iPPS - The Heart of the matter, page-2

“If [you are] over the age of 10, the question isn’t whether or not to eat healthy to prevent heart disease. It’s whether or not you want to reverse the heart disease you already have.”

— Dr. Michael Greger



It's a natural process...what is the role of iPPS, how can it help...what's involved and what indeed is this friend of iPPS's all about, Part 2 will attempt to answer these questions.






Right, so what's the link between iPPS and Heart Failure.

Like a lot of things in the Bio Pharma space the answer involves further understanding and some background...

MYOCARDIAL EXTRACELLULAR MATRIX

Whoa, what's this beast then? Well we can break it down into each component.
Myocardial - easy one, this just relates to the muscular tissue of the heart.
Extracellular network, consider this as the supporting material around the cell. It provides a network of structural and biochemical support to the surrounding cells. It's this environment that's created that allows for the cells to participate in:

• Adhesion
• Migration
• Proliferation
• Differentiation

Lets take a closer look at this myocardium matrix. Here is a pic showing a health heart muscle situation on the left, and a not so health pic on the right.





Bahh too much for me, I need a Mozz Quiz © ....

MOZZ QUIZ QUESTION - What stood out to ol' Mozz in this diagram the most?


A) It's messy....err both left and right sides?!


B) There are way too many scientific beasties embedded in this pic for me to make light of it.


C) It all looks like one big spaghetti mash to me...



@Absentfriend, Meme me outta here!

Well in the above pic, a plethora of science it might be, but ONE word stood out on the Mozz radar when I first sighted this beast of a diagram...that word starts with 'H' and it immediately formed another link within the Mozz Brain...





HYALURONAN...thats the word that starts with H...and this is the super clue...think of it as a link...think of hyaluronan as the friend that partners up with iPPS....that iPPS motivates, well stimulates, the production of hyaluronan.

The best way for me to describe it is to liken it to YOU motivating your best friend. Your best friend is capable of so much more, you know it, they know it...so you give them a gentle push...a motivational talk...a guidance to get them going...that's what mateship is all about. I keep thinking of the great Aussie Digger spirit...the same was true for the Americans, the British and the New Zealanders and no doubt a whole heap of other countries as well...

How tough it would've been to go to war against a foreign enemy in the terrible cold and mucky rainy conditions...but when you have mates by your side...we are capable of so much more...we push ourselves....we are motivated...we help one another for a common goal...it's not unlike this with the incredible action of iPPS...both DIRECT and INDIRECT....there is ample evidence of how our molecule works as a booster and as a direct involved binding agent and we are gathering more of this glorious data by the month.





_{Absolute mateship, looking after your buddies, fighting for your country. A big Thank You to all the Women and Men that served and continue to do so! If it wasn't for them we may not have been here today. If you know of someone that has served or is serving, thank them.}



iPPS is not heparin which also binds two proteins together but then promptly leaves..In the post, PPS - The Ultimate Mediator , we touched on this binding association. Some new material here; it was found to achieve a similar sort of bind between TIMP3 and ADAMTS5 you need a 10 fold increase in concentration of heparin compared to PPS.

In case you are wondering, do other polysaccharides have this effect? I haven't found anything so far and in fact the research paper ^2.5 I'm referring to stated "Other glycosaminoglycans, such as dermatan sulfate, chondroitin 4-sulfate, chondroitin 6-sulfate and hyaluronic acid had no effect on affinity at concentrations up to 1 μM." Looks like hyaluronic fluid and our Pentosan have a special friendship indeed.





_{iPPS and Hyaluronic fluid = Friends forever?}



Amazingly, the research also showed that PPS forms a special "trimolecular PPS-ADAMTS-TIMP3 compex". Furthermore, the researchers went on to state "This rules out the possibility that PPS interacts transiently with the proteins to increase their affinity and then dissociates, as has been shown for the heparin-mediated increase in VEGF (vascular endothelial growth factor)–fibronectin affinity".

Mozz speak? In other words PPS does not connect the two and then leaves like heparin in a transitory fashion, its there for the longer haul. Possibly a bit like the PAR company, they are not here (in just my views) for the short term, make a quick buck and get/sell out. If that was the case I dare say Paul and Co. would've sold out way back at $4 to the highest bidder.... He is here for the super long term to see that one day we address not just a few SAS patients as a proof of concept but we address a very good chunk of the world.

So where have you and I seen this word, hyaluronan before? This is the fluid...the shock absorber in the knee! But wait....it is not just some simple shock absorbing fluid...it has an incredible amount of practical functions...I never knew this, till now. It not only plays a role of shock absorption, it also plays a number of key roles in the knee joint....


Joint lubrication


Anti-inflammatory effect provision


Chondroprotection



So we know it operates and is prevalent in the joints....Just what the heck is it doing in the heart?

