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.


Metabolism


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].


Diabetes


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].


Cancers


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).


Protocols


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].


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