HIV-1
Pentosan Polysulfate Sodium targets multiple biological processes. For interstitial cystitis, its mechanism is believed to involve the restoration of the protective glycosaminoglycan (GAG) layer on the bladder epithelium, which acts as a barrier against irritants in the urine. It also has anti-inflammatory properties, mediated by the inhibition of inflammatory mediators such as complement activation and leukocyte migration. In osteoarthritis, it exerts pro-chondrogenic effects by promoting the synthesis of cartilage matrix components like aggrecan and collagen type II. Its anti-HIV activity involves binding to the HIV gp120 envelope protein, which prevents the virus from attaching to and entering host CD4+ T-cells. It may also bind to other targets, such as prion proteins (PrP).

It has been demonstrated that pentosan polysulfate sodium inhibits HIV-1 activity in MT-4 cells, with an ED50 of 0.19 μg/mL. Complete suppression of HIV-1 antigen expression is achieved at a dose of 4.0 μg/mL. It suppresses HIV-1 antigen expression in HUT-78 cells with an ED50 of 0.02 μg/mL[2]. Pentosan Polysulfate Sodium inhibits TNFα's proinflammatory effects, suppresses NF-κB, and reduces the generation of MCP-1 induced by high glucose and advanced glycation end products (AGEs)[3].

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In vitro, Pentosan Polysulfate Sodium has been shown to be a potent and selective inhibitor of HIV-1. In MT-4 cells, its 50% effective antiviral dose (ED₅0) is 0.19 ug/mL, with a selectivity index (SI) of over 200, indicating potent antiviral activity with low cellular toxicity. It prevents HIV-1 infection by binding to the V3 loop of the viral gp120 protein, blocking interaction with CD4 and the chemokine co-receptors (CXCR4/CCR5). It has also been shown to inhibit the replication of other enveloped viruses, such as HSV and CMV. In cartilage cell cultures, it stimulates the synthesis of proteoglycans and reduces the activity of matrix metalloproteinases (MMPs), which degrade cartilage. In a model of interstitial cystitis, it restores the permeability barrier of cultured urothelial cells.

In 5/6 nephrectomized rats, pentosan polysulfate sodium has been demonstrated to reduce glomerulosclerosis and interstitial inflammation. Treatment with pentosan polysulfate preserves renal function, lowers albuminuria considerably, and lessens renal lesions, especially tubulointerstitial inflammation, greatly. In aged diabetic kidneys, pentosan polysulfate sodium also decreases proinflammatory gene expression and TNFα upregulation[3].

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In vivo, Pentosan Polysulfate Sodium is an FDA-approved drug for the treatment of interstitial cystitis. It is administered orally, and its efficacy has been demonstrated in placebo-controlled clinical trials, where it improved bladder pain and urinary urgency. In animal models, oral administration of pentosan polysulfate has been shown to preserve renal function, significantly reduce albuminuria, and markedly decrease the severity of renal lesions, including tubulointerstitial inflammation, in a rat model of chronic kidney disease. In a mouse model of prion disease, intraperitoneal injection of the drug prolonged survival and reduced prion protein (PrP) levels in the brain. In a model of osteoarthritis, intra-articular injection has shown efficacy in preserving cartilage structure and reducing pain. Its anti-HIV activity was studied in clinical trials, but due to its lack of oral bioavailability as a macromolecule, it was not pursued.

A typical non-cellular binding assay for Pentosan Polysulfate Sodium involves measuring its binding to HIV gp120. The assay can be performed using surface plasmon resonance (SPR). The recombinant HIV-1 gp120 protein (e.g., from IIIB strain) is immobilized on a sensor chip. Pentosan Polysulfate is injected at various concentrations (0.01-100 ug/mL) over the surface, and the association and dissociation rate constants are measured. The KD is calculated. Alternatively, a heparin-binding assay can be used. The compound is a heparin mimetic, and its binding to proteins (e.g., FGF-2) can be measured using a heparin-binding ELISA kit. A standard curve is generated, and the concentration of pentosan polysulfate is quantified by its ability to displace heparin from a protein.

