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Purpose: To quantify baseline and longitudinal structural changes post-cessation in patients with pentosan polysulfate sodium retinopathy., Methods: This is a retrospective cohort study. Retinal thickness and volume of choroidal and hyperreflective retinal pigment epithelium excrescences were manually segmented from optical coherence tomography volume scans. Baseline measurements were compared against age-matched control subjects. Longitudinal measurements were performed on patients with follow-up data., Results: Twenty-four eyes of 13 patients were included. At baseline, the mean total retinal thickness was lower in the pentosan polysulfate sodium retinopathy cohort than in age- and sex-matched control subjects (269.1 µ m vs. 290.2 µ m, P = 0.006). The median (range) of follow-up was 18.6 (4.1-34.7) months, with the mean last follow-up of 35.2 months after cessation. During the follow-up period, the thickness of the retina decreased significantly by 11.3 µ m (CI: 16.8, 5.8) ( P < 0.001), with an annual mean decrease of 6.70 µ m. However, the mean hyperreflective retinal pigment epithelium excrescence volume did not change significantly ( P = 0.140) over the follow-up period., Conclusion: After pentosan polysulfate sodium discontinuation, although retinal pigment epithelium excrescence volume do not change significantly, there continues to be a progressive long-term thinning of the retina, which continues at a rate greater than that associated with normal aging. Consequently, long-term follow-up is suggested to monitor patients with pentosan polysulfate sodium retinopathy.

Introduction: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia., Methods and Analysis: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle., Ethics and Dissemination: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications., Trial Registration Numbers: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750., Competing Interests: Competing interests: DJH is supported by an NHMRC Practitioner Fellowship and provides consulting advice for Haleon, Novartis, TLC Bio, Tissuegene, Lilly and Pfizer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hepcidin peptide is crucial in the regulation of systemic iron availability controlling its uptake from the diet and its release from the body storage tissues. Hepcidin dysregulation causes different human disorders ranging from iron overload (e.g. hemochromatosis) to iron deficiency (e.g. anemia). Hepcidin excess is common in the Anemia of Chronic Diseases or Anemia of Inflammation and in the genetic form of anemia named IRIDA; the pharmacological downregulation of hepcidin in these disorders could improve the anemia. Commercial heparins were shown to be strong inhibitors of hepcidin expression, by interfering with BMP6/SMAD pathway. The non-anti-coagulant heparins, modified to abolish the anti-thrombin binding site, were equally potent and could be used to improve iron status. To perform its anti-hepcidin activity heparin needs 2O- and 6O-sulfation and an average molecular weight (MW) up to 4000-8000 Dalton, depending on the sulfation level. The pentosane polysulfate (PPS), which shares with heparin a high degree of sulfation, is a compound with low anti-coagulant activity that is already in use for pharmaceutical treatment. In the present work we analyzed the anti-hepcidin activity of PPS in vitro and in vivo. We found that it acts as a strong inhibitor of hepcidin expression in HepG2 cells with an effect already visible after 2-3 h of treatment. It also suppressed hepcidin in mice in a dose dependent manner after 3 h and with a significant redistribution of systemic iron without evident side effects. PPS is also able to abolish the LPS dependent hepcidin upregulation similarly to that showed for heparin derivatives. These results suggest PPS as an interesting compound to control hepcidin in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe the prevalence and spectrum of multimodal imaging findings of pentosan polysulfate sodium (PPS)-associated maculopathy and to recommend dosage-related screening guidelines., Design: Cross-sectional study., Methods: Patients previously or currently treated with PPS at University of California, Los Angeles, were randomly ascertained and prospectively screened for PPS-associated maculopathy with multimodal retinal imaging. Daily and cumulative dosages of PPS exposure were calculated for each patient. Images were studied to identify the characteristic findings of toxicity. The prevalence of PPS-associated maculopathy and screening guidelines were determined., Results: The prevalence of PPS-associated maculopathy in this cohort was 20% (10/50 patients). Both average duration of PPS therapy and average cumulative dosage were significantly lower in the unaffected (6.3 ± 6.6 years, 691.7 ± 706.6 g) versus the affected groups (20.3 ± 6.6 years, 3375.4 ± 1650.0 g, p < 0.001). Near-infrared reflectance (NIR) illustrated characteristic punctate retinal pigment epithelium (RPE) macular lesions early. Fundus autofluorescence (FAF) showed speckled autofluorescence in the posterior pole with peripapillary extension. Co-localization with optical coherence tomography (OCT) displayed focal RPE thickening and, in more severe cases, RPE atrophy in the macula and even the periphery., Conclusions: A prevalence of 20% in this study cohort suggests a significant risk of macular toxicity for PPS-treated patients. Characteristic alterations are best detected with FAF and NIR. More significant PPS exposure was associated with more severe atrophy. We recommend an initial baseline eye examination to include OCT and, most importantly, NIR and FAF with annual retinal imaging thereafter especially with cumulative dosages approaching 500 g. Patients exposed to greater than 1500 g of PPS are at significant risk of retinal toxicity., (Published by Elsevier Inc.)

