HIV-1

It has been demonstrated that pentosan polysulfate 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 inhibits TNFα's proinflammatory effects, suppresses NF-κB, and reduces the generation of MCP-1 that is induced by high glucose and advanced glycation end products (AGEs) [3].

In 5/6 nephrectomized rats, pentosan polysulfate 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 also lessens activation of proinflammatory genes and TNFα[3].

Absorption, Distribution and Excretion
Slow
Sprague-Dawley rats were given (3)H-labelled pentosan orally or intravenously at a dose of 5 mg/kg bw, and killed 1 or 4 hours later, respectively. Autoradiography indicated extensive distribution of radiolabel in the whole animal after intravenous administration, with notable labelling of connective tissues, and low activity in bone and cartilage. There was a high concentration of radiolabel in the urine, and preferential localization of radiolabel to the lining of the urinary tract. After oral administration, the tissue distribution of radiolabel was similar, but activity was lower.
In rabbits given 1.0-1.2 mg pentosan by oral administration, median recovery in the urine was 7.45% (range, 2.1-46.0%) for pentosan of low relative molecular mass, and 0.1% (range, 0.0-0.3%) for pentosan of high relative molecular mass.
In rabbits given 1-1.2 mg of pentosan by intravenous administration, median recovery in the urine was 47.2% (range, 19.7-73.2%) for unfractionated pentosan, 74.6% (range, 31.4-96.3%) for pentosan of low relative molecular mass, and 3.3% (range, 2.5-5.0%) for pentosan of high relative molecular mass.
Excretion of pentosan was studied in 34 female patients with interstitial cystitis who were receiving long-term treatment with pentosan. The median concentration of pentosan in the urine of these patients was 1.2 ug/mL (range, 0.5-27.7 ug/mL). All the pentosan recovered from the urine of these patients was of low relative molecular mass.
For more Absorption, Distribution and Excretion (Complete) data for Elmiron (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Orally absorbed pentosan polysulfate sodium undergoes partial desulfation in the liver and spleen and partial depolymerization in the kidneys to form a large number of metabolites. Desulfation and depolymerization pathways can become saturated with continued dosing.
The fraction of pentosan polysulfate sodium that is absorbed is metabolized by partial desulfation in the liver and spleen, and by partial depolymerization in the kidney to a large number of metabolites. Both the desulfation and depolymerization can be saturated with continued dosing.

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Biological Half-Life
4.8 hours
Five healthy male volunteers were given (125)I-labelled pentosan in conjunction with unlabelled pentosan at a dose of 0.1, 1, 7, or 50 mg intravenously. The halflives for doses of 0.1-7 mg ranged from 13 to 18 minutes. At a dose of 50 mg, the half-life was 45 minutes. ...
Following oral administration of a radiolabeled 300- or 450-mg dose of pentosan polysulfate sodium solution, the mean half-life for plasma radioactivity was 27 or 20 hours, respectively.

Toxicity Summary
IDENTIFICATION AND USE: Elmiron (Pentosan polysulfate) 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 associated with interstitial cystitis. It is also used in veterinary medicine. HUMAN STUDIES: Elmiron, a highly sulfated, semisynthetic pentose polysaccharide with properties similar to heparin, is used for the treatment of interstitial cystitis. Overdose of Elmiron has not been reported. Based upon the pharmacodynamics of the drug, toxicity is likely to be reflected as anticoagulation, bleeding, thrombocytopenia, liver function abnormalities, and gastric distress. A case of severe thrombocytopenia and ischemic stroke following Elmiron treatment has been reported. The development of thrombocytopenia was reported in 25 patients receiving either heparin or Elmiron over a 7 month period. Based on platelet aggregation studies it was suggested that an immune allergic reaction to the anticoagulants occurred. ANIMAL STUDIES: Elmiron was orally administered once daily via gavage, 5 days per week, for up to 2 years. The dosages administered to mice were 56, 168 or 504 mg/kg. The dosages administered to rats were 14, 42, or 126 mg/kg for males, and 28, 84, or 252 mg/kg for females. Elmiron was carcinogenic to mice but not rats. Increased incidences of liver hemangiosarcoma, hepatocellular neoplasms (predominantly adenomas), and malignant lymphomas revealed carcinogenic activity of Elmiron in female mice. Reproduction studies have been performed in mice and rats with intravenous daily doses of 15 mg/kg, and in rabbits with 7.5 mg/kg. These studies did not reveal evidence of impaired fertility or harm to the fetus from Elmiron. Elmiron sodium was not clastogenic or mutagenic when tested in the mouse micronucleus test or the Ames test (Salmonella typhimurium).

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Interactions
The effect of pentosan polysulfate sodium on warfarin pharmacokinetics and pharmacodynamics was investigated in healthy subjects. Warfarin was titrated to an international normalized ratio between 1.4 and 1.8. Subjects continued their titrated dose of warfarin and received pentosan polysulfate sodium 100 mg or placebo every 8 hours for 7 days. The Cmax of R- and S-warfarin was approximately 840 to 890 ng/mL and 680 to 730 ng/mL, respectively, and was similar in the absence and presence of pentosan polysulfate sodium. The half-life for R- and S-warfarin was 52 to 56 hours and 36 to 40 hours, respectively. Prothrombin time, partial thromboplastin time, and the international normalized ratio for warfarin + placebo and warfarin + pentosan polysulfate sodium were comparable. The AUC(INR) indicated no treatment effect (P = .772); however, there was a period effect. Analysis of variance for the treatments by period indicated no treatment effect (P > .1). Adverse events were mild and included headache, epistaxis, and rash. Most adverse events were unrelated to treatment and were seen during warfarin titration. Pentosan polysulfate sodium did not affect warfarin pharmacokinetics or pharmacodynamics.
The risk of hemorrhage may be increased when pentosan polysulfate sodium is used concurrently with drugs that affect hemostasis (e.g., oral anticoagulants, heparin, nonsteroidal anti-inflammatory agents (NSAIAs), thrombolytic agents [e.g., alteplase]). Patients receiving such concomitant therapy should be monitored for hemorrhage.

