or some three years I've been researching about iPPS. I still have a lot to cover, I still am uncovering some pretty darned fascinating stuff about this molecule and what it can do.
Tonight we will cover something special. Yes more on the mechanism of action that to date, I have not come across, to date I have not heard about....but also as I sometimes get to do, we have a bonus. For the very first time we will see a percentage, a figure...more on this later on in this post.
Do grab a nice drink/coffee/water and please now enjoy.
MECHANISM OF ACTION
We know Pentosan isn't just asinglemechanistic pure play. We know there aremanyways it acts and some of these are direct and some are quite indirect. We have read about iPPS acting as a down regulator for a number of inflammatory pathways, we realise it acts in signalling, it acts as a mild blood thinner, it forms bonds with certain other molecules. We know that it does not block out all pain, it does not completely halt the production of cytokines, some are still necessary, some must be balanced. We know that it can preserve articular cartilage and it also improves the quality of the synovial fluid. In diminished OA joints it serves to restore the higher weighted HA fluid - I am working on a separate post on just this feature alone.
But I came across an entirely new MOA, just last night.
BACKGROUND
Before we can tackle this new-to-Mozz evidence...we need a little background. One of the many ways in which iPPS acts is via its thromboprophylactic properties.
Hmm a long word, it refers to the process of forming blood clots. Sure this does relate to the fact that iPPS has mild blood thinning properties but tonight's research goes a fraction beyond this fact.
Thrombi is another word that needs to be defined...it essentially means a blood clot, how about a pic here4?
From the pic above you can see this Thrombus gathering, we don't want this, it can easily lead to blockages and that's when we find ourselves in trouble.
One more definition for you before we can continue:
Femural head is the round pivotal part of the top of the femur that joins the hip...yeah a pic here would be a good idea:
Yeah but don't be under the false pretence that the femoral bone (or any other bone for that matter) does not have a huge and intricate vascular supply! You need lots and lots of blood vessels feeding into the living bone! We need precious oxygen and nutrients as a contestant supply. Deprive the bone of this and again, you will have problems. Degeneration of the bone, the femural head no longer fits into the hip socket...the bone becomes fragile, OA abounds!
Ok now you have some background, lets tackle what is iPPS's role here.
"Pentosan mobilizes vascular occlusions by promoting fibrinolysis, reducing fibrinogenesis", we knew this due to the blood thinning properties, the best thing here is that it is only a mild blood thinner. We do want some clotting but we certainly don't want over clotting, this is dangerous, think of DVT for instance. But the new stuff involves something else that it does where there is some overlap, namely addressing lipids.
Lipids we learn in High School Chemistry and Biology are essentially fats.
"Intravascular lipid and thrombi have been reported to be often present in the arterial and venous microvasculature of heads of femur removed at the time of total joint replacement surgery for OA".
"The venous stasis and hypertension resulting from the presence of these emboli in OA joints have been reported to be associated with bone ischemia and osteonecrosis. These pathologic events have been cited as possible causes of pain in OA, and the aim of early surgical treatment of OA was to release the arterial pressure by fenestration of the subchondral compartment of the affected joint".
Mate, what that above paragraph is telling me is that around the time the patient needs surgery due to all the crazy pain, they are observing that you have these blockages and bone ischemia and osteonecrosis...these are pain centres and the early surgical treatment was supposed to alleviate this pain.
WAIT! Have you tried iPPS before you go in for surgery to alleviate that pain??
Dr Ghosh and researchers came up with the most amazing discoveries, here is another paragraph from just one of his studies on iPPS: The reduction back to normal range in terms of the MPA is just another clue for us all.
"NaPPS treatment was associated with modifications in peripheral blood mononuclear cell procoagulant activity (MPA) and differential leukocyte counts. Patients' MPA, which before drug treatment was higher compared with those in non-OA controls, was significantly reduced to within the normal range 24 hours after NaPPS administration. This effect was maintained for 4 weeks after the end of administration of the drug. "
Atypical mononuclear cells are morphologically abnormal lymphocytes or monocytes that may appear in a blood after immunizations or surgery, during infections, or at the onset of autoimmune diseases.6
WE ARE REMOVING THIS PAIN BEFORE THE PATIENT GETS TO THIS STAGE!