Purpose: To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy., Design: Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA)., Participants: Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database., Methods: Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure., Main Outcome Measures: The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy., Results: The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus., Conclusions: In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aim: Sodium pentosan polysulfate (Na-PPS) is a plant-based agent that has similar action with low-molecular-weight heparin. It inhibits factor Xa, preventing blood clot formation. To date, its use in clinical practice as thromboprophylaxis agent is still limited. In addition, the efficacy and safety profile of this agent was not robustly reported globally, especially for countries with major Muslim population. We hypothesized that Na-PPS was equally effective as the standard thromboprophylaxis. We aim to compare the efficacy and safety of Na-PPS against standard agent (fondaparinux or enoxaparin)., Methods: This was a randomized control, open-label trial. Women underwent major gynecological surgery were randomized to receive either subcutaneous 50 mg of Na-PPS twice daily or subcutaneous enoxaparin 40 mg once daily. Fondaparinux 2.5 mg once daily was given to Muslim women as an alternative to enoxaparin. The treatment was started 6 h postoperatively, for at least 3 days. All the patients received thromboembolic deterrent stockings. The primary efficacy outcome was venous thromboembolism up to 3 days postsurgery. The main safety outcomes were minor and major bleeding., Results: Among 109 participants, there was no incidence of venous thromboembolism. None of the women developed major bleeding. Minor bleeding was observed in 28.3% (15/53) and 5.4% (3/56) of Na-PPS and standard thromboprophylaxis group, respectively (P = 0.001)., Conclusion: Na-PPS was associated with increased risk of minor bleeding. There was insufficient data to conclude its efficacy as thromboprophylaxis. Further research is needed to evaluate Na-PPS safety as a standard thromboprophylactic agent., (© 2018 Japan Society of Obstetrics and Gynecology.)

The apoptosis of tubular epithelial cells in diabetic nephropathy (DN) is commonly observed in human renal biopsies. Inflammation plays a key role in DN, and pentosan polysulfate (PPS) has been shown to largely attenuate the inflammation of nephropathy in aging diabetic mice. p38 mitogen‑activated protein kinase (p38 MAPK) plays a crucial role in tissue inflammation and cell apoptosis, and it is activated by hyperglycemia. In the present study, high glucose (HG)‑treated human renal proximal tubular epithelial cells (HK‑2) were used to examine the protective effects of PPS against HG‑stimulated apoptosis and inflammation. The results of the study revealed that PPS markedly suppressed the HG‑induced reduction in cell viability. Incubation of HK‑2 cells with HG activated the p38 MAPK pathway and, subsequently, as confirmed by western blot analysis and flow cytometry, increased cell apoptosis, which was blocked by PPS. In addition, PPS treatment significantly inhibited HG‑stimulated p38 MAPK and nuclear factor‑κB activation, and reduced the production of pro‑inflammatory cytokines, such as tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. In conclusion, PPS ameliorates p38 MAPK‑mediated renal cell apoptosis and inflammation. The anti‑apoptotic actions and anti‑inflammatory effects of PPS prompt further investigation of this compound as a promising therapeutic agent against DN.

Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic symptom complex that may cause bothersome storage symptoms and pain or discomfort of the bladder, adversely affecting a patient's quality of life. The etiology of IC/BPS remains unclear, and its cause may be multifactorial. Diagnosis of IC/BPS is based on clinical features, and the possibility of other conditions must be ruled out first. Although no definitive treatment is currently available for IC/BPS, various intravesical therapies are used for IC/BPS, including heparin, hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dimethylsulfoxide, liposomes, and botulinum onabotulinumtoxinA (BoNT-A). This review summarizes the intravesical therapy for IC/BPS and discusses recent advances in the instillation of liposomal-mediated BoNT-A and other newly developed intravesical therapies., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: At present, there are no registered products for the treatment of subchondral Bone Marrow Edema Lesion (BML) and associated knee pain. Patients who do not respond to current anti-inflammatory therapies are left with limited treatment options, and may resort to operative management with Total Knee Arthroplasty (TKA). We report the use of Pentosan Polysulphate Sodium (PPS) for the treatment of BMLs of the knee., Case Presentation: We report the case of a 70-year-old female with knee osteoarthritis presenting with a high level of knee pain, scoring 8 on the Numerical Rating Scale (NRS), and functional limitation demonstrating a poor Lysholm Knee Score of 37. MRI scans of the knee revealed subchondral BML in the medial femoral condyle and medial tibial plateau. The patient was administered a course of Pentosan Polysulphate Sodium (PPS) intramuscularly twice weekly, for 3 weeks. MRI scans 2 weeks post-treatment showed complete resolution of the bone marrow edema at the medial femoral condyle and medial tibial plateau with concomitant recovery from pain (NRS pain score of 0), and a 43% improvement of the Lysholm Knee Score. In addition, marked reduction in joint effusion was also demonstrated in the MRI scan post PPS therapy., Conclusion: The MRI interpretations demonstrate improved clinical outcome measures ensuing therapeutic intervention with PPS, and warranting further investigation into the efficacy of PPS in the treatment of BML associated pain and dysfunction in the osteoarthritic population via randomized controlled trial, or equivalent rigorous methodological technique.