That's the clue my Dear Paradigmers, this is just another way in which iPPS acts...it helps the production of this little babe known as hyaluronan. I like the straight, more rigid and long lines of hyaluronan on the left of that pic above...in the right they don't look healthy, they don't look strong and definite and mate, they are too short ...this is a clue for us.


Ok in truth I could easily have a full Mozz post on Hyaluronan in itself. Let's take a closer look.
I first mooted the value and the role of it in the following post: iPPS, 8D Audio and something called CTX II


Let me just summarise it in one powerful quote from that same post above:

"In the synovium, pentosan increases both the synthesis and the molecular weight of hyaluronan." ^3,4


We know that iPPS stimulates the production of this guy....it's kinda a team effort.Ok, we gotta explore this fluid some more, it's too important for me just to say it's important and leave it at that......now is the time to explore it...while it's quiet, before any potential explosion of the share price, before the news just keeps flowing (all subjective and speculative personalised opinion type statements).





Ok so what the heck is this fluid?Hyaluronic fluid is a clear, gooey fluid that is naturally produced by our bodies. Larger amounts of this stuff can be found in your skin, eyes and wait for it...connective tissues.What is its primary function? To retain water and keep our tissues well lubricated and moist.

Benefits? Not just a couple, I'll give you 7.



_{Hyaluronan fluid served to you on silver plate? Well at least some research of it. Amazingly important fluid and just recently I learn it's not just present in only the joints.}

1. Promotion of healthier skin
2. Can speed wound healing....DID YOU KNOW - levels of this fluid increase when there is a wound. It helps to regulate inflammation. No, we (iPPS) aren't in competition remember, we help to stimulate the production of hyaluronan fluid.
3. Ok this is where we have covered some of this in the past...relieving joint pain by keeping bones well lubricated. This fluid acts also like a shock absorber and the gel bit helps to reduce the grinding of the bones when cartilage is less. Yes they even tried a massive trial, yeah I'm talking somewhat more than the 1650 odd patients we are going to be testing...I'm talking 12,000 participants! It was found a direct injection of this fluid straight into the knee had moderate if at all affect and risk of serious AE's was increased. ⁶
4. Hyaluronic acid has also been shown to line the esophagus which also speeds up the recovery process in the case of acid reflux.
5. Some 1 out of 7 older adults suffer symptoms of dry eye due to reduced tear production. As hyaluronic acid retains moisture, it's often used to treat dry eye symptoms.
6. Another one for us directly through OA is the preservation of bone strength. Studies have shown that hyaluronic acid play a role in slowing bone loss in rats with osteopenia which is the stage that precedes osteoporosis.
7. Finally most have us have heard of Elmiron (Pill format of PPS) and how it has been safely used to treat interstitial cystitis (Bladder pain). Hyaluronic acid has shown to have benefits here and through the action of PPS this acid synthesis is stimulated thus giving patients relief. Studies are still being done in this area to determine how it works but it is hypothesised that it helps repair tissue damage reducing the pain sensitivity. Aside from that you and I know the action of iPPS on inflammation and pain.

SO we have a better idea of this hyaluronan and how it plays a pivotal role in not just the knee! It could very well be a clue as to the multifaceted action of iPPS. But let's get back to the heart of the matter.....heart failure.

We also know what Myocardial Extracellular Matrix is now. It is the ADAMTS4 enzyme which we need to bring down...and you and I both know the mediator to do this, iPPS of course. Let's explore a bit more about heart failure first.





Again, quite conceivable that I could dedicate a couple of posts just to cover the complexities of heart failure at a high level. One of my good friends that I grew up with became a cardiologist at the Royal Melbourne Hospital...One day I'm going to be able to have a decent conversation with him and discuss such heavier topics...but I reckon I have a few more research nights to get to that level to be even able to ask the right questions!

Cardiac overload due to myocardial infarction leads to adverse tissue remodelling. It is this situation that then progresses to heart failure. As this process goes unabated, the muscle mass can increase, the ventricle (chamber) enlarges and thus the symptoms of heart failure present themselves.






Ah there are a few, again we don't have the bandwidth to cover them all properly so this will be just a high level presentation to wet our appetite as it were.It's important to see what the current std of care actually is so we can then compare iPPS to them and get a sense of why iPPS is appropriate and how exactly it defers. What are any advantages and or disadvantages of iPPS over these treatments.



_{Wetting one's appetite for more..no matter if it is a lovely cake or heart mechanism theory and research....actually its probably linked...eat more cake...increase chance of heart failure?}


Some of the current remedies include:

• Beta Blockers - These block the release of stress hormones such as adrenaline and noradrenaline. ⁷

• Ace Inhibitors - Ace stands for Angiotensin converting enzymes. Examples include captopril, enalapril and quinapril. These are designed to reduce the symptoms of fatigue and improve blood flow along with increasing exercise capacity, correcting hyponatremia and reducing diuretic requirements. ⁸

• AT2 - Antagonists - these are receptors that help in the regulation of vascular response, cardiac growth response and fibrosis response in tissues. ⁹

Ok so the above three points are good but they "are inadequate in slowing disease progression". ^B






So what can iPPS potentially do?