[1]. Schuchman EH, et al. Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses. PLoS One. 2013;8(1):e54459.
[2]. Baba M, et al. Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro. Antiviral Res. 1988 Sep;9(6):335-43.
[3]. Wu J, et al. 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.

[(2R,3R,4S,5R)-2-Hydroxy-5-{[(2S,3R,4S,5R)-5-hydroxy-3,4-bis(sulfooxy)oxan-2-yl]oxy}-4-(sulfooxy)oxan-3-yl]oxidanesulfonic acid is a glycoside.
Pentosan polysulfate is a sulfated pentosyl polysaccharide with heparin-like properties.
Pentosan Polysulfate is a semisynthetic heparin-like glucosaminoglycan. Although its mechanism of action is unknown, pentosan polysulfate may act as a buffer to control cell permeability by preventing irritating solutes from reaching cells coated with it. Administered orally, excreted pentosan polysulfate adheres to the urinary bladder wall, preventing irritants from entering bladder cells and the development or progression of interstitial cystitis (IC), a complication of some chemotherapies. This agent also exhibits anticoagulant and fibrinolytic properties. (NCI04)
A sulfated pentosyl polysaccharide with heparin-like properties.
See also: Beta-D-Xylopyranose (has monomer); Pentosan Polysulfate Sodium (has salt form).

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Drug Indication
For the relief of bladder pain or discomfort associated with interstitial cystitis.
FDA Label

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Mechanism of Action
Pentosan polysulfate is a polymer of xylose hydrogen sulfate and contains two sulfate groups per carbohydrate monomer. It binds Fibroblast growth factors (FGFs) as well as other heparin-binding growth factors. It has been shown to interact also with the heparin-binding site of FGFR-1. It inhibits the growth of SW13 adrenocortical cells transfected with FGF-4 and tumorigenicity of MCF-7 breast carcinoma cells transfected with FGF-1 or FGF-4.

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Therapeutic Uses
Anticoagulants
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Elmiron is included in the database.
Elmiron (pentosan polysulfate sodium) is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. /Included in US product labeling/
VET: Oral pentosan (human) has been used anecdotally for the adjunctive treatment of feline interstitial cystitis (feline idiopathic lower urinary tract disease - FLUTD), but studies have demonstrated that it is not effective for short-term, acute lower urinary tract disease.
For more Therapeutic Uses (Complete) data for Elmiron (13 total), please visit the HSDB record page.

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Drug Warnings
Elmiron is a weak anticoagulant (1/15 the activity of heparin). At a daily dose of 300 mg (n = 128), rectal hemorrhage was reported as an adverse event in 6.3% of patients. Bleeding complications of ecchymosis, epistaxis, and gum hemorrhage have been reported. Patients undergoing invasive procedures or having signs/symptoms of underlying coagulopathy or other increased risk of bleeding (due to other therapies such as coumarin anticoagulants, heparin, t-PA, streptokinase, high dose aspirin, or nonsteroidal anti-inflammatory drugs) should be evaluated for hemorrhage. Patients with diseases such as aneurysms, thrombocytopenia, hemophilia, gastrointestinal ulcerations, polyps, or diverticula should be carefully evaluated before starting Elmiron.
Elmiron has not been studied in patients with hepatic insufficiency. Because there is evidence of hepatic contribution to the elimination of Elmiron, hepatic impairment may have an impact on the pharmacokinetics of Elmiron. Caution should be exercised when using Elmiron in this patient population.
Alopecia, primarily alopecia areata (limited to a single area on the scalp), has been reported in patients receiving pentosan polysulfate sodium, and may occur within the first 4 weeks of initiation of therapy.
Safety and effectiveness in pediatric patients below the age of 16 years have not been established.
For more Drug Warnings (Complete) data for Elmiron (11 total), please visit the HSDB record page.

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Pharmacodynamics
Pentosan polysulfate sodium is a low molecular weight heparin-like compound. It has anticoagulant and fibrinolytic effects.

C10H18O21S4

601.922

37300-21-3

Pentosan Polysulfate Sodium (W/W 43%);140207-93-8

37720

White powder

2.26g/cm3

-5.6

6

21

10

35

1140

8

OS(O[C@H]1[C@H](O)CO[C@@H](O[C@@H]2CO[C@@H](O)[C@H](OS(=O)(O)=O)[C@H]2OS(=O)(O)=O)[C@@H]1OS(=O)(O)=O)(=O)=O

FCCNSUIJIOOXEZ-SJYYZXOBSA-N

InChI=1S/C10H18O21S4/c11-3-1-26-10(8(31-35(22,23)24)5(3)28-32(13,14)15)27-4-2-25-9(12)7(30-34(19,20)21)6(4)29-33(16,17)18/h3-12H,1-2H2,(H,13,14,15)(H,16,17,18)(H,19,20,21)(H,22,23,24)/t3-,4-,5+,6+,7-,8-,9-,10+/m1/s1

[(2R,3R,4S,5R)-2-hydroxy-5-[(2S,3R,4S,5R)-5-hydroxy-3,4-disulfooxyoxan-2-yl]oxy-3-sulfooxyoxan-4-yl] hydrogen sulfate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 1 mg/mL
H2O: 0.67 mg/mL

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.)