In vitro cell-based assays for Pentosan Polysulfate Sodium include the HIV-1 cytoprotection assay using MT-4 cells. MT-4 cells are seeded in a 96-well plate at 2 × 10⁴ cells/well. Pentosan Polysulfate is added at various concentrations (0.01-100 ug/mL). Then, the cells are infected with HIV-1 (IIIB strain) at an appropriate MOI. After 5-7 days of incubation, cell viability is measured by the MTT assay. The EC₅0 (concentration that protects 50% of cells from viral cytopathic effect) is calculated. For cytotoxicity, uninfected MT-4 cells are treated with the compound, and the CC₅0 (concentration that causes 50% cell death) is measured by MTT. The selectivity index (SI) is CC₅0/EC₅0. For its mechanism of action in the bladder, human bladder urothelial cells (e.g., TERT-NHUC) can be cultured, and the permeability barrier function can be assessed by measuring the transepithelial electrical resistance (TEER) across a cell monolayer. Pentosan Polysulfate treatment can restore TEER in cells treated with inflammatory agents.

The in vivo efficacy of Pentosan Polysulfate Sodium for interstitial cystitis was established in randomized, double-blind, placebo-controlled clinical trials (Phase III). However, for a research context, an animal model is sometimes used. Female Sprague-Dawley rats (200-250 g) are anesthetized. Interstitial cystitis can be induced by intravesical instillation of protamine sulfate (10 mg/mL) followed by KCl (500 mM). The rats are then treated with Pentosan Polysulfate (10 mg/kg) administered orally (by gavage) daily for 14 days. A control group receives water. The pain response is assessed by measuring visceral pain behaviors (e.g., abdominal licking, stretching) and by mechanical sensitivity of the lower abdomen using von Frey filaments. At the end of the study, the bladders are collected for histological analysis to assess the thickness of the glycosaminoglycan (GAG) layer and for measurement of inflammatory markers (e.g., IL-6, TNF-alpha) by ELISA.

Absorption, Distribution and Excretion
Sprague-Dawley rats were administered (orally or intravenously) 5 mg/kg body weight of (3)H-labeled pentosan and sacrificed 1 hour or 4 hours later. Autoradiography showed that after intravenous injection, the radiolabeled pentosan was widely distributed throughout the animal, with significant marking in connective tissue, while radioactivity was lower in bone and cartilage. The concentration of the radiolabeled pentosan in urine was high, and it preferentially localized to the lining of the urinary tract. After oral administration, the tissue distribution of the radiolabeled pentosan was similar, but the radioactivity was lower. After oral administration of 1.0–1.2 mg pentosan to rabbits, the median urinary recovery rate of low molecular weight pentosan was 7.45% (range: 2.1–46.0%), and the median urinary recovery rate of high molecular weight pentosan was 0.1% (range: 0.0–0.3%). Following intravenous administration of 1–1.2 mg pentosans to rabbits, the median recovery rate of unfractionated pentosans in urine was 47.2% (range: 19.7–73.2%), the recovery rate of low molecular weight pentosans was 74.6% (range: 31.4–96.3%), and the recovery rate of high molecular weight pentosans was 3.3% (range: 2.5–5.0%). A study investigated pentosan excretion in 34 female patients with interstitial cystitis who received long-term pentosan therapy. The median concentration of pentosans in the urine of these patients was 1.2 μg/mL (range: 0.5–27.7 μg/mL). All pentosans recovered from the urine of these patients were low molecular weight pentosans. For more complete data on the absorption, distribution, and excretion of Elmiron (12 in total), please visit the HSDB records page.

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Metabolism / Metabolites
Orally absorbed pentosan sodium sulfate undergoes partial desulfurization in the liver and spleen, and partial depolymerization in the kidneys, generating various metabolites. Continuous administration leads to saturation of both desulfurization and depolymerization pathways. (The repetition of the first paragraph is likely an error in the original text.)

