A New - Old Drug That Is Making a Major Difference for Me

[reverett123]

I have long been convinced that there are nuggets of gold buried in the massive accumulation of 40 years of research that has built up since Ldopa took the stage. Common sense tells me that it is not possible for such a huge amount of data spread over several disciplines to build up without overlooking something invaluable. So, I look and I think that I have found something.It has made major improvements for me, at least, and continues to do so now, a month after starting it. There has been improvement across the board for me. Particularly impressive has been increased strength in my lower legs, greatly decreased OFF time, a decrease in medication, and a general increase in stamina.

This wonder drug was looked at in the late 1990s and found to increase dopamine in the striatum of the rat by 2.5 times. Most exciting, a small clinical trial tested its effect on seven human PD patients with very positive results.

And there the research stopped.

The drug is an ACE inhibitor called "perindopril" and it is extensively used for hypertension. Since I am already on similar medication, it was rather easy to convince my GP to indulge me. This is an "off label" use of a widely tested drug. I urge you to review the research and discuss with your own doctor a possible trial.

The following excerpts begin with the Pubmed ID Number to save space-

PMID:9048778 - Angiotensin-converting enzyme modulates dopamine turnover in the striatum.- "One week after perindopril treatment, striatal dopamine dialysate levels in the treated group were markedly elevated compared with control values: control, 233 +/- 43 pg/ml; perindopril, 635 +/- 53 pg/ml (p < 0.001)"

PMID: 10386973 - Effect of chronic angiotensin-converting enzyme inhibition on striatal dopamine content in the MPTP-treated mouse.- "Our results demonstrate that perindopril is an effective agent in increasing striatal dopamine content in an animal model of Parkinson's disease."

PMID:10800878 - The angiotensin converting enzyme (ACE) inhibitor, perindopril, modifies the clinical features of Parkinson's disease.- "After a four week treatment period with perindopril, patients had a faster onset in their motor response to L-dopa and a reduction in 'on phase' peak dyskinesia, p=0.021 and p=0.014 respectively. Patients also reported more 'on' periods during their waking day in their movement diary, p=0.007. Perindopril was well tolerated without any significant postural hypotension or renal dysfunction."

[CPT_Tom]

Rick

Many thanks for your excellent post. I have asked for a response to this from our Head of Research, Dr Richard Wyse, who responded as follows:

I've had a quick look at this. It's clear that Perindopril has shown promise in animal models of PD, and also in a small 7 patient study about a decade ago.

I can see why, biochemically, this class of drug might act beneficially in PD. Rick's enthusiasm has to be balanced with the outcomes of the study by Christian Meier (remember he lectured at one of our conferences) who showed in his paper " Use of antihypertensives and the risk of Parkinson disease. Becker C, Jick SS, Meier CR. Neurology. 2008 Apr 15;70(16 Pt 2):1438-44." that people taking calcium channel blockers (such as Isradipine, which is now under clinical trials for PD) for their high blood pressure were about 30% less likely to develop PD. They found no such protection in those who instead were taking the same class of drugs as Perindopril rather than calcium channel blockers. OK, this is not the same as symptom reduction in patients who already have PD, but it's an indicator.

The other balancing factor that may be relevant here is that Captopril, a drug in the same drug class as Perindopril, can actually worsen PD A case of Parkinson's disease worsened by captopril: an unexpected adverse effect.

Chang YP, Shih PY. Mov Disord. 2009 Apr 15;24(5):790,

or even induce it Parkinsonism induced by captopril. Sandyk R.

Clin Neuropharmacol. 1985;8(2):197-8. (Shimoda et al found this also in a separate paper).

Taking all this into account, I think we should seriously consider testing this class of drug in PD patients, but would first need to bring in specific pharmaceutical expertise and advice in the use of Perindopril or Captopril before we could make progress towards setting up a clinical trial in PD patients - remember we prudently brought in world class endocrinologists when we were setting up trials using diabetes drugs, i.e. getting expert advice about using diabetic drug classes that were completely new to PD patients - well it's the same here, we would need the experience of the people who have actually developed these drugs and know their idiosyncrasies and how best to develop them for use completely outside their original hypertensive therapeutic indication.

