Pentosan polysulfate

Pentosan polysulfate (PPS), sold under the name Elmiron, by Ortho-McNeil Pharmaceutical is the only oral medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of interstitial cystitis (IC), also known as painful bladder syndrome. PPS is also sold under the brand name Comfora in India.

In the veterinary field, pentosan polysulfate is sold under the name Cartrophen Vet by Biopharm Australia for the treatment of osteoarthritis (OA) in dogs and horses. PPS is also sold under the names Naturevet Equine and Arthropen. PPS is related to the Disease Modifying Osteoarthritic Drugs (DMOAD).

Interstitial cystitis/painful bladder syndrome
Interstitial cystitis/painful bladder syndrome (IC/PBS) patients struggle with symptoms of urinary frequency, urgency, pressure and/or pain, as well as nocturia (frequent urination at night), dyspareunia (painful intercourse), pain and/or discomfort while sitting in a car, while driving and/or travelling.

The origin/cause of IC/PBS is currently unknown though a number of theories are currently under consideration. Urine cultures are typically negative for infection, yet it is not unusual for patients to believe that they have had infections for years rather than IC/PBS, because the symptoms of IC/PBS mimic those of an infection.

Pentosan polysulfate is available as pills or as a direct infusion into the bladder.

Osteoarthritis (OA)/Degenerative Joint Disease (DJD)
Its application as a disease modifying osteoarthritis drug (DMAOD) has only attracted recent attention. The disease-modifying activity of this molecule has been previously reviewed in terms of its effectiveness in laboratory based studies (Burkhardt & Ghosh, 1987). More recently other derivatives such as the calcium pentosan polysulfate (CaPPS) have been investigated and found to exhibit higher oral bioavailability than the sodium salt (Klocking & Markwardt, 1985; 1986; Klocking, 1993).



Canines
Read et al. (1996) used three different doses of NaPPS to treat 40 geriatric dogs with well-established clinical signs of chronic OA with SC injection. In a study conducted with 10 elderly dogs with osteoarthritis given calcium pentosan polysulfate (3 mg/kg intramuscularly) once weekly for four weeks, the improvement in symptoms was found to correlate with plasma indices of fibrinolytic activity and lipid profiles (Ghosh and Cheras, 2001). Nineteen dogs were randomly assigned to either surgery or NaPPS treatment of fragmented coronoid process and osteochondritis dissecans of the canine elbow joint (Bouck et al., 1995) more recent study in dogs with OA secondary to cranial cruciate ligament (CCL) deficiency, no differences were identified in either functional outcome or radiographic progression using the oral calcium PPS compared with placebo (Innes et al., 2000) Budsberg et al. (2007) evaluated the efficacy of PPS for improving the recovery period and alleviate the progression of osteoarthritis (OA) of the canine stifle after extracapsular stabilization of cranial cruciate ligament (CCL) injuries.

Horses
There are few published reports describing the use of PPS for equine joint disease, however the drug has been used in Australia. When administered to racing Thoroughbreds with chronic osteoarthritis (2 to 3 mg/kg,IM, once weekly for 4 weeks, then as required), PPS treatment improved but did not eliminate clinical signs of joint disease (Little and Ghosh, 1996)

Humans
Verbruggen and Veys (1992) studied the influence of PPS on hyaluronan metabolism of the synovial lining cell in vivo in human volunteers. A double blind, placebo-controlled clinical study in 114 patients with osteoarthritis of the knee has been performed in Perth, Australia (Edelman et al., 1994) where patients either received a salt solution or sodium PPS at 3 mg/ kg as an intramuscular injection once weekly for 4 weeks. In an open study of 23 patients with mild to moderate OA of the hand, hip, or knee, Verbruggan et al., (1994) investigated the effect of 2 mg/kg CaPPS intramuscularly once a week for five weeks on the biochemical and hematologic markers of blood coagulation and thrombolysis (Verbruggen and Veys, 1996). CaPPS also has been studied when given orally to patients with OA of the finger joints under double-blind, placebo-controlled conditions using a broken treatment protocol (360). Fifty patients were recruited (24 CaPPS-treated, 26 placebotreated), (Verbruggen et al., 1999) Eighty-six patients with OA of the knee were subjected to intra-articular sodium PPS injections against an equivalent volume of IA Ringer's solution under double-blind conditions (Rasaratnam et al., 1996). Adam et al. (1996) reported the effects of intra-articular PPS on synovial fluid visco-elasticity and hyaluronan molecular weight in patients with gonarthritis. Anderson et al. (1997) investigated the effects of PPS on peripheral blood leukocyte populations and mononuclear cell procoagulant activity in 11 patients with osteoarthritis. Faaij et al. (1999) assessed the bioavailability of intravenous and oral sodium PPS in 18 healthy male volunteers. Ghosh et al. (2005) performed a pilot study at the Queen Elizabeth II Medical Centre, Perth, Australia on 114 Patients with OA on the knee. Twenty patients were assessed clinically at Nagasaki University Hospital. Treatment consisted of six weekly subcutaneous injections of PPS (2 mg/kg) (Kumagai et al., 2010).

Transmissible spongiform encephalopathies
PPS has gained attention as possibly being effective in the treatment of Creutzfeldt-Jakob disease (CJD), although there is currently no definitive evidence for this idea other than results of the ongoing treatment (published) of one patient in Northern Ireland and around six other patients in mainland Britain.

Around 15 other patients in non-UK countries have also received this PPS treatment in an attempt to halt or slow down CJD and related disease progression. There are also clinical trials of Elmiron to treat Hunters Syndrome (MPS II).

Adverse effects
Patients who have taken PPS orally report a variety of side effects, primarily gastrointestinal complaints such as diarrhea, heartburn, and stomach pain. Hair loss, headache, rash, and insomnia have also been reported. Due to Elmiron's anticoagulant effects, some patients report bruising more easily. In some cases, patients are asked to stop taking the medication before any major surgical procedures to reduce the likelihood of bleeding.

Pharmacology
The anticoagulant activity of PPS is 1/15 that of Heparin.

PPS is believed to work by providing a protective coating to the damaged bladder wall. However, the sodium salt of PPS has exceptionally poor bioavailability when taken orally. Research presented in 2005 by Alza Pharmaceuticals demonstrated that more than 94% of the medication was excreted, intact, in feces without providing any beneficial effect. Their research found that only 6% was excreted through urine. The drug must be taken for several months for most patients to achieve some benefit.

More recently, PPS has been studied as part of a "rescue instillation" which is placed directly in the bladder and can, perhaps, provide better effectiveness. Research presented in 2005 showed PPS had 90% effectiveness in reducing the symptoms of IC/PBS patients by using this instillation.