Pentosan Polysulfate: A Pleiotropic, Antiarthritic Compound

Pentosan polysulfate (PPS) is a semi-synthetic, sulfated polysaccharide from the wood of the beech plant, Fagus sylvatica. Daily oral or weekly subcutaneous administration of PPS has pleiotropic effects on health, including inhibiting the degradation of and increasing the synthesis of joint tissue. As its primary side effect, maculopathy, is seen mostly after many years of use, intermittent or 1-2 years of PPS use may be an attractive option for athletes.

This blog post is a companion piece to a YouTube video, which you can access here. In this post, we will survey papers on PPS’s effects on health, paying particular attention to its effects on joints integrity.


1. PPS has an average molecular weight of 4000-6000 Da, similar to that of low molecular weight heparin[1].

2. Oral PPS, brand name Elmiron, is an FDA-approved treatment for interstitial cystitis (IC).

a. Pharmacokinetics in humans resembles those in rodents. Oral bioavailability is less than 1% with the majority of PPS being excreted, unchanged, in feces (84%). Metabolites in urine (6%) were of a lower molecular weight and desulfated, indicating PPS was metabolized by depolymerization and desulfation[2].

b. Oral PPS is of different molecular weights. This in vivo study of PPS pharmacokinetics in rabbits indicates that urinary recovery of PPS is almost entirely composed of low molecular weight PPS when it is orally administered and less so when it is administered IV[3].

3. Injectable PPS, brand name SP54[4].

a. Injectable heparin, low molecular weight heparin, and SP54 were trialed in humans. Molecular weight was inversely associated with absorption during subcutaneous injection[5].

The Brain

1. PPS, as well as the low molecular weight version of heparin named dalteparin, attenuates hippocampal neuronal damage due to ischemia/reperfusion when administered post-operation, suggesting that PPS may be neuroprotective for ischemic stroke[6].

2. PPS has anti-prion effects in vitro and in vivo[7], likely modulated by PPS’s interaction with heparin binding sites on prion proteins[8].

3. PPS has been shown to reduce the size and number of beta amyloid plaque aggregates, and to protect the blood brain barrier integrity, in a rodent model of Alzheimer’s disease[9].

Iron and Blood

1. Like commercial heparins, PPS is an inhibitor of hepcidin (a central regular of iron homeostasis) synthesis[10].

a. It has 1/15th the anticoagulant activity of heparin.

2. PPS dose-dependently increases the partial thromboplastin time (PTT) in horses[11].

Bladder Ailments

1. Interstitial cystitis (IC) is a disease believed to be caused by a weak bladder epithelium, resulting in diffusion of components of urine across the bladder wall, producing an autoimmune reaction. It is more frequently observed in women and characterized by pelvic pain and urgent, frequent urination.

a. It is effectively treated with oral glycosaminoglycan (PPS) as an add on therapy[12].

b. Fascinatingly, IV infusions of 6000 mg NAC per infusion cycle resolved IC in a case report, likely via a reduction in inflammatory cytokine activity (all reduced, except for IL-6, which increased, inexplicably)[13].

Cardiovascular Disease

1. In Watanabe heritable hyperlipidemic (WHHL) rabbits fed an atherogenic diet who developed severe atherosclerosis, one month of treatment with oral PPS “retards” the progression of atherosclerosis[14].

2. In rodents with heart pressure overload due to aortic banding, PPS treatment’s near 80% inhibition of the aggrecan ADAMTS4 protects systolic function, indicating PPS may be an effective therapy for heart failure[15].

a. Interestingly, ADAMTS2 appears to play a causal role in the development of cardiomegaly due to pressure overloads[16], while in the brain, ADAMTS4 may be necessary for the myelination of oligodendrocytes[17].


1. PPS has been shown to attenuate inflammation in aging diabetic mice.

a. This in vitro study of high glucose treated renal cells found that PPS inhibited apoptosis and inflammation via blocking p38 MAPK activation, inhibiting NF-kB activation, and reducing the synthesis of TNF-a, IL-1B, and IL-6[18].


1. In vitro and in vivo rodent models, PPS treatment inhibits paracrine effects of heparin-binding growth factors (HBGFs, which proliferate endothelial cells and produce local angiogenesis) released from tumor cells[19].