Kind Regards,

Richard"

So watch this space and thank you so much for this contribution.

Any more up your sleeve?

Tom

[compucure in reply to CPT_Tom]

Do you recommend taking Perindopril as an alternative to the existing L-Dopa drug - Madopar - which i am taking? Thanks.

[reverett123 in reply to compucure]

I think that anyone who would recommend anything this early in the game would be foolish as would anyone who would accept such advise. I pointed out that perinderol had been evaluated in the clinic extensively in treating hypertension. That isn't the same thing as saying it is harmless. Among other things, it can destroy your kidneys - in rare cases. It can cause fetal damage, too. We are at a stage of gathering information and trying things

We must be conservative while we take chances. I don't know what I am doing, but I have some ideas to share. But, morally and legally, "recommend" is a loaded word.

Now, all that having been said, let's think about your questions a minute -

Perindopril as an alternative to Madopar Haven't a clue. But it is much like Sinemet, with which I am familiar. And I thinkthat I wpuld have tried it earlier. But I don't know that.

So far as I can tell, exactly seven PWP have tested this drug. I am number eight. I hope to compare notes with number nine eventually.

[reverett123 in reply to CPT_Tom]

Tom-

In the interest of completeness, I am going to post a thread of commentary that I had been running on another forum. I will clip out any possible copyright problems-

reverett123 07-19-2011 09:41 PM

Le Blanc Rodentia - Perindopril test

This White Rat has succeeded in persuading his GP to switch his hypertension medication to perindopril. Perindopril is an ACE inhibitor but is a little special. For one thing, it is one of only two that penetrate the BBB. For another it seems to increase dopamine levels and improve symptoms rather dramatically as the reports below indicate. I took the first one yesterday and another today and I do think that I see a change. I am going to experiment with time of day first. Assuming that my kidney function holds up (the only serious potential side effect) I will keep you all in the loop.

-------------------

1. Aust N Z J Med. 2000 Feb;30(1):48-53.

The angiotensin converting enzyme (ACE) inhibitor, perindopril, modifies the

clinical features of Parkinson's disease.

Reardon KA, Mendelsohn FA, Chai SY, Horne MK.

Neurosciences Department, Monash Medical Centre, Melbourne, Vic.

BACKGROUND: Animal studies have demonstrated an interaction within the striatum

between the angiotensin and dopaminergic systems. In rats, the angiotensin

converting enzyme (ACE) inhibitor, perindopril, crosses the blood brain barrier

and increases striatal dopamine synthesis and release. In humans, angiotensin

type 1 receptors have been found on dopaminergic neurons in the substantia nigra

and striatum. In Parkinson's disease, there is a marked reduction of these

receptors associated with the nigrostriatal dopaminergic neuron loss.

AIMS: We performed a double blind placebo controlled crossover pilot study in

seven patients to investigate the effect of the ACE inhibitor, perindopril on the

clinical features of moderately severe Parkinson's disease.

RESULTS: After a four week treatment period with perindopril, patients had a

faster onset in their motor response to L-dopa and a reduction in 'on phase' peak

dyskinesia, p=0.021 and p=0.014 respectively. Patients also reported more 'on'

periods during their waking day in their movement diary, p=0.007. Perindopril was

well tolerated without any significant postural hypotension or renal dysfunction.

CONCLUSIONS: These results suggest that ACE inhibitors such as perindopril may

have a place in the management of motor fluctuations and dyskinesia in

Parkinson's disease and justify further study.

PMID: 10800878 [PubMed - indexed for MEDLINE]

reverett123 07-25-2011 02:44 PM

Week One

For the first time today I caught myself thinking, "Damn! This stuff may actually be working!" I quickly stifled myself lest the Gods of Placebo be aroused but thought it time to report.

The first days were tough. Perindopril makes my symptoms worse for a couple of hours and I feel like crap, too. This is not a drug for taking when you need a boost. Things were not helped any by my GP's prescription of 8 mg daily when the manufacturer says start at 4 mg and go up to 8 mg after a month to get used to it. So I was a bit disappointed at first. But I twinked and fiddled and have found that 4 mg at bedtime avoids the problems.

