rue, Disease Modifying is certainly more encompassing than any...

rue, Disease Modifying is certainly more encompassing than any other subset in this area. But tonight we explore another concept that used to be more prevalent but I've come across less and less over the years, however its ramifications are none the less thrilling for us long term holders.

Indeed a complete Mozz Special tonight but a warning; This source is just so overwhelmingly massive that I can in no way do any real justice to it. So tonight's post will really only be a partial summary of the true source.

Lets get stuck into it!


Do enjoy!




INTRODUCTION

There are many many studies, observations and research groups that have touched upon Pentosan in a number of formats and models and what it is capable of doing. My fellow Paradigmers, the research in terms of quality and quantity from one source, from one individual is a stand out. Specially when you consider just how much of a pioneer this one person was and how many years ago he experimented and researched our molecule. Indeed it is magic.

Tonight, you dear reader, will start to get a true sense of some of the work that has gone on behind the scenes to get us where we are, the ideal thing about all of that is that we are STILL NOT LATE to this magnificent party that will unfold right before our very eyes (only my views).


I present to you Dr Peter Ghosh.


Yes we have heard of him, well most of us have. But this one article, this one paper quite simply blew me away, it was only a recent discovery for me almost by chance just a week ago and yes, I immediately printed it out and have began the long task of reading and learning.







I'm not there yet in terms of a full read but like a kid at Christmas that has all these presents under the tree, how can I wait even one more day to open this present and start joyfully playing. When it comes to Pentonsan and its marvellous MOA, I am but a kid in a Toy Heaven. (Yes, OARSI will be a playground for me).



_{Jeepers, where do we actually begin?}




A RESEARCH COMPARISON?

I reckon I have done some research on iPPS and PAR in the last 4 years. I can't think of too many days or nights where I haven't at least read a paragraph about us and our drug. Sure I have a life (where?), just last night I went to the Boney M concert (Pool Boy is going to have more fodder now) here in Melbourne.



_{A very fun concert - loved the music, but it was a blast from the past.}



With only one surviving member of the band, Maizie Williams, she could still articulate through the newer members what the original band would've been like to see live. The crowd had a blast and the music was really fun, yeah even I had to get up and have a boogie. My dancing skills are only slightly worse than my singing. Lets not go there.

My point is that I look forward to when we Aussies have a great medicine to export and for us to captivate the world! How proud we will be to not only make a dollar but to address so many that are suffering.

Anyway, I digress, as I was saying, I sometimes get this crazy notion that I actually do a fair bit of research.

I am nothing, let me just state that again in case you missed it, I am nothing before such titans as Dr D Felson, Dr V Kraus, Dr R Krishnan and of course the late Dr P Ghosh.

An example please Mr Mozz...

Here is an example of what I'm talking about - For my larger posts I can reference up to 15 or even 20 references, that takes me literally a couple of weeks! Sure I'm not full time on it but I do spend a lot of time researching and reading what these references are saying and how they are important and relevant to the point I'm trying to make. I try my best to simplify it so I can understand it myself!

Back in 1999 , Peter Gosh came up with this paper, it was some 46 pages long, but that's not the impressive part...how many references did it contain?

Yeah we haven't done this for a while...think it must be time...




QUESTION: How many References were there in Dr P Ghosh's paper from 1999, no cheating and going down to the main ref please.


A) 21 ?



B) Yeah right, 50 ?



C) Something crazy like 150 that would involve a heck of a lot of reading and understanding what others are saying on the subject covering a wide variety of topics on OA, Pathophysiology of the disease and many other demonstrations, experiments and observations of Bio and Chem?




Yeah the answer was 390.....390 references!

Mate, this guy really did research. But not only that, he conducted studies himself and his findings were off the chart.



.WAIT A SEC, SO WHAT'S THE TITLE OF THIS POST ALL ABOUT?


The title of this post is D is for DMOAD, we know this is the gold standard we are all waiting for one day...to see that on a label, to get official first time world classification of this, it will be a huge boost to us all....Our share price might even catch up some of that lag (my thoughts).


So what's this 'S' all about then?


S is for.....


.........wait for it.......






SMOAD



Huh? What the heck is that?


I give you STRUCTURAL MODIFICATION OA DRUG.


It's so topical and timely to us right now that it is not funny. What do I mean? Well 008 6 month data of course, it has a distinct structural component.

Yes great but what has this to do with Peter Ghosh way back when in 1999?His article refers to it multiple times in connection with Pentonsan!!!This has ramifications for us and what we might be about to see sometime after the CTS at OARSI in mid March.



DEFINITION AND OBJECTIVE

Remember, tonight's post in no way could ever do justice to what he has found and written about, its a mere snapshot...lets check out some highlights:


Like a lot of good papers, we need some definitions first, Dr Ghosh started his out with the definition of SMOAD.




Structure-modifying osteoarthritis (OA) drugs (SMOADs) may be defined as agents that reverse, retard, or stabilize the underlying pathology of OA, thereby providing symptomatic relief in the long-term.








What was the ultimate objective of the paper?




The objective of this review was to evaluate the literature on sodium pentosan polysulfate (NaPPS)and calcium pentosan polysulfate (CaPPS), with respect to the pathobiology of OA to ascertain whether these agents should be classified as SMOADs.










MECHANISMS

As we expect, PPS exhibits a wide range of pharmacological attributes, the paper at the start runs through them as a summary:






"Of Significance was the ability of these agents to support chondrocyte anabolic activities and attenuate catabolic events responsible for loss of components of the cartilage extra cellular matrix in OA joints".

Dr Ghosh is essentially saying that the destructive nature of components within the extra cellular matrix are disabled by Pentosan, it has profound effects on normalising the OA related tissues and structures.