2. In vivo phase I human trials have yet to show a prominent anti-tumor effect[20].

a. They have revealed GI bleeding and toxicity from oral PPS treatment in volunteers with advanced malignancies[21]. In this study, 3 patients with sarcomas had their disease progression halt until 1-3 months after PPS cessation, whereby the malignancy began to progress again.

i. Chronic oral dosing also produced rectal ulcers, which were not seen in subcutaneous and intravascular studies.

1. The rectal ulcers were likely due to PPS mostly not being absorbed in the GI tract and accumulating in the distal rectum prior to evacuation, or due to PPS binding to basic fibroblast growth factor (bFGF) and thereby depleting local GI tissue of a protectant.

a. A later study confirmed FGF-2’s role in PPS induced structural changes in intestinal vessels, producing lethal intestinal hemorrhages in mice[22].

ii. The authors suggest intermittent dosing may be more effective because it allows the washing out of bFGF, preventing its upregulation.

Kidney Disease

1. In a rodent model of diabetic nephropathy (DN), oral PPS treatment in elderly rodents preserved kidney function, reduced albuminuria, inhibited pro-inflammatory gene expression[23].

2. PPS may prevent the recurrence of kidney stones by decreasing liver glycollate oxidase (GAO) activity[24].

3. In a rodent model of ischemia/reperfusion-dependent acute kidney injury (AKI), long-term PPS treatment attenuated AKI in diabetic rodents while a single high-dose parenteral administration of PPS prior to revascularization may be protective even in non-diabetic rodents[25].

4. In patients with chronic kidney disease (CKD), 3 months of PPS treatment reduced the expression of pro-inflammatory cytokines TNF-a and IL-18, reduced proteinuria, and improved eGFR. It also lowered total cholesterol levels[26].

5. In rodents, PPS is kidney-protective in the 5/6 nephrectomy model by attenuating glomerular hypertension and suppressing inflammation[27].

6. In rodents, PPS treatment confers kidney protection from sodium-induced hypertension. The protective effect is associated with increased P2X1 receptor reactivity[28].

Immune Function

1. In rodents, oral PPS treatment increases splenic macrophage and natural killer cell activity, stimulating the immune system and producing a reduction in melanoma tumors[29].

2. Th2-dependent cytokines (e.g. IL-4, IL-5, IL-13) are drivers of allergic inflammatory responses, as in allergic rhinitis. PPS binds to and inhibits the activity of these cytokines stronger than heparin, producing an anti-allergic effect comparable to topical nasal steroid treatment[30].

Benign Prostatic Hyperplasia (BPH)

1. In in vitro studies, PPS has been shown to decrease proliferation of smooth muscle cells and decrease extracellular matrix deposition in the prostate, two hallmarks of BPH[31].

Rare Diseases

1. PPS treatment has been found to be protective, via its anti-inflammatory effect, on lysosomal storage disorders such as Gaucher and Fabry diseases[32].

2. Mucopolysaccharidosis (MPS)

a. In a dog model of mucopolysaccharidosis (MPS) type VI, a disease in which complex carbohydrates accumulate in the body, PPS treatment decreased IL-8 and TNF-a in cerebrospinal fluid and was found to be a safe and useful therapy for MPS at a human equivalent dose of 1.6 mg/kg[33].

b. A rodent model of MPS confirmed these findings, adding that neuroinflammation and anxiety/hyperactivity also declined[34].

Anti-viral Effects

1. HIV:

a. PPS is an anti-HIV agent in vitro, inhibiting HIV more than heparin[35].

b. The mechanism of inhibition may be via tyrosine kinase inhibition[36].

2. Human T-cell leukemia virus type 1 (HTLV-1) causes T-cell leukemia and inflammatory diseases.

a. PPS is cytotoxic to HTLV-1, blocking HTLV-1 infection in rodents. It also attenuates symptoms of related inflammatory diseases[37].