I have fixed the problems that I created, but have I gained anything yet? Until today my answer would have had to have been, "Welllll, maybe." After all, it had barely been a week. While I had a feeling of favorable change, it was pretty vague and might have a certain amount of wishful thinking. And just last Friday, a mere three days ago, I had rushed home at mid-day just steps ahead of a couple of hours of "offtime". So I was a little paranoid and was going to be cautious.

Honestly, that was my intent. I don't know how I ended up at WallyWorld. Not just at it, but all over it for over an hour followed by a stop at a grocery store on the way home. Folks, I have pretty much been home bound for the last couple of weeks due to some problems with entacapone. Going up to the mail box in this heat had been a big deal. But today I surprised myself and conquered Mt. WalMart.

True, I did need an hour of recovery when I got home. But it beat collapsing in the floor with the pooches like I would have done a week ago. And tomorrow may be worse. But it may not. And it is true that I have a little dyskinesia. But I am trying to reproduce a bloomin' *40%* increase in the dopamine levels in my brain in one month's time! A little Dk is a sign that it may be happening, so I will start whittling the sinemet and requip down. Already have.

And so, onward - through the fog....

reverett123 07-28-2011 12:57 PM

Serious business

I joke around a bit, but perindopril is turning out to be a very serious matter. I am increasingly pleased with it. Things seem to be improving across the board. Off times have been limited to about an hour at mid-day and even that is dwindling. I no longer feel house bound and am out and about even with this blasted heat. It is an old drug, cheap, and well tested for hypertension. Any GP around can prescribe it if your neuro wont.

reverett123 07-30-2011 05:48 AM

no side effects yet

Other than the problems noted above that led me to bedtime as when to take it, I haven't noticed anything. Also the small study near the beginning of this thread doesn't mention any. My background is a little odd. I studied PD for three years alongside a French surgeon named Anne Frobert, herself a PWP.

Yesterday was the best in a very long time. No "off" time at all until nearly bedtime!

reverett123 07-30-2011 05:56 AM

So why should it work?

Like everything else about this dratted disease, nobody knows, so a guess will have to do. Angiotensin has strong pro-inflammatory action and the perindopril counters that. Since it is one of the few things able to pass the BBB, it is able to go deep into the brain and calm things down. That makes since to me but it is still a guess.

reverett123 07-31-2011 09:28 AM

Yesterday (Sat 7/31) was another good day. No "off"time until evening when I cut short the medication day to see what would happen. Even that was improved. Most interestingly, I experienced a moment of, for lack of a better term, "fluidity" when my muscles worked smoothly as I turned my body. This is hard to explain, but it was as though my body realized that the turn was going to leave me open for a fall, belatedly began to brace for it, and was surprised when it did not materialize.

Another change- My medication cycle has an unfortunate feature. As sinemet comes on I must urinate. But this occurs before motor function returns. The result is that I make regular use of a chairside urinal. Or at least I did until yesterday when I realized that the whole day had passed with the urinal unused.

Found this review of the small study that started this thread:

"esults

Six subjects completed the study - one withdrew with nausea, malaise, and increasing 'off' periods while taking perindopril. After 4 weeks on the ACE inhibitor, 5 of the 6 had a significant increase in the area over the curve for their Webster scores, indicating an increased motor response to their standardized dose of L-dopa. There was a faster onset, and a reduction in 'on' phase peak dyskinesia.

The UPDRS II scores showed that perindopril was associated with improved functional ability in 'off' phases. The patient diaries revealed a modest but significant increase in 'on' periods during ACE inhibitor treatment, which was maximal in the 3rd and 4th weeks on the drug.

While peak dyskinesia scores were reduced, four of six patients had an increase in dyskinesia during the waking day with perindopril. This was probably a reflection of their increased total 'on' times.

There were no perindopril-related adverse effects on blood pressure, postural hypotension, or renal function.