Can you guys just understand how big a market this is going to be. And again I'm not saying we are going to cureeverywoman, every man and his and her dog...(Yeah don't get me started on the dog pathologies)....Even if it doesn't work well for a lot...the ones it does works for will be incredible and there is no down side for everyone trying it and testing out the results. There is no alternative.
The only alternatives DO NOT ADDRESS the underlying disease pathologies, they only simplistically address pain and that too quite poorly, riddled with side effects and certainly detrimental effects over the longer term. They simply aren't designed for longer term use.
GIVE ME A FIGURE
In truth, I didn't really expect we were going to get much actual percentages of the various bio markers falling as a direct result of iPPS'samazingaction at interim readout out (56 days) ....Hmm This 'Amazing' word reminds me of Spiderman.
Well actually, not quite Spidey, I mean:
The AMAZING iPPS!
So we still managed to get some fairly awesome figures at interim 008 but even more telling, they were an improvement on prior statistical release.
Lets go back in history for just a sec as a reminder:
Thanks again to the poster@Torpyfor the above, highlighted in a previous post.
But wait a sec...we got a further improvement in 008 interim:
We saw 73% achieving a greater than 30% pain reduction!
We also saw that a full 60% attained a greater than 50% pain reduction.
I was stoked when I saw this:
Speaking of all these figures...I reckon its bonus time!
BONUS TIME
Before we tackle the bonus, again we need some background so you will understand what these figs mean. We know that another benefit of iPPS is the way in which it produced HA acid. For those of you wanting an insight of what HA is, follow these links:
There are two types of HA acid produced naturally in the body, lower weighted and higher weighted. We want the higher weighted HA (HWHA). iPPS is great atnaturally internallystimulating production of this vital molecule. When OA is prevalent, the HA that's produced is thelowerweight variety and this is what enters into the Synovium cavity, its not what we want, we need the higher weighted flavour.
Lets get stuck into the bonus.
A true bonus must involve a:
QUESTION: How much, as a percentage was it shown that iPPS in previous other studies increased the amount of HWHA?
A) 2%
B) 7%
C) 11%
D) Something a bit more than 15% ???
Try70 to 83% Increase. No wonder our top line was statistically significant resulting in a long effect size!
Here is the quote for the above:
"In other studies, 2 or more intra-articular 50-mg injections of NaPPS into the joints of 14 patients with rheumatoid arthritis patients with OA were associated with a clinically significant increase in synovial fluid hyaluronan MW of 70% to 83%, probably resulting from a direct stimulatory effect on synovial fibroblasts".
Finally another quote from the Ghosh Study:
"The MW and concentration of hyaluronan in the synovial fluid of joints affected by OA are reduced, and the normalization of these parameters by NaPPS could serve to improve the rheologic and cartilage-protective effects of synovial fluid, as has been found with the intra-articular administration of exogenous high-MW hyaluronan. Cartilage hyaluronan and proteoglycans have also been found to be preserved in the joints of animal models of OA after IM administration of NaPPS".
The word 'normalization' always caps it off for me. Finally, at the end of the day, its this back to normal result that what we are after, do it safely and we will have that out of the park scenario that Marco eluded to.
LAUNCH!
THREE MONTHS FOR SIX MONTHS?
I went to the crazy amazing T20 India -v- Pakistan match the other weekend, I haven't ever experienced such a loud crowd...92,500 at the MCG was already compelling but while I have attended footy matches that have come close to this sorta crowd numbers, the volume and enthusiasm was unparalleled. The game also was fairly amazing! 63 runs off 30 balls or so....in the same way, I regard it as exciting that we are just 13 weeks or so away from potential 6 month read out.
In just three months we get 6 month data from 008. This again will show what the science is saying. We already achieved statistical significance from a small sample but this time we may see more separation between the groups, we should get some idea about how thosestructuralbiomarkers are being influenced by the magic, the amazing iPPS.
Indeed some 17 years ago Dr P Ghosh hinted at DMOAD...its been a long time since these initial studies and papers, we finally have constructed a clinical study focusing right into the joint and the effect of iPPS.
Presenting this data to the world and to potential distribution partners is going to be quite an event. Anyone joining us now is really fortunate to potentially be able to take advantage in what indeed, one day, in my opinion, could be the single best selling drug of all time.
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or some three years I've been researching about iPPS. I still have a lot to cover, I still am uncovering some pretty darned fascinating stuff about this molecule and what it can do.
(20min delay)