n the past I've deliberately posted through thick and thin, good...

n the past I've deliberately posted through thick and thin, good times and bad. We have had some ups and some downs. Often times it feels we are more down than up! Specially in the last few years. But via Researching and then Posting, I like to remind myself of what we have, what we have achieved. I am doing my best to stay the course but keep a watchful eye on what's happening.

But I understand there are the rough seas of the market in general right now.





There are issues that we face like many companies. For us it was the fear that we may not even have an approved dosing ....just last year we put though some really big changes to our protocol, would they be accepted?

Well we got through...but now we face another foe....funding. I for one do understand we need this and it's important.
To me, I think the challenges of the science and Reg were much more onerous. I believe financing and funding will come, specially as we have now progressed to the Genuine P3 Company status. That's a big accolade for us. We need to convince the funders of what we have and the rosey future we could have with their funds that they provide. Once that happens, it's full steam ahead.



Convince the funders that the OA and the inflammatory space is a revenue ocean and it's not just rose coloured glasses we are utilising, yeah it's REALITY glasses that we are wearing!


So as we wait patiently for financing...let me cover off some competition and how we compare.

Tonight, I conduct a brief revist of the OA alternatives out there with a focus on NSAIDS.

What are they?
How do they compare to us?
What might the future be like for our drug when held up against the NSAID class of analgesic.

Please now, of course, enjoy.



NSAIDS = ?

Full form, Non Steroid Anti Inflammatory Drugs.

Well it's Non steroid.Tthat's a good start, right?

Well no. You'll see why soon.

NSAIDS themselves are designed for shorter term pain relief. They aren't really supposed to be used in higher doses for a longer period of time. If you do use them like this, there are increased risks. These risks are material.



Possible side effects include²:

• indigestion – including stomach aches, feeling sick and diarrhoea
• stomach ulcers – these can cause internal bleeding and anaemia; extra medicine to protect your stomach may be prescribed to help reduce this risk
• headaches
• drowsiness
• dizziness
• allergic reactions
• in rare cases, problems with your liver, kidneys or heart and circulation, such as heart failure, heart attacks and strokes

THE ECM

We'll cover off another big disadvantage of NSAIDS and CORTICOSTEROIDS soon, but first we need some background, we need to tackle the ECM, short for Extra Cellular Matrix.


Remember, when we deal with OA we are mainly focusing on connective tissues. What is one of the most important areas within these tissues? It's the Extra Cellular Matrix (ECM), think of this as a pool of nutrients. Actually why don't we think of this as a swimming pool!

Sure you and I don't actually drink the water of a swimming pool, but pools need to be very balanced areas. Get a dirty pool and you face risks of all sorts of nasty diseases and inflictions. Have too much Chlorine and that's dangerous too. Are ECM's somewhat similar? Well hey need to have that fine balance and be a vital source of excellent nutrients for our cells to... well... have a dip in. Kinda.



A super clean pool? Looks like one of Pool_Lord's exclusive resorts. He seems humble but just wait for a PAR SP explosion...I really will hit him up once we achieve greatness.



But the ECM is much more complex than just a good pool of nutrients that our cells needs.

As it's name suggests, it forms a biomechanical matrix, a scaffold. It also assists in cell repair and even cell migration and differentiation.

Lets take a closer look at normal ECM -v- not so normal³ :




This is what we want (above), a nice pool of nutrients, ordered composite of cells...


As we all get older, we see more of this:





Worse still, we get wounded or fibrotic situation (see below). Don't just think fibrosis is merely fibre scarring. It can lead to organ malfunction and even death. Paradigm Investors, keep your cells healthy!





And then maybe the worst situation:



Ugh, that's a mess above...just compare that last image to the first.


Mozz note: I have been slowly piecing info on Petosan and tumors, it's a number of months away by the time I post on that..I'll wait for a brighter day for that one...when our SP is higher and we are in another holding (but higher SP base level) pattern.

