Research Review 2012 August 8

This week’s research review focuses on Pentosan

Pentosan polysulfate (Elmiron) is the only oral medication approved by the U.S. FDA for the treatment of interstitial cystitis, also known as painful bladder syndrome.

Pentosan is 1/15 Heparin, an anticoagulant (blood thinner). Pentosan polysulfate repairs damaged glycosaminoglycan (GAG) layers.

The bladder urothelium is naturally coated with a layer of glycosaminoglycan (GAG) that has been shown to be defective in BPS patients. Malfunction of this layer may allow migration of urine solute transepithelially and provoke symptoms.

Pentosan has been shown to be beneficial for:

Osteoarthritis (Ghosh 1999)

Knee osteoarthritis         (Kumagai, Shirabe et al. 2010)

Intervertebral disc degeneration (Zhao, Wang et al. 2011)

Interstitial cystitis (Davis, El Khoudary et al. 2008)

Bladder pain syndrome (Al-Zahrani and Gajewski 2011)

Dr. Ron


Articles

Long-term efficacy and tolerability of pentosan polysulphate sodium in the treatment of bladder pain syndrome

            (Al-Zahrani and Gajewski 2011) Download

OBJECTIVE: The primary objective of this study is to report on the long-term efficacy and tolerability of pentosan polysulphate sodium (PPS) in patients with bladder pain syndrome (BPS). The secondary objective is to find the predictors of the long-term outcome. METHODS: This is a single institution, retrospective study. The study period was from 1994 to 2008. All patients fulfilled the clinical criteria of BPS, as suggested by European Society for the Study of Interstitial Cystitis. We included only patients with de novo BPS diagnosis and no previous PPS or other treatment. The efficacy of PPS was measured with the global response assessment scale (GRA). Patients were stratified into 2 groups based on the duration of the treatment. Group 1 took the drug for less than 12 months. Group 2 took the drug for more than 12 months. RESULTS: There were 271 patients eligible for the study. Most of the patients were female (90%), with the mean age at presentation of 45.5 years. The average duration of symptoms was 28.5 months. The mean follow-up was 22 months (range 3-130). Out of all the patients, 147 patients (54.2%) reported over 50% improvement using the GRA. The reported efficacy was higher in Group 2 (60%). Ninety-three patients (34.3%) decided to stop taking the medication for various reasons. The most common reasons to stop the medication were poor outcome (16.6% of patients) and side effects (11.1% of patients). Poor outcome was associated with nocturia, smoking and detrusor overactivity. Good outcome was associated with longer PPS intake (>12 months) and severe cystoscopic findings of glomerulation. CONCLUSION: Pentosan polysulphate sodium is an effective oral therapy to control the symptoms of BPS with good long-term efficacy and tolerability.

Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial

            (Davis, El Khoudary et al. 2008) Download

PURPOSE: We examined the safety and the efficacy of a combination of intravesical and oral pentosan polysulfate sodium in comparison to only oral pentosan polysulfate sodium in treating interstitial cystitis. MATERIALS AND METHODS: A total of 41 females diagnosed with interstitial cystitis were randomized to receive a combination of intravesical pentosan polysulfate sodium plus oral pentosan polysulfate sodium (21 in treatment group) or intravesical placebo plus oral pentosan polysulfate sodium (20 in placebo group) for 6 weeks. All subjects continued to receive oral pentosan polysulfate sodium for another 12 weeks. The primary outcome was the change in the O'Leary-Sant Interstitial Cystitis Symptoms/Problem Index from baseline to week 6, 12, and 18. Other outcomes included: the changes in Pelvic Pain and Urgency Frequency questionnaire, Health Related Quality of Life index: SF-36, pain scale, urgency scale, voiding log, patient global assessment, and sexual function scales. RESULTS: The change in the total score of O'Leary-Sant Interstitial Cystitis Symptoms/Problems Index from baseline to week 12 among the treatment group (median -12 or approximately a 46% reduction) was significantly greater compared to the placebo group (median -5.5 or approximately a 24% reduction, p = 0.04). At week 18 the treatment group showed statistically significant improvement in all Health Related Quality of Life domains compared to the baseline (p < or = 0.01), while the placebo group showed significant improvement in only 3 Health Related Quality of Life domains, (p < or = 0.05) compared to the baseline. There were no significant differences within major categories of adverse events between treated and placebo groups. CONCLUSIONS: The use of intravesical pentosan polysulfate sodium simultaneously with oral pentosan polysulfate sodium is a safe and effective therapeutic option. These findings will open a new option for patients with interstitial cystitis to reduce their severely devastating symptoms and to improve their quality of life and well-being.