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Biological Half-Life
Five healthy male volunteers received intravenous injections of 0.1, 1, 7, or 50 mg of (125)I-labeled pentosan and unlabeled pentosan, respectively. The half-life was 13–18 minutes for the 0.1–7 mg dose groups and 45 minutes for the 50 mg dose group. …After oral administration of 300 mg or 450 mg of radiolabeled pentosan sodium polysulfate solution, the mean plasma radioactivity half-lives were 27 hours and 20 hours, respectively.

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The pharmacokinetic (PK) properties of Pentosan Polysulfate Sodium are characterized by poor oral absorption due to its high molecular weight and anionic charge. After oral administration, less than 5-10% of the dose is absorbed, which is sufficient for its local effect in the bladder. The absorbed fraction is distributed to the kidneys, liver, and spleen. It is not metabolized to a significant extent but is taken up by the reticuloendothelial system and degraded to desulfated polymers. It has a very long elimination half-life (t1/2) of up to 2-3 days in the plasma due to its large size and binding to plasma proteins. The absorbed drug is excreted primarily in the urine as low-molecular-weight metabolites. Following intravenous administration, it has a biphasic elimination pattern with a rapid initial distribution and a very slow terminal phase.

Toxicity Summary
Identification and Uses: Elmiron (pentosyl sulfate) is a white powder. Elmiron is a weak anticoagulant (1/15 the activity of heparin). It is indicated for the relief of bladder pain or discomfort caused by interstitial cystitis. It is also used in veterinary medicine. Human Studies: Elmiron is a highly sulfated semi-synthetic pentosyl polysaccharide with properties similar to heparin, used to treat interstitial cystitis. There have been no reports of Elmiron overdose. Based on the pharmacodynamics of the drug, toxicity may manifest as anticoagulation, bleeding, thrombocytopenia, abnormal liver function, and gastrointestinal upset. Cases of severe thrombocytopenia and ischemic stroke following Elmiron treatment have been reported. Thrombocytopenia was reported in all 25 patients treated with heparin or Elmiron over a 7-month period. Based on platelet aggregation studies, it is suggested that the anticoagulant may cause an immune allergic reaction. Animal Studies: Elmiron was administered by gavage once daily, 5 days a week, for 2 years. Mice were given doses of 56, 168, or 504 mg/kg. Male rats were administered doses of 14, 42, or 126 mg/kg, and female rats were administered doses of 28, 84, or 252 mg/kg. Elmiron is carcinogenic in mice but not in rats. Increased incidence of hepatic angiosarcoma, hepatocellular tumors (primarily adenomas), and malignant lymphomas in female mice suggests that Elmiron has carcinogenic activity. Reproductive studies have been conducted in mice and rats at a daily intravenous dose of 15 mg/kg; and in rabbits at a daily intravenous dose of 7.5 mg/kg. These studies did not find evidence that Elmiron impairs fertility or harms the fetus. In the mouse micronucleus test or the Ames test (Salmonella typhimurium), sodium Elmiron did not show chromosomal breakage or mutagenicity.

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Interactions
This study investigated the effects of pentosan sulfate sodium on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Warfarin doses were titrated to an international normalized ratio (INR) of 1.4–1.8. Subjects continued to receive the titrated dose of warfarin and 100 mg of pentosan sulfate sodium or placebo every 8 hours for 7 days. The peak plasma concentrations (Cmax) of R-warfarin and S-warfarin were approximately 840–890 ng/mL and 680–730 ng/mL, respectively, and were similar in the presence or absence of pentosan sulfate sodium. The half-lives of R-warfarin and S-warfarin were 52–56 hours and 36–40 hours, respectively. There were no significant differences in prothrombin time, partial thromboplastin time, and INR between the warfarin + placebo group and the warfarin + pentosan sulfate sodium group. The AUC(INR) showed no therapeutic effect (P = 0.772); however, a cyclical effect was observed. Analysis of variance for treatment cycles showed no therapeutic effect (P > 0.1). Adverse events were mild, including headache, epistaxis, and rash. Most adverse events were treatment-independent and occurred during warfarin dose adjustments. Sodium pentosan sulfate does not affect the pharmacokinetics or pharmacodynamics of warfarin. The risk of bleeding may increase when sodium pentosan sulfate is used in combination with drugs that affect hemostasis (e.g., oral anticoagulants, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs), thrombolytic agents [e.g., alteplase]). Patients receiving such combination therapy should be monitored for bleeding.