Modulation of Inflammation in the Context of Arthritis

1. IL-1B-dependent effects: In this in vitro canine model, PPS inhibits interleukin-1beta (IL-1B)-dependent iNOS, c-Jun, and HIF-1a mRNA upregulation which may protect against osteoarthritis (OA)[38].

a. Note that nitric oxide is causal in articular chondrocyte cell death[39].

b. In this in vitro canine model, IL-1B-dependent phosphorylation of p38 and ERK were inhibited while JNK phosphorylation was not. Nuclear translocation of NF-kB was inhibited[40].

2. IL-1a-dependent effects: In this in vitro model using human chondrocytes, PPS was shown to inhibit interleukin-1alpha (IL-1a)-dependent activation of ADAMTS4 – a disintegrin and metalloproteinase that is overexpressed in human osteoarthritic cartilage and associates positively with the extent of cartilage destruction, likely via a causal effect on aggrecan degradation[41].

a. In OA, collagen is degraded by matrix metalloproteinases (e.g. MMP-13) while aggrecan is degraded by ADAMTS metalloproteinases (e.g. ADAMTS4). Mechanical damage and inflammation govern the expression of these enzymes[42].

i. PRP treatment reduces the expression of MMP-13 and TGF-B1 in OA[43].

b. PPS’s inhibition of aggrecanases like ADAMTS4 are dependent on its improving the efficacy of tissue inhibitor of metalloproteinases 3 (TIMP-3) as an aggrecanase inhibitor. It increases TIMP-3’s affinity for ADAMTS-4 and ADAMTS-5 by over 100x[44].

c. Small molecules that directly bind to IL-1a are more successful at inhibiting collagen degradation than molecules that bind to its receptor[45].

3. TNF-a-dependent effects:

a. In this in vitro human model, PPS inhibits TNF-a-induced proNGF secretion and NGF mRNA expression, potentially explaining its attenuation of pain in osteoarthritis[46].

b. PPS also inhibits TNF-a-induced IkB phosphorylation, NF-kB transcription, and p38 phosphorylation, as seen in this rabbit model of atherosclerosis[47].

Viral Models of Arthritis

1. The Chikungunya virus (CHIKV), born by arthropods, leaves millions with arthritis. It’s etiology closely resembles that of rheumatoid arthritis.

a. Rodents with CHIKV treated with PPS sodium exhibited better mobility, reduced local inflammation in their joints, and modulated growth factor related genes variably across tissue[48].

2. An RCT showed that another alphavirus, the Ross River virus (RRV), can be similarly treated with 2 mg/kg twice weekly subcutaneous injections for 6 weeks[49].

Arthritis in Animals

1. In rabbits, PPS pre-treatment appears able to inhibit cartilage damage in the face of inflammatory insult[50].

2. In Mongolian horses, 4 weeks of once weekly injections of PPS altered the balance of anabolic (CPII) and catabolic (COMP) markers of cartilage metabolism in favor of anabolism[51].

3. A survey of 76 Australian veterinarians found that[52]:

a. 80% of the vets used PPS as a prophylactic agent prior to competition.

b. 48% considered it to have a high efficacy in the prevention of osteoarthritis.

c. The most common dose regimen was once weekly intramuscular injections of 3 mg/kg for 4 weeks followed by monthly injections.

d. Most vets combined PPS with other drugs, most commonly, corticosteroids and hyaluronate (HA).

e. 83% of the vets thought a combination of PPS, HA, and glucosamine was more efficacious than PPS monotherapy in the treatment of OA.

4. In dogs, PPS time and dose-dependently encouraged proliferating chondrocytes to remain in the G1 phase and less in the S and G2 phases of their cell cycles. It also promoted chondrocytes to develop into a chondrogenic phenotype by upregulating collagen type II (Col2A1 gene) mRNA and glycosaminoglycan (GAG) synthesis[53].

5. In an allogenous cartilage particle (ACP) model of osteoarthritis, PPS was found to be disease modifying – meaning that it attenuated the progression of the disease as opposed to only alleviating symptoms[54].

Mesenchymal Precursor Cells

1. Mesenchymal precursor cells (MPCs) are self-renewing, undifferentiated cells that can differentiate into various cells of the mesenchymal lineage, including bone, cartilage, tendon, and adipose tissue. PPS promotes the proliferation and chondrogenesis of these cells, making it a likely compliment to cartilage repair technologies using mesenchymal cells[55].

a. PPS induces the proliferation and chondrogenesis of MPCs via modifying their basal gene and protein expression[56].

