplantation (FMT) therapy for Parkinson’s disease - A preliminary study in China
Could Butyrate Be Bad for PWP? (MIT Study)
