PENTOSAN POLYSULFATE

More than 27 million Americans are affected by osteoarthritis, a degenerative disease that is the most common form of arthritis.

Osteoarthritis (OA) is caused by a breakdown of cartilage – the tissue that covers the ends of bones where they form a joint. Healthy cartilage allows bones to glide over one another, and it absorbs energy from the shock of physical movement. In osteoarthritis, the surface layer of cartilage breaks down and wears away. This results in bones under the cartilage rubbing together, causing pain, swelling, and stiffness. Bone spurs can develop, permanently changing the joint’s shape.

OA is by far the most common form of arthritis and has a growing impact on health care. Even now, there is no therapeutic agent that works directly on OA. However, a drug called pentosan polysulfate (PPS) is showing great promise for the treatment of OA.

In addition to arthritis it has beneficial properties in many other tissue processes such as cartilage protection, sports medical applications in joint tissue repair, stimulation of stem cells and differentiation of stem cells in repair biology, as well as anti-viral, anti-bacterial and anti-tumor properties. Pentosan is a multifunctional tissue-protective molecule of potential therapeutic application for a diverse range of disease processes.

Pentosan polysulfate sodium (PPS) Uses

Australian researcher and physician, Dr. Peter Ghosh from the University of Sydney has brought an old drug back into the light for arthritis sufferers. The drug is called pentosan polysulfate sodium (known in medical circles as PPS). To date, trials of the drug involving human patients have been proven highly successful. As PPS eliminates pain associated with arthritic disease by acting on bone marrow lesions that cause pain and cartilage degeneration. By controlling these lesions there is a reduction in symptoms and pain.

PPS is a very safe drug and has been successfully used for 70 years to treat urinary infections in women and is FDA-approved and used for the treatment of interstitial cystitis (or painful bladder syndrome), deep vein thrombosis and is fast tracked for use in osteoarthritis. The drug is neither an anabolic steroid nor an opioid-based pain reliever so is not considered to enhance performance.

Established and potential new therapeutic applications for Pentosan

The benefits of pentosan polysulfate include:

• Treats bone marrow edema lesions (BMLs)
• Sports medicine treatment of damaged joint tissues including tendons, menisci, and articular cartilage (Limiting cartilage deterioration & promoting new cartilage formation)
• Promotion of tissue repair and regeneration and pain relief in OA/RA
• Inhibition of Nerve Growth Factor production by osteocytes providing pain relief in OA/RA
• Stimulation of Hyaluronic acid synthesis by synoviocytes, fibroblasts
• Anti-inflammation: regulation of cytokine and inflammatory mediator production & inhibition of leucocyte trafficking in inflamed tissues
• Promotion of Intervertebral disc disease repair and regeneration and alleviation of low back pain
• Modulation of vascular coagulation, fibrinolysis and thrombocytopenia
• Promotion of protease inhibitor efficiency in tissues offering greater protection from proteolysis
• Thickening the joint fluid – thus acting as a better lubricant. Improving blood supply to the joint, in turn helping it heal. By virtue of these actions, it provides pain relief for a much longer period of time
• Prevention of lipid accumulation in blood vessels in atherosclerosis
• Anti-viral prevention of host cell infection/viral replication. Inhibits in vitro replication of HIV and other enveloped viruses
• Promotion of stromal Mesenchymal stem cells differentiation/proliferation/expansion for repair biology applications

Side Effects of Pentosan

Common side effects of PPS include swelling, headache, dizziness, nausea, indigestion, malaise and diarrhea.

How does pentosan work in arthritis? 

In osteoarthritis, pentosan reduces the destruction of cartilage by affecting inflammatory mediators. It also increases the number of proteoglycans into the extracellular matrix. Proteoglycans are important because they allow tissues like collagen to withstand compression and swelling forces. Joint cartilage also contains Proteoglycans.