Human Trials

1. An in vivo study on PPS (6 once weekly subcutaneous 2 mg/kg injections) greatly improved knee osteoarthritis parameters for up to a year[57].

2. In a human RCT, 4 weeks of once weekly injections of 3 mg/kg sodium pentosan polysulfate improved knee function for 8 weeks after the cessation of treatment in osteoarthritic people[58].

3. Intraventricular PPS extends life in Creutzfeldt-Jakob disease through an unknown, potentially direct mechanism that this post-mortem study was unable to elucidate[59].

4. In humans, short term administration of PPS with pentoxifylline alleviated impacts of diabetic neuropathy on cardiovascular autonomic function[60].

2. An observational study of humans with prion disease found that those who used PPS may have lived longer than mean survival times[61].

Side Effect: Maculopathy

1. The unique pigmentary maculopathy presents on average after a cumulative exposure of 2263 g over 186 months. This would require 11k injections of 200 mg or 15.5 years of exposure[62].

2. The retinopathy appears to progress for at least 10 years on average[63].

3. PPS-induced maculopathy is easily distinguished from hereditary maculopathies[64] including age-related macular degeneration[65] during imaging.

4. Postulated mechanisms producing damage to the retinal pigment epithelium (RPE) include[66]:

a. Damage to choriocapillaris.

b. Blockade of fibroblast growth factor (FGF).


1. Dosing:

a. In osteoarthritic dogs, it appears that 5 mg/kg/week is a worse dosing than 1 mg/kg, with 3 mg/kg yielding the best effects[67].

2. Injection vs. capsule:

a. In a canine model, daily oral dosing compared to every other week subcutaneous injection revealed that subcutaneous injections better reduced inflammation in cerebrospinal fluid (CSF) and in the vascular structure, likely due to greater bioavailability[68].

3. Co-administration:

a. As oral PPS’s anticoagulant and fibrinolytic effects are 1/40th those of heparin (PPS prolongs prothrombin time and activated partial thromboplastin time by less than 1%), combined treatment with oral PPS and heparin has been found to be safe for patients with interstitial cystitis (IC). Trials using 900 mg/day of oral PPS and long-term studies using PPS for up to 90 months reported no coagulopathies in people with IC[69].

i. Note that there are case reports of coagulopathy from oral PPS monotherapy in individuals with IC[70].

