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
Sprague-Dawley rats were administered 5 mg/kg body weight of (3)H-labeled pentosan orally or intravenously and sacrificed 1 hour or 4 hours later, respectively. Autoradiography showed that after intravenous injection, the radiolabeled pentosan was widely distributed in the animals, 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 activity was lower. In rabbits, after oral administration of 1.0–1.2 mg pentosan, the median urinary recovery rate of low molecular weight pentosans was 7.45% (range 2.1–46.0%), and the median urinary recovery rate of high molecular weight pentosans was 0.1% (range 0.0–0.3%).
Following intravenous administration of 1–1.2 mg pentosans in rabbits, the median urinary recovery rate for unfractionated pentosans was 47.2% (range 19.7–73.2%), for low molecular weight pentosans it was 74.6% (range 31.4–96.3%), and for high molecular weight pentosans it was 3.3% (range 2.5–5.0%).
Pentan excretion was investigated in 34 female patients with interstitial cystitis. These patients were receiving long-term pentosan therapy. The median concentration of pentosans in their urine 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.
For more complete data on the absorption, distribution, and excretion of Elmiron (12 items), please visit the HSDB records page.

---

Metabolism/Metabolites
Orally absorbed sodium pentosan polysulfate undergoes partial desulfurization in the liver and spleen and partial depolymerization in the kidneys, forming numerous metabolites. Continuous administration leads to saturation of both desulfurization and depolymerization pathways.
Absorbed sodium pentosan polysulfate is partially metabolized in the liver and spleen via partial desulfurization and in the kidneys via partial depolymerization, forming numerous metabolites. Continuous administration can saturate both desulfurization and depolymerization.

---

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

Toxicity Summary
Identification and Uses: Elmiron (pentosan 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 pentosaccharide 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. There have been reports of severe thrombocytopenia and ischemic stroke following Elmiron treatment. Thrombocytopenia was reported in all 25 patients treated with heparin or Elmiron within 7 months. Based on platelet aggregation studies, an immune allergic reaction to the anticoagulant is suggested. Animal Studies: Elmiron was administered once daily by gavage, 5 days a week, for up to 2 years. Mice were administered 56, 168, or 504 mg/kg. Male rats were administered 14, 42, or 126 mg/kg, and female rats were administered 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 carcinogenic activity of Elmiron. Reproductive studies were 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 found no evidence of fertility or fetal impairment caused by Elmiron. In mouse micronucleus assays or Ames assays (Salmonella typhimurium), Elmiron sodium did not show chromosomal breakage or mutagenicity.

---

Interactions
The effects of pentosan sulfate sodium on the pharmacokinetics and pharmacodynamics of warfarin were investigated in healthy subjects.
Warfarin doses were titrated to an international normalized ratio (INR) of 1.4 to 1.8. Subjects continued to receive the titrated dose of warfarin and 100 mg of pentosan sulfate or placebo every 8 hours for 7 days. The 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. 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 international normalized ratio (INR) between the warfarin + placebo group and the warfarin + pentosan sulfate group. AUC(INR) showed no therapeutic effect (P = 0.772); however, a periodic effect was observed. Analysis of variance over the periodic period 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 concomitantly with medications that affect hemostasis (e.g., oral anticoagulants, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs), thrombolytic agents [e.g., alteplase]). Patients receiving such concomitant therapy should be monitored for bleeding.

[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(sulfonoxy)oxacyclohexane-2-yl]oxy}-4-(sulfonoxy)oxacyclohexane-3-yl]oxacyclohexanesulfonic acid is a glycoside. Pentosan polysulfate is a sulfated pentosyl polysaccharide with heparin-like properties. Pentosan polysulfate is a semi-synthetic heparin-like glucosamine polysaccharide. Although its mechanism of action is not fully understood, pentosan polysulfate may act as a buffer, controlling cell permeability by preventing irritating solutes from reaching the cells it coats. After oral administration, pentosan sulfate adheres to the bladder wall, preventing irritants from entering bladder cells, thereby preventing the occurrence or progression of interstitial cystitis (IC). Interstitial cystitis is a complication of certain chemotherapy drugs. This drug also has anticoagulant and fibrinolytic properties. (NCI04)
A pentosaccharide sulfate polysaccharide with heparin-like properties.
See also: β-D-xylopyranose (monomer); pentosaccharide sulfate sodium (salt form).
Indications

For relief of bladder pain or discomfort caused by interstitial cystitis.
FDA label
Mechanism of Action

Pentosaccharide sulfate is a polymer of xylose hydrogen sulfate, with each carbohydrate monomer containing two sulfate groups. It can bind fibroblast growth factor (FGF) and other heparin-binding growth factors. Studies have shown that it can also interact with the heparin binding site of FGFR-1. It inhibits the growth of SW13 adrenocortical cells transfected with FGF-4 and the tumorigenicity of MCF-7 breast cancer cells transfected with FGF-1 or FGF-4.

---

Therapeutic Use
Anticoagulants
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides summary information on the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Elmiron is listed in the database.
Elmiron (sodium pentosan sulfate) is indicated for the relief of bladder pain or discomfort caused by interstitial cystitis. /US Product Label Includes/
Veterinarian: Oral pentosan (for human use) has been used as adjunctive therapy for feline interstitial cystitis (feline idiopathic lower urinary tract disease - FLUTD), but studies have shown it to be ineffective for short-term acute lower urinary tract disease.
For more complete data on the therapeutic uses of Elmiron (of 13), please visit the HSDB record page.

---

Drug Warnings
Elmiron is a weak anticoagulant (1/15 the activity of heparin). At a daily dose of 300 mg (n = 128), 6.3% of patients reported adverse events of rectal bleeding. Bleeding complications such as ecchymosis, epistaxis, and gingival bleeding have been reported. Patients undergoing invasive procedures or with potential coagulopathy or other increased risk of bleeding (e.g., due to the use of coumarin anticoagulants, heparin, t-PA, streptokinase, high-dose aspirin, or other nonsteroidal anti-inflammatory drugs) should be assessed for bleeding risk. Patients with conditions such as aneurysms, thrombocytopenia, hemophilia, gastrointestinal ulcers, polyps, or diverticula should be carefully evaluated before starting Elmiron. Elmiron has not been studied in patients with hepatic impairment. Because there is evidence that the liver is involved in the clearance of Elmiron, hepatic impairment may affect its pharmacokinetics. Caution should be exercised when using Elmiron in this patient population. Hair loss, primarily alopecia areata (limited to a single area of the scalp), has been reported in patients treated with sodium pentosan sulfate and may occur within the first 4 weeks after starting treatment. The safety and efficacy in children under 16 years of age have not been established. For more complete data on drug warnings for Elmiron (11 in total), please visit the HSDB record page.

---

Pharmacodynamics
Sodium pentosan sulfate 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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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