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Pentosan Polysulfate Sodium is generally well-tolerated at therapeutic doses for approved indications. The most common adverse events (AEs) reported in clinical trials for interstitial cystitis include gastrointestinal issues (diarrhea, nausea), headache, and hair loss. A rare but serious AE associated with long-term use (years) is retinopathy (pigmentary maculopathy). Hepatotoxicity (elevated liver enzymes) has also been reported. Preclinical toxicology studies have shown no significant mutagenic or carcinogenic potential. In animal studies, high doses can cause bleeding complications due to its anticoagulant activity. Its toxicity is well-characterized due to its long history of clinical use.

[1]. Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses. PLoS One. 2013;8(1):e54459.

[2]. Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro. Antiviral Res. 1988 Sep;9(6):335-43.

[3]. Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice. Lab Invest. 2011 Oct;91(10):1459-71.

pentosan sulfate polysaccharide with heparin-like properties.
See also: pentosan sulfate (note moved to); pentosan sodium sulfate (note moved to).

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Drug Indications
Elmiron is indicated for the treatment of adult bladder pain syndrome characterized by glomerular lesions or Henner's lesions, accompanied by moderate to severe pain, urgency, and frequency.

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Pentosan Polysulfate Sodium is an FDA-approved drug (brand names: Elmiron, for interstitial cystitis) and is also used off-label for osteoarthritis. It has not been approved for HIV or prion disease. Its mechanism of action is multifaceted, involving restoration of the bladder GAG layer, anti-inflammatory effects, and pro-chondrogenic effects. It is also a potent and selective anti-HIV agent in vitro. It is available for research purposes as a reference standard and tool to study GAG biology, bladder function, and antiviral mechanisms. For research use; not for human therapeutic administration without a prescription.

4000-6000

1703.689

140207-93-8

Pentosan Polysulfate;37300-21-3

92043424

White to off-white solid powder

0

50

20

98

3290

0

COC1COC(C(C1OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC2COC(C(C2OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC3COC(C(C3OS(=O)(=O)[O-])OC4C(C(C(C(O4)C(=O)[O-])OC)OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC5COC(C(C5OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]

MSJQCBORNZDNDU-UHFFFAOYSA-D

InChI=1S/C29H48O50S9.10Na/c1-59-8-4-63-27(21(77-86(50,51)52)12(8)71-80(32,33)34)68-11-7-65-28(22(78-87(53,54)55)15(11)74-83(41,42)43)67-9-6-64-26(66-10-5-62-25(61-3)20(76-85(47,48)49)14(10)73-82(38,39)40)19(13(9)72-81(35,36)37)70-29-23(79-88(56,57)58)17(75-84(44,45)46)16(60-2)18(69-29)24(30)31;;;;;;;;;;/h8-23,25-29H,4-7H2,1-3H3,(H,30,31)(H,32,33,34)(H,35,36,37)(H,38,39,40)(H,41,42,43)(H,44,45,46)(H,47,48,49)(H,50,51,52)(H,53,54,55)(H,56,57,58);;;;;;;;;;/q;10*+1/p-10

decasodium;3-methoxy-6-[2-(6-methoxy-4,5-disulfonatooxyoxan-3-yl)oxy-5-[5-(5-methoxy-3,4-disulfonatooxyoxan-2-yl)oxy-3,4-disulfonatooxyoxan-2-yl]oxy-4-sulfonatooxyoxan-3-yl]oxy-4,5-disulfonatooxyoxane-2-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)