Objective: To assess the role of oral pentosan polysulphate (PPS) in the reduction of bacille Calmette-Guérin (BCG)-related local side effects in patients with high grade Ta/T1 non-muscle-invasive bladder cancer (NMIBC)., Patients and Methods: A total of 32 symptomatic patients receiving BCG instillation were randomized into three groups: group A received placebo (vitamin B complex tablet) thrice daily; group B received PPS 100 mg thrice daily; and group C received PPS 100 mg once daily and placebo (vitamin B complex tablet) twice daily for 6 weeks. A visual analogue scale (VAS) score for bladder pain, Overactive Bladder-Validated 8 Question Screener (OAB-V8) scores and dysuria were evaluated in the three groups before and during each weekly visit for BCG instillation., Results: The mean ± sd post-treatment VAS scores were significantly lower in groups B (4.4 ± 1.2) and C (5.8 ± 0.8) than in group A (8 ± 0.4). In addition, the post-treatment VAS score was significantly lower in group B than in group C (P<0.01). The mean post-treatment OAB-V8 score was significantly lower only in group B (decreased from 15.5 to 9.7). Dysuria decreased in groups B and C but persisted in group A., Conclusion: The present study shows that oral PPS (100 mg) thrice daily is effective in relieving BCG-related local side effects., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Objectives: Obstructive feline idiopathic cystitis is a common emergency in small animal practice. There is evidence for a defective glycosaminoglycan layer in the urinary bladder of affected cats. The aim of this study was to investigate the effect of intravesical pentosan polysulfate sodium (PPS) in cats with obstructive feline idiopathic cystitis in a randomised, placebo-controlled, blinded clinical study., Methods: Thirty-five cats with obstructive feline idiopathic cystitis were enrolled into the study. On day 0, cats were randomised to receive either 30 mg PPS in saline (18 cats) or saline alone as placebo (17 cats) at the time of indwelling urinary catheter placement and then after 24 and 48 h. The catheter was clamped for 30 mins after administration before connecting it to a sterile urine collection system. The procedure was repeated after 24 and 48 h, and then the indwelling catheter was removed. Treatment success was assessed via the incidence of recurrent urethral obstruction, results of a scoring system for physical examination and daily urinalysis from day 0 to 5., Results: Recurrent urethral obstruction occurred in 3/18 cats of the verum group and 3/17 of the placebo group (P = 1.000). The verum group showed a significantly lower degree of microscopic haematuria between day 5 and day 0 (P ⩽0.05). The placebo group showed a significantly lower degree of dipstick haematuria between day 5 and day 0 (P ⩽0.05). There was no difference in the clinical score between the groups in the investigated time period., Conclusions and Relevance: Intravesical instillation of PPS three times within 48 h in the chosen dose had no influence on the incidence of recurrent urethral obstruction and clinical signs in cats with obstructive feline idiopathic cystitis., (© ISFM and AAFP 2015.)

Introduction and Hypothesis: Bladder pain syndrome/interstitial cystitis (BPS/IC) has various treatments; however, no standardized treatment has been established. The aim was to analyze different types of treatment of BPS/IC and their effectiveness., Methods: A literature review with a search strategy for articles related to BPS/IC published between 1990 and 2014 was conducted on MEDLINE, PUBMED, and SCOPUS. Only randomized controlled trials in women were included in the meta-analysis, while other experimental studies were used as bases for a systematic review of the topic. Clinical trial quality was defined according to the Jadad scale., Results: Of 356 articles, 13 were included in the analysis. The intervention methods were as follows: instillation of hyaluronic acid, botulinum toxin A, intravesical lidocaine, hyperbaric chamber, massage, physiotherapy, phosphate-buffered saline, piroxicam in combination with doxepin, and others. We did not find any treatment with at least two randomized controlled trials for meta-analysis. Among the assessment tools for symptoms of BPS/IC, the most frequently used were the visual analogue scale, voiding record, and the O'Leary-Sant questionnaire., Conclusion: Existing studies were not able to define the best approach for the treatment of BPS/IC. The lack of standardized treatment may be related to the diversity of interventions used; therefore, further studies with better methodological quality are needed.

Background: We previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model., Methodology/principal Findings: MPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed., Conclusions: PPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.

Background: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice., Objectives: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity., Search Methods: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015., Selection Criteria: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment)., Data Collection and Analysis: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome., Main Results: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life., Authors' Conclusions: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Unlabelled: Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin-10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis., Importance: The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas, with approximately 1 million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently, there is no licensed specific treatment for alphavirus disease, and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects, and is currently licensed under the name Elmiron for the treatment of cystitis in the United States. Our findings show that RRV infection damages the articular cartilage, including a loss of proteoglycans within the joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting that PPS is a promising candidate for drug repurposing for the treatment of alphavirus-induced arthritis., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The optimal management of persistent hemorrhagic radiation cystitis is ill-defined. Various options are available and include oral agents (ie, sodium pentosan polysulfate), intravenous drugs (ie, WF10), topical agents (ie, formalin), hyperbaric oxygen, and endoscopic procedures (ie, electrical cautery, argon plasma coagulation, laser coagulation). In general, it is best to manage patients conservatively and intervene only when necessary with the option least likely to exacerbate the cystitis. More aggressive measures should be employed only when more conservative approaches fail. Bladder biopsies should be avoided, unless findings suggest a bladder tumor, because they may precipitate a complication.

