A Drug Shown To Actually Slow Progression in Humans

[jimcaster]

The team identified 2880 Parkinson's patients taking one of the three drugs that target PGK1 and a comparison group of 15,409 PD patients taking tamsulosin. Using ICD-9/ICD-10 medical codes to track PD-related diagnoses and hospital or clinic visits for all the patients, the data suggested that under real world conditions, terazosin and related drugs reduce the signs, symptoms, and complications of Parkinson's disease.

sciencedaily.com/releases/2...

[MBAnderson]

Good fine, Jim.

Another 1 of those choices between 'there is no evidence,' but there is a compelling rationale.

[park_bear in reply to MBAnderson]

The study actually presented some pretty good evidence.

[MBAnderson in reply to park_bear]

I agree. I meant FDA approval for the indication of PD.

I already take tamsulosin and the evidence is good enough for me to switch -- so I see no reason not to.

[marnegro in reply to MBAnderson]

I agree. Past month I was prescribed Tamsulosin for benign enlarged prostate. I didn't start because I want to keep my body drug free as possible (unwanted med side effects) it's enough to me dealing with C/L and by now it doesn't bother me to have few additional trips to the bathroom because of the prostate issue. Now I'm motivated to give it a trial at least for a year...… I already sent an email to my doc this morning asking to switch for terazosin...…...

[JAS9 in reply to marnegro]

Exactly my situation. I sent a link to my neurologist. This sounds more promising than nearly anything I've seen in the last few years. The fact that they have real-world data that not only tells them that it probably does something for PD, but also that it's relatively safe, is all good.

[marnegro in reply to JAS9]

Hi guys, it may be a little bit more complex than it looks....my GP doc already sent to my pharmacy a prescription of the pill starting at 2mg. She advise me it's a very potent med for lowering Blood pressure and wants me to monitor BP daily for 30 days. If BP readings are acceptable and urine flow still needing to improve she may increase to 5mg the dose I read in the proposed paper for trial will be administered to PD patients. I will take the challenge and keep a close look on my BP because I'm a long timer PWP (13 years) and we get use to have BP changes because of PD meds....

[sharoncrayn in reply to MBAnderson]

MBA

12/03/2020 (looking at your comment 1 year ago prior to FUS)

TZ--- Interesting "repurposed" drug but a long shot. Cheap generic. PGK 1 enhancer. Mice, flies, and rat study baby although they did scan the PPMI database (very small sample)and the IBM data base (RR=.76 for TZ which is good)

Are you still taking it? How long did you take it? how much 1-2-10 mgs (low is better)? (it is biphasic)

--- if not, why not?

Did it mitigate/change in any, shape, or form your motor problems?

--- which ones specifically?

Adverse side effects?

Probably more relevant for males with PD than females.

Sharon

[MBAnderson in reply to sharoncrayn]

Yes, I still take it, but for nighttime urinary frequency. I have not detected any change in motor symptoms. No side effects. 10 mg.

[sharoncrayn in reply to MBAnderson]

MBA

Thanks so much for the feedback ...

TZ is not prescribed very frequently here by Oncologists for BPH. Nor have I seen many participants in my CTs identify it as being used. I was holding out hope you had some positive response in terms of motor problems, which they were proposing. Disappointing since it is a very cheap generic.

Any off label drug or supplement you would consider "effective and worth taking consistently" for reducing motor problems? I ask because you have probably taken everything that might work.

Sharon

[MBAnderson in reply to sharoncrayn]

I would consider taking Exenatide and/or a drug similar to terazosin which I think is called doxazosin, but I'm not sure that is the name. (I don't have BPH.) I'll rummage through my notes and see if there's anything else.

[MBAnderson in reply to MBAnderson]

PS. I do not think doxazosin is what I was thinking of.

[WinnieThePoo]

2 consecutive posts on this one. (Prostate drug) Sounds hopeful, although a way to go yet. Just what has happened to exanatide and the other glp1 receptor agonists scheduled for phase 3 repurposed trials?

[MBAnderson in reply to WinnieThePoo]

I agree with you, the odds are high that it will never be FDA approved for the indication of PD and it'll take several years for that failure/approval to occur, so do you see any reason I should not switch from tamsulosin?

[WinnieThePoo in reply to MBAnderson]

The main reason would be a prolonged and painful 4 hour erection

More seriously, every drug has side effects and interactions, so it would depend on your personal circumstances and you should consult your doctor.

Also - it may not just be a case of getting FDA approval. It may not work. I need to do something about my blood pressure and am taking Ramipril (an ACE inhibitor) - with barely adequate results. I declined Amlodipine (a calcium channel blocker) which was my cardiologist first pick - because my PD onset was coincidental with starting Amlodipine, and my "cold turkey" cessation of the drug gave me probably my worst 3 weeks of PD symptoms to date.

I could have pushed for Isradipine (another Calcium channel blocker). My French GP is prepared to prescribe it. I didn't originally because I didn't want to confuse the SPARK trial (even though the trial didn't prohibit me using it). Maybe the trial knew a thing or two, because the phase 3 trial for Isradipine found it had no statistically significant effect. So I could have been taking a drug with side effects of its own that didn't affect my PD.