"NaPPS and CaPPS also have been shown to enter chondrocytes and bind to promoter proteins and alter gene expression of matrix metalloproteinases and possibly other mediators".

We know the chondrocytes are specialised cells charged with the responsibility of production of key components of the extra cellular matrix, one such example is the producing of our precious Higher Weighted Hyaluronic acid. I will have more to say on HA in a post coming to you soon.



Reduction of joint swelling and inflammatory mediator levels were observed.



"...synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS andCaPPS or after intraarticular injection of NaPPS into arthritic joint".



Preservation of cartilage integrity.



Proteglycan synthesis.



Reduction of metalloproteinase activity (An example to come later in this post).



Salts of Pentosan "stimulated the release of tissue plasminogen activator (t-PA). (Yeah that's a new one for Mozz, back to the books I feel).



Decreasing plasma levels of the endogenous plasminogen activator inhibitor PAl-l (See above point, another new one, more studying).



There were net thrombolytic and lipolytic effects exhibited by Pentosan which can lead to improvements of improved blood flow through subchondral capillaries of OA joints and improve bone cell nutrition.



We know we are about to get results on our canine program to give us a sense of Pentosan's impact on the equivalence of 3 human years. Even back then Dr Ghosh reported the following: "In geriatric dogs, NaPPS and CaPPS reduced symptoms, as well as normalized their thrombolytic status, threshold for platelet activation, and plasma triglyceride levels. These hematologic parameters were shown to be abnormal in OA animals before drug treatment".

And it was noted that the above results were shown in human patients in open as well as double blinded trials.




THE DETAILS

As I mentioned, this paper is enormous and would take a number of Mozz posts to cover it properly. But, I so do want to give you all just a taste, a small sense of how detailed and what observations have already been sighted many many years ago.

Here are just two examples:







Some background required firstly.

Aggrecan, (AGG) like a lot of things to do with the body's tissues, is a protein! It's produced from a specific gene and forms a bond with guess what?! One of my ultimate favourite molecules, Hyaluronan (HA). Look at how pivotal this HA chain is...one HA molecule binds to up to 100 chains of AGG) ^2,3.

What does all this conglomerate do? What is it responsible for? It results in the endowment of articular cartilage and gives it the raw ability to withstand compressive loads. When we jump up and down at our kid's tennis match, when we dance and prance around at a Boney M Concert (!) ...this is what you want of your cartilage, yeah?

Right, so now we know that the more of this AGG we have, the better....

YOU are now ready and equipped to take a look at what Dr Ghosh unrecovered in our example 1:


They took 4 samples...and checked out how much AGG is produced...here are three of the cohort samples...what is your guess of where CaPPS ended up?

(For those that are curious, Ca is calcium and thus CaPPS is a similar blend to our NaPPS version).




Ok time for the reveal...where did you position that Green arrow for the CaPPS...was it anywhere and anything like this:







Mate. Now that's the column of AGG I want to see. Ourdrug at work.


Lovely.







Remember, these are random bits of evidence I'm gleaning from this massive report (see Main Ref below)....Example 2 relates to a recent post I did involving MMP-3. I know a number of readers will have forgotten this post though it was not long ago, here is the link to it ----> Mozz's MMP-3 POST


I also know a few of you won't be bothered traversing through that above link so as a refresher; let me quote just one quote from that last Mozz post on MMP-3:




MMP-13 is the enzyme responsible for the degeneration of the cartilage ECM and the degenerative process of OA pathogenesis.









MMP-3 is a biomarker culprit that we want to see reduced in terms of inflammation and OA.

What then did Dr Ghosh and team discover about this one cytokine all those years ago?



We see above that PPS in two cohorts (labelled as 256 and 77 which relate to two different Kbase groupings).
Look at that green arrow, that's a massive reduction in this MMP-13 inflammatory cytokine. I'm calculating it at about a 78% reduction compared to control in that 77 group !



CONCLUSION

An enormous amount of data and further evidence presented here in this report by Ghosh. But all done in 1999 ! It was ages ago. I've already had a couple of buddies ask in wonderment, how can this have taken till now for someone to instigate trials and further commercially aimed programs? Why has it taken so long??

I just said in my opinion they knew how onerous starting out on this journey would be.

Pre Clinical model studies set up with a view and aim of eventually getting human studies done. This doesn't just mean take ten mice and dosing them. There is a lot involved, progressively bigger animal models would need to be done, it takes time and effort...then you possibly progress to human studies in a P1....amazing amount of safety data and Tox studies and Pharmacokinetic observations are required to progress....then if you are lucky, you get to P2.

Look at how long it has taken us? We are still going....Millions of dollars and so much time and dedication.

Well done PAR for sticking with it. Again, I state publicly how hard they are working and I for one, as a long term holder, as a believer of most likely what is to come - I say thank you to the staff and please be ready for some more hard (but oh so fun!) work ahead of you. Did someone say pioneers?


SO - At the end of the day, was it or wasn't it?


A SMOAD?



YOU be the judge, here is the exec summary:




The data presented in this review support the contention thatNaPPS and CaPPS should be classified as SMOADs. However, additionallong-term clinical studies employing methods of assessing joint structuralchanges will be needed to confirm this view.











Indeed, this is exactly what we are finally now doing...






- Mozz






DYOR required





REFERENCES


MAIN REFERENCE

1] https://pubmed.ncbi.nlm.nih.gov/10073500/


OTHER REFERENCES

2] Invertebrate Cartilages, Notochordal Cartilage and Cartilage OriginsBrian K. Hall, in Bones and Cartilage (Second Edition), 2015
3] https://jeo-esska.springeropen.com/articles/10.1186/s40634-014-0008-7