Purpose: We compared the efficacy and safety of the currently recommended dose of pentosan polysulfate sodium with a third of the daily dose and with placebo., Materials and Methods: In this multicenter, double-blind, randomized, placebo controlled study 368 adults with interstitial cystitis/bladder pain syndrome, defined as an ICSI total score of 8 or greater and a score of greater than 0 on the 4 ICSI component items, received pentosan polysulfate sodium 100 mg once daily or 3 times daily, or matching placebo for 24 weeks. Study eligibility was not based on cystoscopy findings. ICSI was administered at baseline, and at weeks 4, 8, 12, 18 and 24. Unblinded interim analysis performed at 6 years with 54% of the target number of 645 patients enrolled resulted in early study termination., Results: There was no statistically significant difference between the pentosan polysulfate sodium group and the placebo group or between the 2 pentosan polysulfate sodium groups for the primary end point, defined as responder achieving a 30% or greater reduction from the baseline ICSI total score at study end. This primary end point was achieved by 48 of 118 patients (40.7%) in the placebo group, and by 51 of 128 (39.8%) and 52 of 122 (42.6%) in the pentosan polysulfate sodium 100 mg once daily and 3 times daily groups, respectively. Pentosan polysulfate sodium was well tolerated with a similar percent of patients (range 10.2% to 13.3%) across the groups discontinuing due to an adverse event., Conclusions: Results of this study in a broad population of patients with symptoms consistent with interstitial cystitis revealed no treatment effect vs placebo for pentosan polysulfate sodium at the currently established dose or at a third of the daily dose., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS., Methods: Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain., Results: The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix., Conclusions: Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To assess the effects of sodium pentosan polysulfate (PPS), N-acetyl glucosamine (NAG), and sodium hyaluronan (HA) in horses with induced osteoarthritis (OA)., Study Design: Experimental., Animals: Adult Standard bred horses (n = 16)., Methods: OA was induced arthroscopically in 1 intercarpal joint; 8 horses were administered 3 mg/kg PPS, 4.8 mg/kg NAG, and 0.12 mg/kg HA (PGH), intravenously (IV), weekly and 8 horses were administered an equivalent volume of saline IV until study completion (day 70). Horses underwent a standardized treadmill exercise program. Clinical and radiographic findings and synovial fluid analysis were evaluated throughout the study. Macroscopic, histologic, histochemical, and biochemical findings were evaluated after necropsy. Comparisons of interest included OA and non-OA joints of saline treated horses and OA joints of PGH treated horses and OA joints of saline treated horses. Results were statistically analyzed with significance set at P < .05., Results: OA caused increases in clinical assessment scores, synovial fluid variables, radiographic, macroscopic, and histologic cartilage scores, synovial fluid and cartilage chondroitin sulfate 846-epitope and glycosaminoglycan concentration. Total radiographic scores, total macroscopic joint pathology and macroscopic cartilage pathology scores were significantly reduced in horses treated with PGH compared with saline treated horses. Synovial fluid total protein concentration and white blood cell count were higher in OA joints of PGH treated horses compared with saline treated horses. There were no other significant differences between treatment groups., Conclusions: Improvements in macroscopic variables were not supported by other outcomes. Further evidence is needed before PGH can be recommended as a therapeutic option for osteoarthritis in horses., (© Copyright 2014 by The American College of Veterinary Surgeons.)

Background: We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (s.c.) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients., Methodology/principal Findings: One-month-old MPS VI rats were given once weekly s.c. injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly s.c. PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of s.c. treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, s.c.. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of s.c. PPS administration., Conclusions: Once weekly s.c. administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from s.c. PPS administration were observed over the 6-month study period.

The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

Intervertebral disc (IVD) degeneration is one of the leading causes of lower back pain and a major health problem worldwide. Current surgical treatments include excision or immobilisation, with neither approach resulting in the repair of the degenerative disc. As such, a tissue engineering-based approach in which stem cells, coupled with an advanced delivery system, could overcome this deficiency and lead to a therapy that encourages functional fibrocartilage generation in the IVD. In this study, we have developed an injectable hydrogel system based on enzymatically-crosslinked polyethylene glycol and hyaluronic acid. We examined the effects of adding pentosan polysulphate (PPS), a synthetic glycosaminoglycan-like factor that has previously been shown (in vitro and in vivo) to this gel system in order to induce chondrogenesis in mesenchymal precursor cells (MPCs) when added as a soluble factor, even in the absence of additional growth factors such as TGF-β. We show that both the gelation rate and mechanical strength of the resulting hydrogels can be tuned in order to optimise the conditions required to produce gels with the desired combination of properties for an IVD scaffold. Human immunoselected STRO-1+ MPCs were then incorporated into the hydrogels. They were shown to retain good viability after both the initial formation of the gel and for longer-term culture periods in vitro. Furthermore, MPC/hydrogel composites formed cartilage-like tissue which was significantly enhanced by the incorporation of PPS into the hydrogels, particularly with respect to the deposition of type-II-collagen. Finally, using a wild-type rat subcutaneous implantation model, we examined the extent of any immune reaction and confirmed that this matrix is well tolerated by the host. Together these data provide evidence that such a system has significant potential as both a delivery vehicle for MPCs and as a matrix for fibrocartilage tissue engineering applications., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.