And Isradipine was being trialled as a repurposed drug - like terazosine - on the basis of an analysis of slower PD progression in humans taking this medication. (ie it wasn't rodent based research which first put it in the spotlight)

That said - it's also used in treating hypertension. Any reason I shouldnt switch from Ramipril? (Apart from the 4 hour erection)

[MBAnderson in reply to WinnieThePoo]

You must not have gotten the memo re the Isradapine trials were ended because it failed to show a difference.

[WinnieThePoo in reply to MBAnderson]

No - I knew that. At the time SPARK weren't bothered about me taking Isradipine , the phase 3 Isradipine trial had finished but not reported results. Now we know the result is it didn't work - so the SPARK trial attitude turned out to be correct

[sharoncrayn in reply to WinnieThePoo]

Israpidine ---- Phase 3 DOA

Israpidine PD research goes back well before 2010 and before any significant "human" trials were started. The earliest pre-clincial Phase 1 trial (2010) should have raised questions (but it obviously didn't). "Heavy" dosing (20 mg) with humans was a DISASTER.

We never learn, or never consider the "probabilities, or the paycheck is more important than raising questions, or most likely, all three.

Sharon

[MBAnderson in reply to sharoncrayn]

What were the problems with Isradapine -- which, of course, I also took.

[sharoncrayn in reply to MBAnderson]

MBA

re: israpidine.....

From Sumni, et al study of 2010....52% of participants experienced TOLERABILITY events at 20 mgs which is beyond my comprehension in that phase 1 "safety" trial. 52%! IOW, half of the early PD patients (n=31) couldn't take it at that dose level due to adverse events.

Phase 2 tolerability was even worse at 20 mgs, but let;s journey onward and upward.

Failure in its Phase 3 (early PD only, not on L-dopa, no hypotension, no CVD, 336 sample size, 3 years long) was due non-existent differences between intervention and placebo (based on UPDRS score) not adverse events. Sumni stayed far away from using the problematic 20 mg. dose.

Actually the placebo arm in phase 3 did better!

So much for the hype...DOA from Phase 1 onward.

Sharon

[lingfield222 in reply to WinnieThePoo]

Hi, I have been tracking this as my husband (with tremor dominant PD) is under the care of the neurologists at University College London (UCL). He is signed up to their Movement Disorder register and they have notified they will be starting the next phase trial (larger Phase 3 ?) of Bydureon (aka Exenatide) over the next 2/3 or so months. This is being overseen by Prof Thomas Foltynie.

ucl.ac.uk/ion/research/cent...

This trial will take two years and they haven't started recruiting participants yet.

I wonder if exenatide is being trialled anywhere else in the world?

[WinnieThePoo in reply to lingfield222]

Thanks. That's really interesting. It's been a long time getting this one set up but good to know it will get a phase 3

[MarionP in reply to WinnieThePoo]

The various studies I looked at, starting with the one Jim noticed (very good catch) suggested that only terazosin shows the mechanism that results in a benefit, which is probably why the other two did not show promise. The evidence here was small but seemed realistic at its scale, it's good evidence, just that it is a single small narrow study, but the evidence therein is fairly direct.

I know that Hytrin is also, as an anti-cholinergic, often prescribed off label for some forms of excess sweating. The main risk of side effects stem from that, being anticholinergic. For some, that is sometimes an advantage.

Only question is whether it has ever been tried in females, who once in a great while get PD.

It shows promise as long as the person is not in need of the older class of antihypertensives, its side effects and interaction risks are already well known. It would take some kind of money at this point to have it re-purposed, but physicians are free to prescribe off label anyway.

[WinnieThePoo in reply to MarionP]

At least you won't have to worry about priapism as a side effect 😉

[jeffmayer]

Looks like there's hope after all?

[LAJ12345]

Here is the structure of terazosin out of interest.

google.com.au/search?q=tera...

[sharoncrayn]

I am familiar with TZ given cancer drugs are in my wheel house.

With empathy for those who feel TZ is a possible remedy to slow PD progression, I would strongly suggest taking 2-3 hours out of your day to read the study very, very carefully. (not the news releases).

This study is based completely on the correlations found in two supposedly reliable data bases and some mice models. Potential validity for sure, but not particularly strong statistically or realistically.

Males can obviously start to take this drug if they have benign prostate issues or even PC ... if they believe this study and their physician does as well.

For others, I would suggest at least waiting for the results of the limited TZ CT, which started recruiting in April, which is another weak placebo control trial.

My concerns with another placebo control CT? Why not try all PGK1 drugs (3) head to head with PD patients who already have severe (or even moderate) UPDRS scores? NO other drug therapies allowed. 2 year time frame with measurements every quarter. Stop it if progression is seen.

This approach gets to the heart of the matter; placebo control groups without UPDRS measurements go nowhere and result in time delays to get the drug approved for PD, if ever. Can we wait another 10 years for an FDA approval of a PD drug?

