Pentosan polysulfate

Interstitial cystitis/painful bladder syndrome

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a condition where 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 traveling. PPS, as Elmiron, is the only oral medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of IC. Elmiron is available as pills or as a direct infusion into the bladder. A review of four placebo-controlled studies concluded that PPS was significantly more effective than placebo for pain, urgency and frequency of urination, but not different from placebo for nocturia (needing to urinate during the night).

In IC, PPS is believed to work by providing a protective coating to the damaged bladder wall. PPS is similar in structure to the natural glycosaminoglycan coating of the inner lining of the bladder, and may replace or repair the lining, reducing its permeability. This lining is important in preventing urinary toxins from irritating the underlying cell layers. Evidence for this mechanism was found by irritating the lining of the bladders of female rats with acrolein. If the rats were pre-treated with PPS, the damage was much less. Potassium sensitivity tests (PST) showed abnormal cell lining permeability in most patients with IC and indicated a significant reduction in permeability after successful PPS therapy (32-week trial of 300, 600, or 900 mg PPS/day). Another possible mechanism of PPS action in IC is by inhibiting the inflammatory response of the bladder cells, either by indirectly blocking the activity of mediators such as NF-κB, by preventing an influx of mast cells or by preventing mast cells releasing histamine.

The sodium salt of PPS has low bioavailability when taken orally. Research presented in 2005 by Alza Pharmaceuticals demonstrated that 94% of the medication was excreted, intact, in faeces. This means that 6% was excreted through urine and in contact with the bladder. The drug appears to be most effective when taken for several months. 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.

Osteoarthritis

PPS was first reported as a chondroprotective drug in 1988 with a detailed rationale of the disease-modifying activity of this molecule subsequently published in 1999. The mechanism of PPS action in osteoarthritis is multifactorial, with both stimulation of cartilage matrix synthesis and prevention of cartilage breakdown. There are also systemic effects on blood lipids and fibrinolysis that may help clear the subchondral circulation. Calcium pentosan polysulfate (CaPPS) was shown to be absorbed better when taken orally than the sodium salt and maintained the proteoglycan content in the articular cartilage in experimentally inflamed rabbit joints.

Canines

Read et al. (1996) used three different doses of sodium PPS to treat 40 geriatric dogs with well-established clinical signs of chronic OA with SC injection. The 3 mg/kg dose was the most effective. In a study conducted with 10 elderly dogs with osteoarthritis given calcium PPS (3 mg/kg intramuscularly) once weekly for four weeks, the improvement in symptoms (seen at 1, 2, 3 and 7 weeks after initiation of therapy) was found to correlate with plasma indices of fibrinolytic activity and lipid profiles. In a study in dogs with OA secondary to cranial cruciate ligament (CCL) deficiency, although no differences were identified in either functional outcome or radiographic progression using the oral calcium PPS compared with placebo, there were significantly lower levels of proteoglycan breakdown products in the synovial fluid of the osteoarthritic joints. The efficacy of subcutaneous sodium PPS (3 mg/kg) was tested in 40 dogs with cranial cruciate ligament (CCL) instability and found to hasten recovery, as measured by more rapidly improved ground reaction forces (GRF), over 48 weeks.

Horses

There are few published reports describing the use of PPS for equine joint disease, however the drug is being used for this indication in Australia. When administered to racing Thoroughbreds with chronic osteoarthritis (2 to 3 mg/kg, intramuscularly, once weekly for 4 weeks, then as required), PPS treatment improved but did not eliminate clinical signs of joint disease. Articular cartilage fibrillation was substantially reduced by similar NaPPS treatment intramuscularly in nine horse with experimentally-induced carpal osteoarthritis. Despite limited published studies on the effect of PPS in horses, most surveyed owners and trainers in Australia found the intramuscular PPS treatment to be highly efficacious when used as a prophylactic prior to competition.

Humans

After a series of four to six intra-articular PPS injections into knees of human volunteers, there was a significant increase in the size of the synovial fluid hyaluronan without causing any inflammation or bleeding into the joint cavity. Preliminary reports of an open study of 23 patients with mild to moderate OA of the hand, hip, or knee, found that CaPPS (2 mg/kg intramuscularly once a week for 5 weeks) provided relief of symptoms and normalised hematologic parameters of coagulation and thrombolysis. Another preliminary report described the first 31 of 86 patients with OA of the knee who were subjected to intra-articular sodium PPS injections (n=15) compared to an equivalent volume of IA Ringer's solution (n=16) under double-blind conditions. NaPPS was significantly better than placebo for patient stiffness, walking on a level surface and pain in the previous 48 hours and previous month for multiple time points after treatment. The patients who had intra-articular PPS injections had synovial fluid with significantly better viscoelasticity (lubricating properties) due to significantly higher molecular weight hyaluronan.

When eleven women with knee or hip OA were injected with 3 mg/kg NaPPS, both hepatolipases and lipoprotein lipases were significantly elevated in their plasma for at least eight hours but had returned to normal levels by 24 hours. A double blind, placebo-controlled clinical study in 114 patients with osteoarthritis of the knee was performed in Perth, Australia where patients either received a salt solution or sodium PPS at 3 mg/ kg as an intramuscular injection once weekly for 4 weeks. Overall, NaPPS treatment significantly improved the duration of joint stiffness and pain at rest compared with controls for 20 weeks after the cessation of treatment, and significantly improved pain on walking and overall function for 8 weeks after the cessation of treatment. Twenty patients with knee OA were assessed clinically at Nagasaki University Hospital in a single-center, open-label trial. Treatment consisted of 6 weekly subcutaneous injections of pentosan (2 mg/kg). Knee flexion, pain while walking, pain after climbing up and down stairs were improved significantly for up to a year.

Transmissible spongiform encephalopathies

PPS gained attention as possibly being effective in the treatment of Creutzfeldt–Jakob disease (CJD). The rationale for this treatment was unclear but it was subsequently shown in prion-infected mouse neuroblastoma cells that PPS could rapidly reduce the levels of abnormal (scrapie) prion without affecting the normal cellular isoform. As PPS can bind to the cellular isoform of the prion protein, it may stabilise this form and prevent its conversion to the pathological (scrapie) isoform.

The treatment of one patient in Northern Ireland and around six other patients in mainland Britain were reported in the press. No patients showed signs of clinical improvement, however the disease was very advanced when the therapy was initiated.

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.

Names

Various brand names include Elmiron (as sodium salt), Hemoclar, Anarthron, Fibrase, Thrombocid and SP54. PPS Capsule is sold as Pentossan-100 by Molclone Labs India. PPS is also sold under the brand name Comfora in India. In the veterinary field, pentosan polysulfate is sold as Cartrophen Vet and Sylvet by Biopharm Australia, and Pentosan by Naturevet Australia.