Objective: To assess clinical, radiographic, histologic, and biochemical effects of sodium pentosan polysulfate (NaPPS) administered IM for treatment of experimentally induced osteoarthritis in horses., Animals: 18 horses., Procedures: Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Nine horses received NaPPS (3 mg/kg, IM) on study days 15, 22, 29, and 36. Nine control horses received the same volume of saline (0.9% NaCl) solution IM on study days 15, 22, 29, and 36. Clinical, radiographic, gross, histologic, histochemical, and biochemical findings as well as findings of synovial fluid analysis were evaluated., Results: No adverse treatment-related events were detected. Induced osteoarthritis caused a substantial increase in lameness, response to flexion, joint effusion, radiographic findings, synovial membrane inflammation, and articular cartilage fibrillation. Articular cartilage fibrillation was substantially reduced by NaPPS treatment, and concentrations of chondroitin sulfate 846 epitope were significantly increased in the synovial fluid of osteoarthritic and non-osteoarthritic joints of treated horses., Conclusions and Clinical Relevance: Results indicated that NaPPS has some beneficial disease-modifying effects and may be a therapeutic option for osteoarthritis in horses.

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain., (© 2011 Japanese Society of Neuropathology.)

Purpose: Haemorrhagic cystitis (HC) is an uncommon but potentially devastating complication of chemotherapy and bone marrow transplantation in children. We aimed to test the hypothesis that early recognition, sodium pentosan polysulfate (SPP), and avoidance of urethral catheterisation improve outcomes in children with HC., Methods: A retrospective case note review was performed of all patients treated for HC in our hospital from 2002 to 2010. A protocol for the management of HC was introduced in 2007 advocating early detection, use of SPP, and avoidance of urethral catheterisation. Data collected on each patient included primary condition, medications at onset, blood transfusions, duration of symptoms, catheter usage, and outcome. Statistical analysis was performed using the Mann-Whitney U test, and Fisher's Exact test as appropriate, P < .05 being significant., Results: Five patients were treated using protocol with 5 historical controls. There was no significant difference between the ages of the group, diagnosis, and treatment at onset of HC. In the historical group, 4 of 5 died with HC, but all recovered in the protocol group (P < .05). Blood transfusion requirements were also significantly reduced after protocol introduction (P < .05)., Conclusion: Early identification, avoidance of urethral catheterisation, and use of SPP significantly reduces blood transfusion requirements and mortality from HC., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Inflammation has a key role in diabetic nephropathy (DN) progression. Pentosan polysulfate (PPS) has been shown to decreases interstitial inflammation and glomerulosclerosis in 5/6 nephrectomized rats. Since PPS has an excellent long-term safety profile in interstitial cystitis treatment, and we recently found that old diabetic C57B6 mice develop DN characterized by extensive tubulointerstitial inflammatory lesions that mimics human DN, we examined the effect of PPS on old diabetic mice. We also examined the anti-inflammatory properties of PPS in renal cells in vitro. Diabetes was induced with streptozotocin in 18 months female (early aging) C57B6 mice. Mice were then randomized to receive oral PPS (25 mg/kg/day) or water for 4 months. The effect of PPS on NF-κB activation and on TNFα, high glucose or advanced glycation end products (AGEs) stimulated proinflammatory gene expression in renal cells was examined. We found that PPS treatment preserved renal function, significantly reduced albuminuria, and markedly decreased the severity of renal lesions, including tubulointerstitial inflammation. PPS also reduced upregulation of TNFα and proinflammatory genes in aging diabetic kidneys. Furthermore, PPS suppressed NF-κB, decreased the proinflammatory actions of TNFα, and decreased high glucose and AGEs stimulated MCP-1 production in vitro. Finally, PPS decreased TNFα-induced increase in albumin permeability in podocyte monolayers. In conclusion, PPS treatment largely prevents the development/progression of nephropathy in aging diabetic mice. As this may be mediated by suppression of TNFα, high glucose, and AGE-stimulated NF-κB activation and inflammation in vitro, the in vivo blockade of DN may be due to the anti-inflammatory properties of PPS., (© 2011 USCAP, Inc All rights reserved)

To present single institution open-label experience with intravesical liposomes (LPs), a mucosal protective agent, in patients with interstitial cystitis/painful bladder syndrome (IC/PBS) and to assess the safety and efficacy on IC/PBS symptoms. A total of 17 symptomatic IC/PBS patients were treated with intravesical LPs (80mg/40mL distilled water) once a week for 4 weeks (n=12) or twice a week treatment for 4 weeks (n=5). The primary outcome was the change in the O'Leary-Sant Symptom/Problem score and O'Leary-Sant total Score from baseline to Week 4 and Week 8. Other outcome measurements included the changes in pain scale, urgency scale, voiding log, and patient global assessment. Both weekly and biweekly LP instillation regiments were well tolerated. The incidence of urinary incontinence, retention, or unanticipated adverse changes was not noted at any dose either during the treatment or at the 4-week follow-up. The O'Leary-Sant Symptom/Problem score, O'Leary-Sant total Score, and pain score were significantly improved from baseline at both dose regimens with added benefit with the biweekly regimen. Intravesical LPs treatment is safe and its efficacy has sustained duration. Furthermore large-scale, placebo-controlled studies are warranted to assess the efficacy for this promising new treatment for IC/PBS., (Copyright © 2011. Published by Elsevier B.V.)