Sharon

[WinnieThePoo in reply to sharoncrayn]

"NO other drug therapies allowed"

Surely you are not proposing a phase 2 CT lasting 2 years for PD patients with severe PD scores unmedicated for the duration of the trial? You may find difficulties with recruitment. The trial iqbal refers to in his post, although it calls itself a phase 2, is very small, short, and not testing dosage, and looks like a phase 1 really. But its fairly short duration and happening now, and in my limited recent experience of PD trials, that is greased lightening. Presumably a funding premlinary to organising a proper multi-centre trial with a much larger cohort.

[sharoncrayn in reply to WinnieThePoo]

Winnie:

Thanks for your comment, but I think you completely misunderstood the purpose of my post. I obviously should have done a better job, but I don't always have the time.

KEY POINT --- We have a bottle neck in the PD drug pipeline, and it is called the US FDA and its approval process. This bottle neck has to be removed or reduced whenever possible.

MY STRATEGY --- With "repurposed drug" CTs, I see absolutely no reason to go through placebo control trials which prove nothing. Many of these drugs have gone through multiple trials.

Now, if Iowa and its funders are claiming TZ is a stand alone drug for PD, then go head to head with 1) sinemet and 2) rytary (I would avoid stalevo.) Or if they want to really prove their point, go head to head with the other PGK1s. Regardless, you have 3 cohorts. Forget the placebo

If it isn't intended as a stand alone, which I doubt it would even qualify as one, then couple it with both drugs with only two cohorts and run it as I said for two years. You NEED sufficient time to elapse to see if it really works or not. If progression is seen at any quarter by objective measurement, stop the CT.

I hope some of what I have said helps

By the way, good luck with your various medical conditions.

Sharon

[WinnieThePoo in reply to sharoncrayn]

Sharon.

Thank you for a comprehensive explanation and your good wishes.

You are correct. I had misunderstood you.

Surely the claim is not that this is a stand alone.

It is suggested it slows Progression. Not that it regenerates already dead neurons. Like the BIIB054 I am trialling the hope is that it stops the disease process (a-syn misfolding?) But still leaves a need for symptomatic therapies, to the extent symptoms are due to permanent damage to neurons

As such, the placebo control remains relevant. There are no current drugs against which it would go head to head for progression.

It does not need to halt progression. Slowing it by a statistically significant measure would suffice. So I wouldn't stop the trial if there is any progress at all after just 3 months. I think it needs 2 years to assess an effect on rate of disease progress. But statistically significant improvement, in the absence of any competition can only be measured against a placebo.

And I see no merit in comparing the drug combined with one symptomatic co-therapy against the drug and another. Existing symptomatic treatment can continue without confusing assessment of the disease modifier providing the trial cohort is large enough.

Assessment of progress is best made without normal meds, as in the Bristol gdnf trial or the exanatide trial (or my SPARK trial)

[SilentEchoes in reply to sharoncrayn]

Why not Viagra? I'm a female and have taken Flomax for kidney stones pre-MND diagnosis. I have autonomic dysfunction and had come across research supporting the use of Viagra for vasodilation. What are the pros and cons?

Thanks in advance for sharing your opinion. The upside is I don't have to worry about 4 hour erections. 😉

[jimcaster in reply to SilentEchoes]

Ha! I believe there must be a huge number of men with PD who take Viagra. If there was even the most tenuous anecdotal evidence that Viagra slowed or stopped the progression of Parkinson's disease, we would have heard about it by now.

[SilentEchoes in reply to jimcaster]

We've been joking about Viagra, but there actually is evidence for off label use. I was investigating it for its vasodoalation properties.

Sildenafil (Viagra) is a phosphodiesterase type 5 inhibitor that prevents cGMP breakdown, thus boosting vasodilation and erection. The vasodilatory effects of sildenafil also make for interesting off-label uses, including the treatment of heart disease and Raynaud phenomenon. Notably, the “little blue pill” is already approved for pulmonary arterial hypertension.

Similarly, Terazosin relaxes your veins and arteries so that blood can more easily pass through them, and is used alone or with other drugs to treat high blood pressure (hypertension).

I just found out that cannabis is a vadsodialator, maybe we should skip the pharmaceuticals.

[Gioc in reply to sharoncrayn]

Sharon I agree.

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P.S. a little less acronyms would be appreciated for a more fluent reading.

[MarionP in reply to sharoncrayn]

head to head will never happen again, the drug companies long ago realized that it was "bad for business" and influenced congress and administrations, using many pretext explanations, to disfavor such comparisons, starting in the 1980s or so and continuing today as standard practice.

[jeffmayer]

I still believe a positive mental attitude and exercise are the best remedy

[KemptonD]

The recently published result of of study of existing databases (of men) finds lower incidence of PD in patients on Terazosin. Not found for Tamsulosin, reviewed also as a control.'These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.' This may be useful if you are reviewing medical with specialists. I recently was found to have a normal prostate and I don't have hypertension, so I am thankful for that. But I will be interested to learn anecdotally as well if Terazosin has helped others 'manage' or slow PD.

t.co/hqp8bjaOw5?amp=1