Comment

This study confirmed the concept that an ACE inhibitor can improve the motor response to L-dopa in patients with Parkinson's disease. The drug also increased the proportion of the day spent in the 'on' state, as well as showing an improvement in the functional disability scale used.

Most effective agents in Parkinson's disease induce dyskinesia; perindopril, on the other hand, produced a greater amplitude of motor response to L-dopa with a reduction in peak dyskinesia, i.e. it seems to have an effect beyond simply increasing dopamine release.

The authors of the study point out that the benefits of perindopril were "modest, and not of the magnitude of L-dopa itself". However, the dose was relatively small, and treatment duration was short. As tolerance as good, there is every reason to conduct further studies with higher doses, for longer treatment periods.

Trandolopril, spiropril and perindopril are ACE inhibitors that can penetrate the blood-brain barrier, while enalapril cannot."

reverett123 07-31-2011 10:01 AM

patent

Patents are mind-numbing, but if anyone wants to interpret for the rest of us

Neurogenesis by modulating angiotensin

United States Patent 7858611

reverett123 07-31-2011 04:11 PM

more baseline data

A basic exercise- How long can one stand on one foot? Best out of five attempts. Test during maximum "on" period for the day.

Two days ago I got zero on each foot.

Today I got five on my right foot and six on my left.

reverett123 08-01-2011 04:11 PM

This afternoon it is seven seconds on the right and nine seconds on the left. Also, I skipped a pill at 2:00 with seeming impunity.

reverett123 08-19-2011 04:38 PM

It has been rughly a month now and I am quite encouraged with the perindopril. I am also a little hacked off that I wasn't taking it from the day of diagnosis.

I am still a work in progress. My days are much more stable with very little OFF time. I have ditched the ropinerol again and am running on 8x sinemet cr, two hours apart, and continue to lower that. I turn over in bed with little trouble. When I waken to Nature's call in the night (roughly every two hours), my legs are much stronger. There is more muscle mass there, too, and the atrophy has been reversed.

The biggest problem is dyskinesia. I am not too surprised since the earlier study indicated dopamine increase.

I pronounce this to be "Good Stuff"!

Quote:

Originally Posted by reverett123 (Post 791786)

This afternoon it is seven seconds on the right and nine seconds on the left. Also, I skipped a pill at 2:00 with seeming impunity.

reverett123 08-25-2011 06:52 PM

RLSmi, thank you. It is nice to know someone is watching. Plus I have a question for you in particular. As I recall, you have been taking low dose dextromethorphan at bedtime for several years. My question is, "What prompted you to select that timing?"

I have settled on a similar schedule for the practical reason that for a couple of hours after taking perindopril my symptoms actually worsen. Taking it at bedtime gets around that. But I have to consider the possibility that other factors similar to those that guide you are at work.

Yesterday I experienced zero time either off or frozen. Almost no dyskinesia as well.

reverett123 08-26-2011 11:33 AM

It is not so much that there is a better response as it is an initial negative effect lasting a couple of hours. I haven't run across the calcium link. One suggested explanation was that angiotensin2 is a pro-inflammatory cytokine and that its suppression is thus beneficial.

A couple of interesting points- There are only two ACEIs that can pass the BBB, captopril and perindopril.

Research indicates that blueberries have something going for them vis-a-vis PD. Blueberries are also a natural ACEI.

And check this one out-

1. J Neurochem. 1999 Jul;73(1):214-9.

Effect of chronic angiotensin-converting enzyme inhibition on striatal dopamine

content in the MPTP-treated mouse.

Jenkins TA, Wong JY, Howells DW, Mendelsohn FA, Chai SY.

Howard Florey Institute of Experimental Physiology and Medicine, University of

Melbourne, Parkville, Victoria, Australia.