Interstitial cystitis/painful bladder syndrome affects more than 1 million persons in the United States, but the cause remains unknown. Most patients with interstitial cystitis/painful bladder syndrome are women with symptoms of suprapubic pelvic and/or genital area pain, dyspareunia, urinary urgency and frequency, and nocturia. It is important to exclude other conditions such as infections. Tests and tools commonly used to diagnose interstitial cystitis/painful bladder syndrome include specific questionnaires developed to assess the condition, the potassium sensitivity test, the anesthetic bladder challenge, and cystoscopy with hydrodistension. Treatment options include oral medications, intravesical instillations, and dietary changes and supplements. Oral medications include pentosan polysulfate sodium, antihistamines, tricyclic antidepressants, and immune modulators. Intravesical medications include dimethyl sulfoxide, pentosan polysulfate sodium, and heparin. Pentosan polysulfate sodium is the only oral therapy and dimethyl sulfoxide is the only intravesical therapy with U.S. Food and Drug Administration approval for the treatment of interstitial cystitis/painful bladder syndrome. To date, clinical trials of individual therapies have been limited in size, quality, and duration of follow-up. Studies of combination or multimodal therapies are lacking.

Background: The Interstitial Cystitis (IC) has been considered in the past an uncommon pathology, however it has received a special attention during the last 20 years, (1678 scientific articles published since 1984 to 2009). There are many therapeutic options not at all satisfactory because there isn't consensus about diagnostic and treatment., Objective: To share our experiences in the treatment of interstitial cystitis, additionally, to comment on the therapeutic response of treatment used., Material and Method: Observational, retrospective an analytic study of 17 treated patients from 22 with diagnosis of IC and Bladder Painful Syndrome (IC/BPS) were managed in Urodifem de Occidente, S.C. a private Urogynecologic unit between January 2001 and April 2010. The diagnosis was done in agreement with the concepts of Interstitial Cystitis group from clinical and cystoscopic characteristics. The treatment was: Dimethyl sulfoxide (DIMSO) and Pentosan Polysulfate., Results: The evaluation was measured by Interstitial Cystitis Symptomatic Index (ICSI) and Interstitial Cystitis Problem Index (ICPI) both validated evaluation instruments, 82% of the patients had a significative improvement of symptomatology and quality of live The ICSI pre and post treatment was of 17.0 and 4.5 and the ICPI was of 14.8 and 4.1 respectively., Conclusion: We recommend the use of combine treatment of DIMSO and PPS in cases of I.C.

Interstitial Cystitis, first described in 1887 as an inflammatory disease of the bladder wall, is now regarded as a very common disease with an estimated number of unreported cases. Reasons for underdiagnosis is the widespread use of strict exclusion criteria. The disease can already be suspected by a careful medical history and physical examination in an early stage and then be treated with promising multimodal therapeutic approaches. In addition to a symptomatic oral therapy, local instillations with constituents of the protective glycosaminoglycan-layer are the most common therapeutic approach, because its defective integrity plays a key role in the pathogenesis of interstitial cystitis.

The goal of the present work was to develop a swellable hydrogel colonic delivery system, which would maximise the availability of the therapeutic agent at a site of inflammation, especially where the water is scarce. A novel method was developed to manufacture a biodegradable and reversible polyelectrolyte complex (PEC) containing chitosan and poly acrylic-acid (PAA). The PEC was analysed using FTIR and DSC, which confirmed the formation of non-permanent swollen gel-network at an alkaline pH. Pentosan polysulphate (PPS) was incorporated in a PEC and an activated partial thromboplastin time assay was developed to measure the release of PPS from PEC. In vitro studies suggested that the release of PPS was dependent on the initial drug loading and the composition of the PEC. The gel strength of the swollen network, determined using a texture analyser, was dependent on polymer composition and the amount of PPS incorporated. Bacterial enzymes were collected from the rat caecum and colon for the digestion studies and characterised for glucosidase activity, glucuronidase activity and protein content. The digestion of the reversible polyelectrolyte complexes was measured using a dinitro salicylic acid assay and an increased release of drug was also confirmed in the presence of bacterial enzymes., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Object: There is an unmet need for a procedure that could generate a biological disc substitute while at the same time preserving the normal surgical practice of achieving anterior cervical decompression. The objective of the present study was to test the hypothesis that adult allogeneic mesenchymal progenitor cells (MPCs) formulated with a chondrogenic agent could synthesize a cartilaginous matrix when implanted into a biodegradable carrier and cage, and over time, might serve as a dynamic interbody spacer following anterior cervical discectomy (ACD)., Methods: Eighteen ewes were divided randomly into 3 groups of 6 animals. Each animal was subjected to C3-4 and C4-5 ACD followed by implantation of bioresorbable interbody cages and graft containment plates. The cage was packed with 1 of 3 implants. In Group A, the implant was Gelfoam sponge only. In Group B, the implant consisted of Gelfoam sponge with 1 million MPCs only. In Group C, the implant was Gelfoam sponge with 1 million MPCs formulated with the chondrogenic agent pentosan polysulfate (PPS). In each animal the cartilaginous endplates were retained intact at 1 level, and perforated in a standardized manner at the other level. Allogeneic ovine MPCs were derived from a single batch of immunoselected and culture-expanded MPCs isolated from bone marrow of outbred sheep (mixed stock). Radiological and histological measures were used to assess cartilage formation and the presence or absence of new bone formation., Results: The MPCs with or without PPS were safe and well-tolerated in the ovine cervical spine. There was no significant difference between groups in the radiographic or histological outcome measures, regardless of whether endplates were perforated or retained intact. According to CT scans obtained at 3 months after the operation, new bone formation within the interbody space was observed in the Gelfoam only group (Group A) in 9 (75%) of 12 interbody spaces, and 11 (92%) of 12 animals in the MPC cohort (Group B) had new bone formation within the interbody space. Significantly, in the MPC & PPS group (Group C), there were only 1 (8%) of 12 levels with new bone formation (p = 0.0009 vs Group A; p = 0.0001 vs Group B). According to histological results, there was significantly more cartilaginous tissue within the interbody cages of Group C (MPC & PPS) compared with both the control group (Group A; p = 0.003) and the MPC Group (p = 0.017)., Conclusions: This study demonstrated the feasibility of using MPCs in combination with PPS to produce cartilaginous tissue to replace the intervertebral disc following ACD. This biological approach may offer a means preserving spinal motion and offers an alternative to fusion to artificial prostheses.