Mozz Second note: Can you just imagine, our little iPPS assists in wound repair at a cellular level. What natural occurring molecule does this? It is my sincere desire to meet bene again, the ultimate manufacturers. I'm hoping in a year or so...yep, I'll be heavily armed with even more questions and more material this time!


Guys, what I am saying to you now is that those NSAIDS that are currently prescribed, they aren't great for the swimming pools between our cells, particularly near and part of our joint areas.

Rightio, due to extreme popular demand, it is time.


Time for what?

Yes of course, a famous Mozz Quiz^© .





HOW MANY DOSES OF NSAIDS ARE PRESCRIBED IN EACH TYPICAL YEAR IN THE USA?

A) Mateee, it's gonna be a few shades greater than 10,000 right? My first answer is a v strong 50 Million!



B) Well After Answer A), we prob can't go too much more crazy.... 100 Million?



C) 400 million and 70 thousand (for good measure) !!







Well I think anything north of 500 million is plenty...ie. too much!


The answer? What's your guess?









THIRTY BILLION


OMG








Now that Mozz Quiz © fact above doesn't just come from any ol' backyard operator, thats from Harvard Health Publishing.⁴


Well we have seen some of the side effects, but what do they actually, positively, do for OA? Surely this reduction in pain and possibly reducing some inflammation that NSAIDS might provide is beneficial from an OA stand point?



Nope.



There is evidence that long term, it actually WORSENS OA.


Take a read of the following two extracts ⁵.


"Repair of connective tissue, including cartilage in osteoarthritis (OA), requires DNA synthesis and proliferation (mitosis) of cells within the tissue matrix. Many non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids suppress this important cellular process and can impair recovery. Complexation of the pentosan polysulphate with the multivalent metals was found to stimulate DNA synthesis over a very low concentration range of the drugs".



Mozz note: NSAIDS and corticosteroids SUPPRESS the important cellular processes and impair recovery. This ain't something we want to see.


...and further...


"Furthermore, prolonged therapy with these prior art compounds and compositions while providing continuing pain relief for many sufferers can lead to breakdown and failure of connective tissues, particularly articular cartilage which in fact may exacerbate the problem".




COMPARISON

Now don't get me wrong, if you are in pain, I would think NSAIDS are possibly better than taking Corticosteroids. Corticosteroid will stop the pain for a typical 3 month period. But jeepers, it comes at a cost. Perhaps one course won't do too much harm but multiple courses are linked to loss of cartilage and joint degradation over time.

Take a read of this one:


"Corticosteroids, while still extensively used as anti-inflammatory agents for intra-articular treatment of severe arthropathies, are amongst the most potent inhibitors of connective tissue growth, repair and biosynthesis of matrix components". ¹


At the end of the day, the one thing you DON'T WANT TO STOP, is the "connective tissue growth"....that's the one thing you want to PROMOTE.

How about this statement from the main reference:



"Moreover, it has been found that the compounds of the invention are capable of stimulating mitosis and DNa synthesis in a variety of connective tissue cell lines. (e.g. fibroblasts, chondrocytes, dibrochondrocytes) and together with their ability to promote matrix component (proteoglycan, hyaluronate and collagen) biosynthesis are of immense benefit in the healing and repair of damages tissues".




Immense benefit in the healing and repair of damaged tissues is enough for me to ride this play out for however long it takes. I for one have been already waiting 10 full years, I will wait another 3 to get this baby moving and my core holding will wait ten years plus...but in actuality, if all things progress like I anticipate...I can't see myself ever really selling...why would you if it continues to benefit society...







HA TREATMENT?

Yes a number take this treatment by direct injection into the joint. But I came across this statement the other day:


"However, it would appear that the results of such [HA] treatments in the past have been disappointing since the newly introduced hyaluronate is itself rapidly broken down by the inflammatory cells free radicals and their enzymes within the joint thereby losing its beneficial properties".