[1] Lin, L., Yu, Y., Zhang, F., Xia, K., Zhang, X., & Linhardt, R. J. (2019). Bottom-up and top-down profiling of pentosan polysulfate. Analyst, 144(16), 4781-4786. [2] Simon, M., McClanahan, R. H., Shah, J. F., Repko, T., & Modi, N. B. (2005). Metabolism of [3H] pentosan polysulfate sodium (PPS) in healthy human volunteers. Xenobiotica, 35(8), 775-784. [3] Erickson, D. R., Sheykhnazari, M., & Bhavanandan, V. P. (2006). Molecular size affects urine excretion of pentosan polysulfate. The Journal of urology, 175(3), 1143-1147. [4] Kalbhen, D. A., & Fischer, W. (1973). Pharmacologic studies on the anti-inflammatory effect of pentosan polysulfate (SP 54) in combination with other analgesic or antiphlogistic agents. Arzneimittel-Forschung, 23(5), 712-718. [5] Dawes, J., Prowse, C. V., & Pepper, D. S. (1986). Absorption of heparin, LMW heparin and SP54 after subcutaneous injection, assessed by competitive binding assay. Thrombosis research, 44(5), 683-693. [6] Sakurai-Yamashita, Y., Kinugawa, H., & Niwa, M. (2006). Neuroprotective effect of pentosan polysulphate on ischemia-related neuronal death of the hippocampus. Neuroscience letters, 409(1), 30-34. [7] Bone, I., Belton, L., Walker, A. S., & Darbyshire, J. (2008). Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. European journal of neurology, 15(5), 458-464. [8] Dealler, S., & Rainov, N. G. (2003). Pentosan polysulfate as a prophylactic and therapeutic agent against prion disease. IDrugs, 6(5), 470. [9] Deli, M. A., Veszelka, S., Csiszár, B., Tóth, A., Kittel, A., Csete, M., ... & Niwa, M. (2010). Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity. Journal of Alzheimer's Disease, 22(3), 777-794. [10] Asperti, M., Denardo, A., Gryzik, M., Castagna, A., Girelli, D., Naggi, A., ... & Poli, M. (2020). Pentosan polysulfate to control hepcidin expression in vitro and in vivo. Biochemical pharmacology, 175, 113867. [11] Dart, A. J., Perkins, N., Dowling, B. A., Batterham, T., Livingston, C., & Hodgson, D. R. (2001). The effect of three different doses of sodium pentosan polysulphate on haematological and haemostatic variables in adult horses. Australian veterinary journal, 79(9), 624-627. [12] Kasyan, G., Kupriyanov, Y., Karasev, A., Baibarin, K., & Pushkar, D. (2021). Safety and efficacy of pentosan polysulfate in patients with bladder pain syndrome/interstitial cystitis: a multicenter, double–blind, placebo–controlled, randomized study. Central European Journal of Urology, 74(2), 201. [13] Maharaj, D., Srinivasan, G., Makepeace, S., Hickey, C. J., & Gouvea, J. (2021). Clinical Remission Using Personalized Low-Dose Intravenous Infusions of N-acetylcysteine with Minimal Toxicities for Interstitial Cystitis/Bladder Pain Syndrome. Journal of Personalized Medicine, 11(5), 342. [14] Lupia, E., Zheng, F., Grosjean, F., Tack, I., Doublier, S., Elliot, S. J., ... & Striker, G. E. (2012). Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and-9. Laboratory investigation, 92(2), 236-245. [15] Vistnes, M., Aronsen, J. M., Lunde, I. G., Sjaastad, I., Carlson, C. R., & Christensen, G. (2014). 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. PLoS One, 9(3), e89621. [16] Wang, X., Chen, W., Zhang, J., Khan, A., Li, L., Huang, F., ... & Chen, X. (2017). Critical role of ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs 2) in cardiac hypertrophy induced by pressure overload. Hypertension, 69(6), 1060-1069. [17] Pruvost, M., Lépine, M., Leonetti, C., Etard, O., Naveau, M., Agin, V., ... & Vivien, D. (2017). ADAMTS‐4 in oligodendrocytes contributes to myelination with an impact on motor function. Glia, 65(12), 1961-1975. [18] Chen, P., Yuan, Y., Zhang, T., Xu, B., Gao, Q., & Guan, T. (2018). Pentosan polysulfate ameliorates apoptosis and inflammation by suppressing activation of the p38 MAPK pathway in high glucose‑treated HK‑2 cells. International journal of molecular medicine, 41(2), 908-914. [19] Zugmaier, G., Lippman, M. E., & Wellstein, A. (1992). Inhibition by pentosan polysulfate (PPS) of heparin-binding growth factors released from tumor cells and blockage by PPS of tumor growth in animals. JNCI: Journal of the National Cancer Institute, 84(22), 1716-1724. [20] Lush, R. M., Figg, W. D., Pluda, J. M., Bitton, R., Headlee, D., Kohler, D., ... & Cooper, M. R. (1996). A phase I study of pentosan polysulfate sodium in patients with advanced malignancies. Annals of oncology, 7(9), 939-944. [21] Marshall, J. L., Wellstein, A., Rae, J., DeLap, R. J., Phipps, K., Hanfelt, J., ... & Hawkins, M. J. (1997). Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer. Clinical cancer research, 3(12), 2347-2354. [22] Jerebtsova, M., Wong, E., Przygodzki, R., Tang, P., & Ray, P. E. (2007). A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice. American Journal of Physiology-Heart and Circulatory Physiology, 292(2), H743-H750. [23] Wu, J., Guan, T. J., Zheng, S., Grosjean, F., Liu, W., Xiong, H., ... & Zheng, F. (2011). Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice. Laboratory investigation, 91(10), 1459-1471. [24] Subha, K., & Varalakshmi, P. (1992). Enzymatic changes in liver in Calcium oxalate stone forming rats treated with sodium pentosan polysulphate. Indian Journal of Clinical Biochemistry, 7(2), 121-124. [25] Hardi, P., Nagy, T., Fazekas, G., Arató, E., Menyhei, G., Sétáló Jr, G., ... & Jancsó, G. (2016). Sodium pentosan polysulfate reduced renal ischemia-reperfusion-induced oxidative stress and inflammatory responses in an experimental animal model. Journal of vascular research, 53(3-4), 230-242. [26] Dudari, O., Shifrisi, M., Driyanska, V. Y., Krot, V. F., Loboda, O. M., Krasiuke, K., ... & Bryzhachenko, T. P. (2015). PENTOSAN POLYSULPHATE INFLUENCEON THE COURSE OF CHRONICKIDNEYDISEASE ST'. II-IV. Ukrainian Journal of Nephrology and Dialysis, (3 (47)), 10-16. [27] Bobadilla, N. A., Tack, I., Tapia, E., Sánchez-lozada, L. G., Santamaría, J., Jiménez, F., ... & Herrera-acosta, J. (2001). Pentosan polysulfate prevents glomerular hypertension and structural injury despite persisting hypertension in 5/6 nephrectomy rats. Journal of the American Society of Nephrology, 12(10), 2080-2087. [28] Guan, Z., Singletary, S. T., Cha, H., Van Beusecum, J. P., Cook, A. K., Pollock, J. S., ... & Inscho, E. W. (2016). Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. American Journal of Physiology-Renal Physiology, 310(6), F456-F465. [29] Thakur, S. A., Nyska, A., White Jr, K. L., Smith, M. J., Auttachoat, W., & Germolec, D. R. (2014). Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice. Food and chemical toxicology, 68, 196-203. [30] Sanden, C., Mori, M., Jogdand, P., Jönsson, J., Krishnan, R., Wang, X., & Erjefält, J. S. (2017). Broad Th2 neutralization and anti‐inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis. Immunity, inflammation and disease, 5(3), 300-309. [31] Elliot, S. J., Zorn, B. H., McLeod, D. G., Moul, J. W., Nyberg, L., Striker, L. J., & Striker, G. E. (2003). Pentosan polysulfate decreases prostate smooth muscle proliferation and extracellular matrix turnover. Prostate cancer and prostatic diseases, 6(2), 138-142. [32] Crivaro, A. N., Mucci, J. M., Bondar, C. M., Ormazabal, M. E., Ceci, R., Simonaro, C., & Rozenfeld, P. A. (2019). Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease. Plos one, 14(5), e0217780. [33] Simonaro, C. M., Tomatsu, S., Sikora, T., Kubaski, F., Frohbergh, M., Guevara, J. M., ... & Haskins, M. E. (2016). Pentosan polysulfate: oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PloS one, 11(4), e0153136. [34] Guo, N., DeAngelis, V., Zhu, C., Schuchman, E. H., & Simonaro, C. M. (2018). Pentosan polysulfate treatment of mucopolysaccharidosis type IIIA mice. In JIMD Reports, Volume 43 (pp. 37-52). Springer, Berlin, Heidelberg. [35] Baba, M., Nakajima, M., Schols, D., Pauwels, R., Balzarini, J., & De Clercq, E. (1988). Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro. Antiviral research, 9(6), 335-343. [36] Srivastava, A. K., Sékaly, R. P., & Chiasson, J. L. (1993). Pentosan polysulfate, a potent anti HIV and anti tumor agent, inhibits protein serine/threonine and tyrosine kinases. Molecular and cellular biochemistry, 120(2), 127-133. [37] Ma, G., Yasunaga, J. I., Ohshima, K., Matsumoto, T., & Matsuoka, M. (2019). Pentosan polysulfate demonstrates anti-human T-cell leukemia virus type 1 activities in vitro and in vivo. Journal of virology, 93(16), e00413-19. [38] Bwalya, E. C., Kim, S., Fang, J., Wijekoon, H. S., Hosoya, K., & Okumura, M. (2017). Pentosan polysulfate inhibits IL-1β-induced iNOS, c-Jun and HIF-1α upregulation in canine articular chondrocytes. PLoS One, 12(5), e0177144. [39] Akaraphutiporn, E., Sunaga, T., Bwalya, E. C., Yanlin, W., Carol, M., & Okumura, M. (2020). An Insight into the Role of Apoptosis and Autophagy in Nitric Oxide–Induced Articular Chondrocyte Cell Death. Cartilage, 1947603520976768. [40] Sunaga, T., Oh, N., Hosoya, K., Takagi, S., & Okumura, M. (2011). Inhibitory effects of pentosan polysulfate sodium on MAP-kinase pathway and NF-κB nuclear translocation in canine chondrocytes in vitro. Journal of Veterinary Medical Science, 1112250746-1112250746. [41] Takizawa, M., Yatabe, T., Okada, A., Chijiiwa, M., Mochizuki, S., Ghosh, P., & Okada, Y. (2008). Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS letters, 582(19), 2945-2949. [42] Troeberg, L., & Nagase, H. (2012). Proteases involved in cartilage matrix degradation in osteoarthritis. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 1824(1), 133-145. [43] M Halfaya, F., GH, R., & OM, A. (2021). Effect of Platelet-rich Plasma on MMP-13, ARE and TGF β1 in MIA-Induced Osteoarthritis in Rats. Journal of Veterinary Medical Research, 27(2), 109-118. [44] Troeberg, L., Fushimi, K., Khokha, R., Emonard, H., Ghosh, P., & Nagase, H. (2008). Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. The FASEB Journal, 22(10), 3515-3524. [45] Kar, S., Smith, D. W., Gardiner, B. S., & Grodzinsky, A. J. (2016). Systems based study of the therapeutic potential of small charged molecules for the inhibition of IL-1 mediated cartilage degradation. PloS one, 11(12), e0168047. [46] Stapledon, C. J., Tsangari, H., Solomon, L. B., Campbell, D. G., Hurtado, P., Krishnan, R., & Atkins, G. J. (2019). Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis. PloS one, 14(9), e0222602. [47] Lupia, E., Zheng, F., Grosjean, F., Tack, I., Doublier, S., Elliot, S. J., ... & Striker, G. E. (2012). Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and-9. Laboratory investigation, 92(2), 236-245. [48] Rudd, P. A., Lim, E. X., Stapledon, C. J., Krishnan, R., & Herrero, L. J. (2021). Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation. Plos one, 16(9), e0255125. [49] Krishnan, R., Duiker, M., Rudd, P. A., Skerrett, D., Pollard, J. G., Siddel, C., ... & Griffin, P. (2021). Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, randomized, double-blind, placebo-controlled study. BMC musculoskeletal disorders, 22(1), 1-11. [50] Smith, M. M., Ghosh, P., Numata, Y., & Bansal, M. K. (1994). The Effects of Orally Administered Calcium Pentosan Polysulfate on Inflammation and Cartilage Degradation Produced in Rabbit Joints by Intraarticular Injection of a Hyaluronate—Polylysine Complex. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology, 37(1), 125-136. [51] Tsogbadrakh, M., Sunaga, T., Bwalya, E., Wijekoon, S., Akaraphutiporn, E., Wang, Y., ... & Okumura, M. (2020). Clinical evaluation of pentosan polysulfate as a chondroprotective substance in native Mongolian horses. Japanese Journal of Veterinary Research, 68(3), 203-208. [52] Kramer, C. M., Tsang, A. S., Koenig, T., Jeffcott, L. B., Dart, C. M., & Dart, A. J. (2014). Survey of the therapeutic approach and efficacy of pentosan polysulfate for the prevention and treatment of equine osteoarthritis in veterinary practice in A ustralia. Australian veterinary journal, 92(12), 482-487. [53] Akaraphutiporn, E., Bwalya, E. C., Kim, S., Sunaga, T., Echigo, R., & Okumura, M. (2020). Effects of pentosan