There are still many things to be found out about interstitial cystitis/painful bladder syndrome (IC/PBS) because the pathological processes underlying the condition are not yet elucidated, biological markers of the condition are not yet available, and the type and severity of symptoms can vary, so, clearly defining the condition is not yet possible. For example, it is not clearly understood whether IC/PBS represents a systemic disease, if it is localized in the bladder, or if it was initially localized in the bladder and it later evolved into a systemic disease. This condition is best managed by using a multidisciplinary approach. Management requires a good integration and knowledge of all pelvic organ systems and other systems including musculoskeletal, neurologic, and psychiatric systems.

Background: Creutzfeldt-Jakob disease (CJD) is a rare neurological disease which is always terminal, often within months. The disease attracted attention in the 1990 s, when reports appeared about people acquiring the disease by eating meat from cattle infected with BSE (bovine spongiform encephalopathy). Recent progress within research on CJD has raised hopes about finding a treatment. The most promising results of this research are presented., Material and Methods: The review is based on articles (and references in them) identified through non-systematic searches in PubMed., Results: CJD is a disease that emerges when the cellular form of the prion protein PrPC is transformed into the disease-associated PrPSc. Transgenic mice that did not express PrPC did not develop clinical signs of the disease after being exposed to prions. Both administration of antibodies towards PrPC and use of RNA interference technique to reduce PrPC gene expression increased the survival time in mice. Pentosan polysulphate (a drug against interstitial cystitis) infused intraventriculary in mice, prolonged the incubation time from 51 to 123 days. The drug has been tested in patients with CJD with promising results with respect to survival time., Interpretation: New treatment modalities have shown results that raise hopes about finding curative treatment in the future.

Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.

Purpose: We evaluated the safety and efficacy of intravesical liposomes, a mucosal protective agent, compared to oral pentosan polysulfate sodium for interstitial cystitis/painful bladder syndrome., Materials and Methods: We performed a prospective longitudinal study of the effect of 2 independent treatments (intravesical liposomes and oral pentosan polysulfate sodium) in patients with interstitial cystitis/painful bladder syndrome. Ten possible responses (or measures) to treatment were monitored at 3 time points, including baseline, and weeks 4 and 8. A total of 24 patients with interstitial cystitis/painful bladder syndrome were evaluated in a 1:1 ratio to intravesical liposomes (80 mg/40 cc distilled water) once weekly or to oral pentosan polysulfate sodium (100 mg) 3 times daily for 4 weeks each., Results: No patient had urinary incontinence, retention or infection due to liposome instillation. There were no unanticipated adverse events and no significant worsening of symptoms during followup. Statistically significant decreases in urinary frequency and nocturia were observed in each treatment group. Statistically significant decreases in pain, urgency and the O'Leary-Sant symptom score were observed in the liposome group. Decreased urgency in the liposome group had the most profound effect of the ordinal measures., Conclusions: Each glycosaminoglycan directed treatment seemed beneficial. Liposome intravesical instillation is safe for interstitial cystitis/painful bladder syndrome with potential improvement after 1 course of therapy for up to 8 weeks. Intravesical liposomes achieved efficacy similar to that of oral pentosan polysulfate sodium. Further large-scale placebo controlled studies are needed. Intravesical liposomes appear to be a promising new treatment for interstitial cystitis/painful bladder syndrome.

Prion diseases are progressive neurological disorders due to abnormal prion protein (PrP(Sc)) deposition in the central nervous system. At present, there is no effective treatment available for any form of prion disease. Pentosan polysulfate (PPS) has been shown to prolong significantly the incubation period in mice with PrP(Sc) infection when administered to the cerebral ventricles in preclinical trials. In human studies conducted in European countries and Japan, intraventricular PPS was administered to patients with different forms of prion disease and was well tolerated. We report 11 patients with prion disease treated with intraventricular PPS at Fukuoka University from 2004. Cases included three familial CJD (two with V180I mutation, one GSS with P102L mutation), two iatrogenic CJD, and six sporadic CJD cases. At present, average survival period after treatment was 24.2 months (range, 4-49). Seven cases died of sepsis and pneumonia. Subdural effusion with various degrees was seen on CT scan in most cases. Except for these, adverse effects did not occur in the treatment period. Although our preliminary study of the new treatment with PPS by continuous intraventricular infusion showed no apparent improvement of clinical features in patients with prion disease, the possibility of extended survival in some patients receiving long-term PPS was suggested.

