Pentosan Polysulfate Sodium (PPS) is a semi-synthetic drug manufactured from European beech xylans that are sulfated to produce a negatively charged product that mimics glycosaminoglycans (GAGs). These complex carbohydrates have a regulatory role in the body through interacting with proteins involved with inflammation. PPS also has a mild antithrombotic activity.

Safety profile

To achieve European and FDA approval, PPS has been examined in toxicology and safety studies across several species of animals to humans for more than 50 years. It has been ingested orally, infused in the bladder, injected (IV, intramuscularly and subcutaneously) and administered intranasally in a recent Paradigm toxicology study. It has a robust safety profile for long term use in humans at 300mg daily dose ingested, and when injected at doses of 3mg/kg into inflamed tissue.

Interstitial cystitis

While interstitial cystitis has a complex pathology, PPS provided in tablet form or through bladder infusion is suggested to act through a coating effect on the bladder epithelium to replace a defective glycosaminoglycan layer, as well as through anti-inflammatory action by inhibition of mast cell degranulation. Elmiron for oral administration is approved in the US (FDA) and Australia (TGA) and marketed by Janssen Pharmaceuticals.

Deep vein thrombosis

PPS in injectable form is well established in Europe for prevention of thromboembolism and acute blood vessel occlusions in humans. A key activity of PPS in this application is its anti-clotting activity.

PPS delivery for human use in an injectable form is not currently approved in Australia, so the above treatments are not available in Australia.

Repurposing PPS for new applications

Currently we focus on repurposing PPS for the treatment of osteoarthritis (OA) and bone marrow lesions (BML), chronic heart failure (CHF) and alphaviral arthritis (Ross River Virus and Chikungunya), where a key feature of the activity of PPS is its anti-inflammatory and tissue regenerative properties. There are other disease applications involving inflammation that are of possible interest to Paradigm.

Repurposing PPS for new indications

Biological ProcessChronic DiseaseKey Pathological MechanismsPPS Therapeutic ActionReference
Heart Failure
*Overexpression of the inflammatory cytokines IL-1 beta and TNF-alpha instigate tissue damaging cellular immune responses within heart tissue and cartilage.

*These cytokines are common to inflammation in OA and Heart Failure.
*PPS Blocks translocation of transcription factor NF-kB from the cytoplasm to the nucleus mediated by IL-1 or TNF-alpha.

*Reduced NF-kB transcription results in down-regulation of IL-1 and TNF synthesis, leading to reduction in inflammation in cartilage and heart tissues.
Inhibitory effects of pentosan polysulfate sodium on MAP-kinase pathway and NF-κB nuclear translocation in canine chondrocytes in vitro.
Sunaga T, Oh N, Hosoya K, Takagi S, Okumura M.
J Vet Med Sci. 2012 Jun;74(6):707-11. Epub 2011 Dec 28.
InflammationHay Fever
*High expression of inflammatory TH2 cytokines-IL-4, IL-5, IL-13 causes infiltration of immune cells into the nasal mucosa and lungs.

*Damage to the nasal barrier causes chronic sensitivity to the allergen in Hay Fever.
Antagonist effect of PPS mediated by binding of PPS to pro-inflammatory ligands of TH2 cytokines, resulting in inhibition of TH2 cytokine mediated inflammation in allergic disease.Broad Th2 neutralization and anti-inflammatory action of pentosanpolysulfate sodium in experimental allergic rhinitis.
Sanden C, Mori M, Jogdand P, Jönsson J, Krishnan R, Wang X, Erjefält JS.
Immun Inflamm Dis. 2017 Sep;5(3):300-309. doi: 10.1002/iid3.164. Epub 2017 May 12.
Tissue Damage & Adverse RemodellingOsteoarthritis *Increased levels of cartilage degrading enzymes ADAMTS-4, ADAMTS-5, MMP3.

*Involved in impairment of joint function and potentially cause bone marrow edema and bone pain.
*PPS forms a stable complex with the enzyme inhibitor (TIMP-3) for ADAMTS-4 and ADAMTS-5 (Ref: Troeberg).

*PPS also inhibits the synthesis of the metalloproteinase MMP-3 (Ref: Troeberg) involved in degrading cartilage.

*PPS thus reduces or prevents cartilage degradation in OA by inhibiting and/or binding cartilage degrading enzymes.
Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex.
Troeberg L, Mulloy B, Ghosh P, Lee MH, Murphy G, Nagase H.
Biochem J. 2012 Apr 1;443(1):307-15. doi: 10.1042/BJ20112159.
Tissue Damage & Adverse Remodelling Heart Failure*Increased levels of versican degradation products and increased ADAMTS-4 enzyme activity resulting in adverse remodelling of heart tissue leading to increase size of the heart and poor cardiac function.*Reduction in the synthesis of mRNA for ADAMTS-4.

*Reduction in ADAMTS-4 protein.

* Inhibition of adverse cardiac tissue remodelling evidenced by reduction in versican degradation.

*Improved cardiac function.
Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding.
Vistnes M, Aronsen JM, Lunde IG, Sjaastad I, Carlson CR, Christensen G.
PLoS One. 2014 Mar 3;9(3):e89621. doi: 10.1371/journal.pone.0089621. eCollection 2014.
PainOsteoarthritisIncreased expression of NGF mRNA and protein in osteocytes in the subchondral bone of osteoarthritic joints *PPS Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulfate Sodium (PPS) and implications for pain associated with knee osteoarthritis.
Stapledon CJM, Tsangari H, Solomon LB, Campbell DG, Hurtado P, Krishnan R, Atkins GJ.
PLoS One. 2019 Sep 26;14(9):e0222602. doi: 10.1371/journal.pone.0222602. eCollection 2019.