In the synovium, the part that surrounds the inner lining of your joint, pentosan increases both the production and the molecular weight of hyaluronan. Hyaluronan or Hyaluronic acid is a compound that occurs naturally in your body, and it is responsible for attracting and retaining moisture. Pentosan also has another anti-inflammatory function due to its fibrinolytic activity. This activity improves the blood flow not only in the synovium but also in the subchondral bone.

Nerve growth factor production in osteocytes is inhibited by Pentosan, reducing bone pain in osteoarthritis and rheumatoid arthritis (OA/RA). It also removes fatty compounds from lipid-engorged subchondral blood vessels in OA/RA cartilage, reducing joint pain.

Pentosan Polysulfate Studies

Recently, Paradigm Pharmaceuticals an Australian biotech company doing studies on Pentosan had reported an average 51.2% reduction in chronic knee pain by a group of osteoarthritis patients being treated with its injectable Pentosan Polysulfate Sodium drug. Researchers hope that it may work as well in relieving pain in other parts of the body.

Paradigm Biopharmaceuticals also concluded a phase 2A clinical trials of Pentosan Polysulfate to treat viral arthritis caused by mosquito-borne alphavirus infections, including the debilitating Ross River virus (RRV) and chikungunya virus (CHIKV).  The clinical trials passed both safety and efficacy measures amongst participants with chronic RRV-induced arthralgia who were treated with the injectable pentosan polysulfate sodium (PPS). At their three-month follow-up, 72.7% of the study participants treated with PPS showed near remission of symptoms in contrast to those participants who were administered with a placebo (14.3%). 

Research

Smith MM, Melrose J. Pentosan Polysulfate Affords Pleotropic Protection to Multiple Cells and Tissues. Pharmaceuticals. 2023; 16(3):437. https://doi.org/10.3390/ph16030437

Liu, X.; Virk, S.; Federova, T.; Oo, W.M.; Hunter, D.J. The effect of pentosan polysulfate sodium for improving dyslipidaemia and knee pain in people with knee osteoarthritis: A pilot study. Osteoarthr. Cartil. Open. 2023, 10030343.

Ennemoser, M.; Rieger, J.; Muttenthaler, E.; Gerlza, T.; Zatloukal, K.; Kungl, A.J. Enoxaparin and pentosan polysulfate bind to the SARS-CoV-2 spike protein and human ACE2 receptor, inhibiting Vero cell infection. Biomedicines 2022, 10, 49.

Hayes, A.; Farrugia, B.L.; Biose, I.J.; Bix, G.J.; Melrose, J.; Perlecan, A. Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration. Front. Cell Dev. Biol. 2022, 10, 856261.

Kenji Kumagai, Susumu Shirabe, Noriaki Miyata, Masakazu Murata, Atsushi Yamauchi, Yasuhumi Kataoka and Masami Niwa. Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial. BMC Clin Pharmacol. 2010; 10:7. Published online 2010 Mar 28. doi: 10.1186/1472-6904-10-7. PMCID: PMC2873929. PMID: 20346179

Ghosh P, Edelman J, March L, Smith M. Effects of pentosan polysulfate in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled pilot study. Current Therapeutic Research. 2005;66:552–571. doi: 10.1016/j.curtheres.2005.12.012.

Ghosh P. The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Semin Arthritis Rheum. 1999 Feb;28(4):211-67.

Takizawa M, Yatabe T, Okada A, Chijiwa M, Mochizuki S, Ghosh P, Okada Y. Calcium pentosan polysulphate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS Letters. 2008;582:2945–2949. doi: 10.1016/j.febslet.2008.07.036.

Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P, Nagase H. Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J. 2008;22:3515–3524. doi: 10.1096/fj.08-112680. 

Munteanu SE1, Ilic MZ, Handley CJ. Calcium pentosan polysulfate inhibits the catabolism of aggrecan in articular cartilage explant cultures. Arthritis Rheum. 2000 Oct;43(10):2211-8.