...and further...

"This finding also suggests that even if hyaluronate of the correct molecular size range was applied to diseased joints, it is likely that only temporary relief would result unless the hyaluronate was provided to the joint on a continuous basis".¹





It's certainly beyond the scope of this post to cover too much contents about any other given class of OA relevant medication other than a cursory high overview, but one point I wanted to make here is that there is real potential for iPPS certainly as a stand alone BUT also in combination. There is some evidence trialing of stem cells in combo with iPPS for example, but have a read of this statement and accompanying figure below.

Note: 'SP54' is Pentosan.

FIG. 2--Effects of (A) hyaluronic acid (HA) alone, (B) Pentosan polysulphate (SP54®) alone, and (C) a combination of HA and SP54 on the in vitro biosynthesis of HA by human synovial fibroblasts.





Higher Weighted HA has a plethora of positive effects for us, a small sample includes:

1) Hydration of fibres, particularly involving the Higher weighted blend.
2) Assistance in wound repair
3) Increased biomechanical properties
4) Increase of viscoelasticity in Synovial Fluid (Remember, the synovial fluid consists of approx 60% of HA)
5) Increase in quality of ECM
6) Plays a role in angiogenesis (increasing blood vessels)



EXAMPLE TIME

The main body of this research comes from a patent focusinging on Pentosan as an anti inflammatory. Function was one of the highest scoring endpoints in our studies to date. In the example section of the aforementioned patent the following case is presented (my emphasis added):



In one example of the invention, it was found that in the canine, an injection containing 5 mg of sodium hyaluronate and 5 mg of SP 54 dissolved in 1 ml of sterile saline injected into the stifle joints or the metacarpal joints of animals troubled with traumatically induced or inflammatory arthritis, resulted in the recovery of function within five days of administration.




Within five days of administration.

Most ordinary shareholders want a share price double in a few months. If you give them an alternative of a 5 X in two years, they will still go for the double in a few short months. I'm not sure how many of you in a snap HC poll would vote for the double, but I'm hoping there are more than a handful of you retail blokes (and lasses) that actually want to keep at least SOME shares for the v long term?



So don't get me wrong, I understand that many patients need to take NSAIDS as they are in dire pain...what's the alternative anyway?

The market is -so- setup for us. There are so many people just in pain. I mean that's their number one wish. To be pain free, then we can worry about all the rest of the good attributes; function improvement, patient convenience....let alone the DM side, addressing additional attributes like, but I'm sure not limited to:

• Joint Space width,
• Rescinding BMEL's (but this is further stratified to Volume, size, grade for example)
• Regressing the Osteophyte growth
• Addressing inflammation
• Heck, even possibly growing back some cartilage

We may find that the off label use just to address the many forms and degrees of chronic pain may bring in substantial sums of money. Sure we have been waiting ages, a few of us even from IPO days...many others for the last few years. But the way i see it, we are currently so low in price...it will not take much at all to get us buzzing...





I'm not even talking about what we might just be in 2 years...5 years and certainly 7 years from now...







DYOR essential









REFERENCES

MAIN REFERENCE
1] https://patents.google.com/patent/US5145841A



OTHER REFERENCES

2] https://www.nhs.uk/conditions/nsaids/
3] https://pmc.ncbi.nlm.nih.gov/articles/PMC2995612/
4] https://www.health.harvard.edu/blog/are-you-taking-too-much-anti-inflammatory-medication-2018040213540
5] https://patents.google.com/patent/US5145841A
6] https://pmc.ncbi.nlm.nih.gov/articles/PMC4883592/#:~:text=The%20extracellular%20matrix%20is%20a,the%20field%20of%20tissue%20engineering.
7] https://pmc.ncbi.nlm.nih.gov/articles/PMC10299688/#:~:text=Consequently%2C%20HMW%20HA%20is%20preferably,mechanisms%20%5B53%2C55%5D.