We have previously shown that chronic treatment with the angiotensin-converting

enzyme inhibitor perindopril increased striatal dopamine levels by 2.5-fold in

normal Sprague-Dawley rats, possibly via modulation of the striatal opioid or

tachykinin levels. In the present study, we investigated if this effect of

perindopril persists in an animal model of Parkinson's disease, the

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. C57BL/6 mice

were treated with the neurotoxin (30 mg/kg/day intraperitoneally) for 4 days and

then left for 3 weeks to allow the degeneration of striatal dopaminergic

terminals. At this time, the mice exhibited a 40% decrease in striatal dopamine

content and an accompanying 46% increase in dopamine D2 receptor levels compared

with control untreated mice. The dopamine content returned to control levels, and

the increase in dopamine D2 receptor levels was attenuated in mice treated with

perindopril (5 mg/kg/day orally for 7 days) 2 weeks after the last dose of MPTP.

When the angiotensin-converting enzyme inhibitor was administered (5 mg/kg/day

for 7 days) immediately after the cessation of the MPTP treatment, there was no

reversal of the effect of the neurotoxin in decreasing striatal dopamine content.

Our results demonstrate that perindopril is an effective agent in increasing

striatal dopamine content in an animal model of Parkinson's disease.

PMID: 10386973 [PubMed - indexed for MEDLINE]

reverett123 08-26-2011 11:41 AM

Went shopping this morning. As I came out into the bright sunshine, I was briefly blinded and missed the curb. Went careening toward a 3-point landing onto my nose. But my feet managed to catch up with the rest of me and avert disaster. A similar mishap back in the winter cost me seven stitches in the forehead.

reverett123 09-01-2011 04:42 PM

still looking good

The last few days have featured a good bit of dyskinesia. But yesterday I started taking half pills on the same time frame and am seeing big improvement. Probably a rocky road ahead as I walk a tightrope between quiver and catatonic.

But isn't that what I should expect if neurotransmitters are ramping up? I mean 2.5x is an impressive number.

mrsD 09-01-2011 05:03 PM

There are other ACEs that cross the BBB:

medscape.com/viewarticle/55...

I am following this thread with interest. I switched to lisinopril a few years ago from Vasotec for this neuroprotective reason. Altace is to be avoided if possible because it has some toxic long term effects. This drug may cause liver problems and should not be used by patients with pre-existing liver damage.

Lisinopril on the other hand is not appreciably liver metabolized and is excreted for the most part whole by the kidneys.

reverett123 09-02-2011 07:19 PM

Today was another of those where I suddenly got a flash of "Hey! I AM doing better than I would expect! Twice this afternoon I cut a sinemet CR in two. Not bad.

[reverett123 in reply to reverett123]

Another change noted last night. A thunderstorm knocked out our power, wife was out for the evening, and it looked like peanut butter in the dark for supper. I threw caution to the winds, drove to a local restaurant in the dark, ate and returned home. In the last five years I could count the times that I have driven in the dark and alone on one hand.

[Israel1]

Parkinson's Movement is about listening to the patient's perspective and moving forward to improve the quality of life of those living with PD, and eventually finding a cure. Should we follow up with reverett123's suggestion? Definitely! Being well-informed patient-advocates will make the Movement powerful because we will research what is published, follow up with researchers by seeking their input, and acting independently to seek funding for a "patient-driven research agenda". I've mentioned before that we can let researchers know what we like about their work if it serves the good of the PD community, let them know what we don't agree with in terms of the direction their research is heading, but more importantly, provide input to effect change. They can't find a cure without us as part of the process. Like Tom, I'd like to know if you have any more up your sleeve. Excellent contribution!

[reverett123]

Actually, I do have quite a collection of possible therapies that I have divided into 85 different files. They range from "acetyl-L- carnitine" to "yoga" and each had a reason to make the cut. However, my approach has been to download any abstract that MIGHT bear fruit and I assume that the majority will ultimately prove useless. The problem is figuring out which is which. We are talking about several thousand individual abstracts and our new born effort here could quickly collapse.

I will be happy to share it all - Tom is an old friend - but I urge a slow start and this perindopril seems ideal. It has already gone through the regulatory hoops and seems relatively safe. It has been widely used for hypertension so there is good clinical data. Early research hinted at positive PD effects and even included human trials. And we've even got a mad Yank who is actively trying it! I will be happy to contribute in any way that I can.

[Hidden]

perindopril ?

[ParlePark in reply to Hidden]

I tried ace inhibitors for BP. Horrible side effects in lungs.