Pentosan polysulfate sodium (PPS) demonstrated benefits associated with unique anti-remodelling action in an established preclinical heart failure model.

PPS provides a novel therapeutic modality not reported in other heart failure agents.

No significant safety issues compared to significant side effects reported with current cardiac drugs.

PPS has the potential to reverse progression of heart failure addressing unmet medical need.



A rat study peer reviewed in 2014 demonstrated the above results...As part of this data set a biomarker, namely ADAMTS4, was observed. It plays a key role when heart failure may be an issue. One study found a link in terms of ADAMTS4 to "have high predictivity for CVD risk" (CVD = Cardiovascular disease) in certain patients with other conditions. ¹⁰

Another study observed just how important ADAMTS4 is in determining the status of the heart in case of Type A acute aortic dissection (AAD). This AAD is deemed to be a cardiovascular emergency which possess a very high mortality rate of some 1-2% per hour during the first 48 hours. What this means is that about 50% die within 48 hours if left untreated! ¹¹


Ok so we see how important this biomarker is...how about a Mozz Quiz © at this point.



MOZZ QUIZ QUESTION - In the rat study, what percentage reduction did Pentosan (the wonder drug) have on myocardial ADAMTS4 levels?


A) 0.003% reduction


B) (A. was silly, let's try something higher), 1.5% reduction?


C) 10%?


D) 13%?



Any of those answers would be something....the actual answer was 80%

Yes, an 80% reduction was observed: "We observed an ~80% reduction in myocardial ADAMTS4 mRNA (p=<0.03), and ~50% reduction in the extracellular amount of the p150 versican fragments (p=<0.05), suggesting reduced versicanase activity." ^B

To give you some background before the next quote, (AB stands for Aortic banding, it's the process of actually simulating heart constriction to observe the effects of treatments). Versicanese is the hydrating properties when the heart tissues are under duress. In concluding, this research team stated it like this:

"Our findings suggest that AB induces an increase in myocardial ADAMTS4 versicanase activity, and that PPS-treatment improved systolic function in the pressure-overloaded heart, holding promise as a novel therapeutic agent in heart failure."


Promising therapeutic agent in heart failure is the key takeaway for me.








All of the wonderful action of iPPS isn't in theory...it isn't JUST from old research conducted in the past and we have years and years before we start working on it...we are working on it right now.

Huh?

Yep, before the end of the year (or possibly at the start of next year) we will get data back on our own heart failure preclinical model. It's happening, it's real and it could just be another eye opener for us. Eye opener indeed when the data comes out, eye opener also when we one day get approved for such a condition, and within just 3.5 years from now it is expected the market size for heart failure alone will cross $11.8 Billion per annum.^A Even if we can address just 20% of it, it will be outstanding.

Paradigmers yes we seem to be in a hold at the present moment...but there is loads of exciting and potentially incredible data to come in the next couple of years and it will come at the most surprising and unexpected moments...out of the blue in my views...



Love it.


DYOR









While researching for this one, I came across a couple of good quotes which I scattered throughout this post, here was a funnier one...



"It’s not that diabetes, heart disease, and diabetes runs in your family… it’s that no one runs in your family!”

— Tony Robbins







Main references used:

A] https://paradigmbiopharma.com/wp-content/uploads/2017/07/PHS0038-Heart-failure-product_PFO_HR.pdf
B] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089621

Other references used:

1] https://www.nhlbi.nih.gov/health-topics/heart-failure
2] https://www.cdc.gov/heartdisease/heart_failure.htm#:~:text=About%206.2%20million%20adults%20in%20the%20United%20States%20have%20heart%20failure.
2.5] https://portlandpress.com/biochemj/article/443/1/307/80461/Pentosan-polysulfate-increases-affinity-between
3] https://www.atlantaequine.com/pages/pentosan.html
4] https://pubmed.ncbi.nlm.nih.gov/7689248/
5] https://www.healthline.com/nutrition/hyaluronic-acid-benefits#TOC_TITLE_HDR_9
6] https://pubmed.ncbi.nlm.nih.gov/22868835/
7] https://www.bhf.org.uk/informationsupport/heart-matters-magazine/medical/drug-cabinet/beta-blockers#:~:text=Beta%20blockers%20block%20the%20release,well%20without%20significant%20side%20effects.
8] https://www.bhf.org.uk/informationsupport/heart-matters-magazine/medical/drug-cabinet/beta-blockers#:~:text=Beta%20blockers%20block%20the%20release,well%20without%20significant%20side%20effects.
9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976824/
10] https://link.springer.com/article/10.1007/s40618-018-0948-3
11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566203/
12] https://academic.oup.com/cardiovascres/article/114/12/1680/5033447