polysulfate on cell proliferation, cell cycle progression and cyclin-dependent kinases expression in canine articular chondrocytes. Journal of Veterinary Medical Science, 20-0091. [54] Elmesiry, A. M., Seleim, M. A., Mansour, A. A., & Hill, D. C. (2016). Pentosan Polysulfate as a Disease Modifier of Cartilage Degeneration in Experimental Osteoarthritis. J Arthritis, 5(199), 2. [55] Ghosh, P., Wu, J., Shimmon, S., Zannettino, A. C., Gronthos, S., & Itescu, S. (2010). Pentosan polysulfate promotes proliferation and chondrogenic differentiation of adult human bone marrow-derived mesenchymal precursor cells. Arthritis research & therapy, 12(1), 1-17. [56] Wu, J., Shimmon, S., Paton, S., Daly, C., Goldschlager, T., Gronthos, S., ... & Ghosh, P. (2017). Pentosan polysulfate binds to STRO-1+ mesenchymal progenitor cells, is internalized, and modifies gene expression: a novel approach of pre-programing stem cells for therapeutic application requiring their chondrogenesis. Stem cell research & therapy, 8(1), 1-15. [57] Kumagai, K., Shirabe, S., Miyata, N., Murata, M., Yamauchi, A., Kataoka, Y., & Niwa, M. (2010). Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis-An open clinical trial. BMC clinical pharmacology, 10(1), 1-9. [58] Ghosh, P., Edelman, J., March, L., & Smith, M. (2005). Effects of pentosan polysulfate in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled pilot study. Current therapeutic research, 66(6), 552-571. [59] Newman, P. K., Todd, N. V., Scoones, D., Mead, S., Knight, R. S. G., Will, R. G., & Ironside, J. W. (2014). Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate. Journal of Neurology, Neurosurgery & Psychiatry, 85(8), 921-924. [60] Laczy, B., Cseh, J., Mohás, M., Markó, L., Tamaskó, M., Kőszegi, T., ... & Wittmann, I. (2009). Effects of pentoxifylline and pentosan polysulphate combination therapy on diabetic neuropathy in type 2 diabetes mellitus. Acta diabetologica, 46(2), 105-111. [61] Bone, I., Belton, L., Walker, A. S., & Darbyshire, J. (2008). Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. European journal of neurology, 15(5), 458-464. [62] Pearce, W. A., Chen, R., & Jain, N. (2018). Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology, 125(11), 1793-1802. [63] Shah, R., Simonett, J. M., Lyons, R. J., Rao, R. C., Pennesi, M. E., & Jain, N. (2020). Disease course in patients with pentosan polysulfate sodium–associated maculopathy after drug cessation. JAMA ophthalmology, 138(8), 894-900. [64] Barnes, A. C., Hanif, A. M., & Jain, N. (2020). Pentosan polysulfate maculopathy versus inherited macular dystrophies: comparative assessment with multimodal imaging. Ophthalmology Retina, 4(12), 1196-1201. [65] Christiansen, J. S., Barnes, A. C., Berry, D. E., & Jain, N. (2021). Pentosan polysulfate maculopathy versus age-related macular degeneration: comparative assessment with multimodal imaging. Canadian Journal of Ophthalmology. [66] Abou-Jaoude, M. M., Davis, A. M., Fraser, C. E., Leys, M., Hinkle, D., Odom, J. V., & Maldonado, R. S. (2021). New insights into pentosan polysulfate maculopathy. Ophthalmic Surgery, Lasers and Imaging Retina, 52(1), 13-22. [67] Read, R. A., Cullis‐Hill, D., & Jones, M. P. (1996). Systemic use of pentosan polysulphate in the treatment of osteoarthritis. Journal of Small Animal Practice, 37(3), 108-114. [68] Simonaro, C. M., Tomatsu, S., Sikora, T., Kubaski, F., Frohbergh, M., Guevara, J. M., ... & Haskins, M. E. (2016). Pentosan polysulfate: oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PloS one, 11(4), e0153136. [69] van Ophoven, A., Heinecke, A., & Hertle, L. (2005). Safety and efficacy of concurrent application of oral pentosan polysulfate and subcutaneous low-dose heparin for patients with interstitial cystitis. Urology, 66(4), 707-711. [70] Gill, S., Naiman, S. C., Jamal, A., & Vickars, L. M. (2002). Massive bleeding on a bladder protectant: A case report of pentosan polysulfate sodium–induced coagulopathy. Archives of internal medicine, 162(14), 1644-1645.