The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment

            (Ghosh 1999) Download

OBJECTIVES: Structure-modifying osteoarthritis (OA) drugs (SMOADs) may be defined as agents that reverse, retard, or stabilize the underlying pathology of OA, thereby providing symptomatic relief in the long-term. The objective of this review was to evaluate the literature on sodium pentosan polysulfate (NaPPS) and calcium pentosan polysulfate (CaPPS), with respect to the pathobiology of OA to ascertain whether these agents should be classified as SMOADs. METHODS: Published studies on NaPPS and CaPPS were selected on the basis of their relevance to the known pathobiology of OA, which also was reviewed. RESULTS: Both NaPPS and CaPPS exhibit a wide range of pharmacological activities. Of significance was the ability of these agents to support chondrocyte anabolic activities and attenuate catabolic events responsible for loss of components of the cartilage extracellular matrix in OA joints. Although some of the anti-catabolic activities may be mediated through direct enzyme inhibition, NaPPS and CaPPS also have been shown to enter chondrocytes and bind to promoter proteins and alter gene expression of matrix metalloproteinases and possibly other mediators. In rat models of arthritis, NaPPS and CaPPS reduced joint swelling and inflammatory mediator levels in pouch fluids. Moreover, synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS and CaPPS or after intraarticular injection of NaPPS into arthritic joints. In rabbit, canine, and ovine models of OA, NaPPS and CaPPS preserved cartilage integrity, proteoglycan synthesis, and reduced matrix metalloproteinase activity. NaPPS and CaPPS stimulated the release of tissue plasminogen activator (t-PA), superoxide dismutase, and lipases from vascular endothelium while concomitantly decreasing plasma levels of the endogenous plasminogen activator inhibitor PAI-1. The net thrombolytic and lipolytic effects exhibited by NaPPS and CaPPS may serve to improve blood flow through subchondral capillaries of OA joints and improve bone cell nutrition. In geriatric OA dogs, NaPPS and CaPPS reduced symptoms, as well as normalized their thrombolytic status, threshold for platelet activation, and plasma triglyceride levels. These hematologic parameters were shown to be abnormal in OA animals before drug treatment. Similar outcomes were observed in OA patients when CaPPS or NaPPS were given orally or parenterally in both open and double-blind trials. CONCLUSIONS: The data presented in this review support the contention that NaPPS and CaPPS should be classified as SMOADs. However, additional long-term clinical studies employing methods of assessing joint structural changes will be needed to confirm this view.

Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis--an open clinical trial

            (Kumagai, Shirabe et al. 2010) Download

BACKGROUND: Pentosan polysulfate sodium (pentosan) is a semi-synthetic drug manufactured from beech-wood hemicellulose by sulfate esterification of the xylopyranose hydroxyl groups. From in vitro and animal model studies, pentosan has been proposed as a disease modifying osteoarthritis drug (DMOAD). The objective of this study was to assess the efficacy, safety, and patient satisfaction in patients with mild radiographic knee osteoarthritis (OA) findings and OA-associated symptoms and signs. METHODS: Twenty patients were assessed clinically at Nagasaki University Hospital. The radiographic indications of OA were grade 1 to 3 using the Kellgren-Lawrence Grading System (K/L grade). Pentosan used in this study was manufactured and supplied in sterile injectable vials (100 mg/ml) by bene GmbH, Munich, Germany. The study was a single-center, open-label trial. Treatment consisted of 6 weekly subcutaneous injections (sc) of pentosan (2 mg/kg). Patients were clinically assessed at entry and 1 to 8, 11, 15, 24 & 52 weeks post treatment. The results were analyzed using one way ANOVA and Dunnett's method. RESULTS: Hydrarthroses were reduced quickly in all cases. The clinical assessments, i.e., knee flexion, pain while walking, pain after climbing up and down stairs, etc, were improved significantly and these clinical improvements continued for almost one year. The dose used in this study affected the blood coagulation test, but was within safe levels. Slightly abnormal findings were noted in serum triglycerides. CONCLUSIONS: Pentosan treatment in twenty patients with mild knee OA seemed to provide improvements in clinical assessments and C2C level of cartilage metabolism.


Calcium pentosan polysulfate and sodium pentosan polysulfate may be used to treat intervertebral disc degeneration

            (Zhao, Wang et al. 2011) Download

Intervertebral disc degeneration (IDD) is a major health problem world-wide, and several spinal disorders are closely associated with it. Although people have invested a great deal of time and effort, how to prevent and reverse the IDD for the researchers is still a difficult and hot issue. Intervertebral disc belongs to cartilage tissue, and IDD also is the cartilage degeneration disease. A large quantity of studies have shown that Calcium pentosan polysulfate (CaPPS) and sodium pentosan polysulfate (NaPPS) possess chondroprotective activities and play an important role in maintaining cartilage integrity. We reasonably hypothesize that NaPPS and CaPPS may be used to treat IDD. The possible mechanism may include that: (1) the significant effects of NaPPS and CaPPS in improving capillary blood flow could maintain nutritional supply to intervertebral disc, and preserve intervertebral disc tissue against degeneration; (2) CaPPS and NaPPS preserve cartilage integrity, proteoglycan synthesis, and improve cartilage biomechanical properties; (3) as the multifaceted exosite inhibitors of proteinases NaPPS and CaPPS strongly impede the activity and production of proteinases; (4) promotion of the balance between proteinases and TIMPs also may be involved in treating IDD; (5) NaPPS and CaPPS exhibit potent anti-inflammatory effects, and then reduce inflammation-induced IDD. If the hypothesis were conformed, the symptoms caused by IDD and its related diseases would be a corresponding alleviation or even disappearance, which could greatly alleviate the suffering of patients from disc degeneration diseases. Certainly, many roles of CaPPS and NaPPS, such as effectiveness, safety and side effects, need to be tested, and further works such as animal model and clinical trial, need to be done to prove this hypothesis.


References

Al-Zahrani, A. A. and J. B. Gajewski (2011). "Long-term efficacy and tolerability of pentosan polysulphate sodium in the treatment of bladder pain syndrome." Can Urol Assoc J 5(2): 113-8.

Davis, E. L., S. R. El Khoudary, et al. (2008). "Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial." J Urol 179(1): 177-85.

Ghosh, P. (1999). "The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment." Semin Arthritis Rheum 28(4): 211-67.

Kumagai, K., S. Shirabe, et al. (2010). "Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis--an open clinical trial." BMC Clin Pharmacol 10: 7.

Zhao, J. G., J. Wang, et al. (2011). "Calcium pentosan polysulfate and sodium pentosan polysulfate may be used to treat intervertebral disc degeneration." Med Hypotheses 76(4): 610-3.