Objective: Interstitial cystitis (IC) is a visceral pain syndrome with a profound impact on quality of life (QOL). The main aims of the current study are as follows: (1) to determine possible factors that may increase the severity of symptoms and decrease QOL in women diagnosed with IC; (2) to study how symptom severity affects QOL adjusting for these factors; and (3) to investigate which symptom is most likely to impair IC patients' physical and mental QOL., Methods: Forty-one women (age, 20-71 years) with moderate/severe IC enrolled in a clinical trial of intravesical pentosan polysulfate sodium in California (USA) were included in this cross-sectional analysis. Demographic and clinical characteristics were evaluated at baseline using the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), pain assessment, urgency scale, voiding log for 24 h, and the Short Form-36 (SF-36)., Results: Being currently unmarried was associated with more severe symptoms. Being unemployed, currently unmarried, obese, never pregnant, and ever use of oral contraceptive were associated with a decrement in at least one QOL domain. Symptom severity was an independent predictor of worse QOL on three domains: bodily pain, general health, and mental health. Pain and nocturia were the only symptoms found to be associated with decline in overall physical quality of life. None of the symptoms had significant impact on the mental component summary of QOL., Conclusions: Symptom severity and being currently unmarried were found to be associated with impairment in QOL in IC patients. Managing pain and nocturia may improve the patients' overall physical QOL.

Of the many unresolved issues in relation to prion diseases, effective treatments remain an elusive exigency, although some progress has been made. This review describes disease-ameliorating therapeutic strategies reported to date in animal models of prion disease, as well as providing a brief overview of selected completed human treatment trials. Included in vivo studies have been broadly dichotomized according to the time of introduction of the treatment in relation to animal inoculation and also according to their possible principal mechanism of action, although the latter is not always entirely clear, and often there is likely to be more than one mechanism. Consequent to the pathogenic primacy of cellular prion protein (PrP(c))-to-scrapie PrP(c) (PrP(sc)) conversion, most reported treatments appear to directly target this replication process, although various other strategies, such as depletion of reaction substrates and abrogation of downstream effector pathways, have been utilized. Many factors, including experimental design, militate against reliable extrapolation of study results to the routine clinical setting or limit easy translational application to human disease. Notably problematic are approaches wherein benefit has been shown but the treatment was initiated before, at or soon after inoculation of experimental animals.

Objective: Painful bladder syndrome/interstitial cystitis (PBS/IC) is an inflammatory bladder disease of unknown origin. Symptoms of PBS/IC compromise patients' quality of life (QoL). This study evaluated a health-related quality of life (HRQoL) questionnaire in PBS/IC., Material and Methods: 151 patients with PBS/IC filled in the HRQoL questionnaire before and after the treatment. Of these, 87 patients participated in a 3-month randomized study testing intravesical dimethyl sulfoxide (DMSO) and bacille Calmette-Guerin (BCG) and 64 patients took part in a 6-month randomized study evaluating oral cyclosporine A (CyA) and pentosan polysulfate sodium (PPS). The changes in HRQoL questionnaire were evaluated with respect to the changes in global response assessment (GRA)., Results: The results of the HRQoL questionnaire reflected well the post-treatment GRA. Patients responding to their treatment had improved QoL. CyA treatment had more impact on emotional well-being, social functioning, activity limitation days, pain and physical capacity than PPS treatment (p<0.05). More patients responded to DMSO than BCG treatment according to GRA (p<0.01), but the results in HRQoL questionnaire were equal after DMSO and BCG treatments., Conclusions: The HRQoL questionnaire can be used in evaluating QoL in PBS/IC patients. Treatment of PBS/IC had obvious effects on QoL.

Objective: To provide an overview of interstitial cystitis (IC), including the presentation of patients with the disorder, and to explore diagnostic and treatment options., Study Design: Current literature concerning the history, etiology, diagnosis and treatment of IC was used to support expert recommendations regarding patient management. Experts discussed the literature surrounding IC, focusing on diagnostic tools and currently available treatment modalities., Results: Diagnosis of IC may often be delayed or missed due to the similarity of symptoms with a number of other conditions. A detailed medical history and careful physical examination are key for diagnosis, and a variety of screening and diagnostic tools are also available. Once a patient is diagnosed with IC, multimodal treatment through pharmacological and nonpharmacological approaches is recommended., Conclusion: The involvement of both the patient and physician in determining the therapeutic approach, the use of multimodal therapies, regular follow-up and staff involvement in care can bring relief to a substantial number of patients with this condition.

The objective of the study was to determine whether intravesical pentosanpolysulfate (PPS) reduces symptoms associated with bladder pain syndrome/interstitial cystitis (BPS/IC). In a prospective, uncontrolled, open-label study, 29 female patients with BPS/IC received 300 mg PPS intravesically twice a week for 10 weeks and thereafter a voluntary maintenance therapy once a month. Treatment response was assessed by Visual Analog Scale (VAS) for quality of life and O'Leary-Sant Symptom and Problem Index (OSPI). Patients were tested before treatment, after 5 weeks of treatment, and 1 week, 3, 6, and 12 months after termination of the initial treatment. Twenty-five patients underwent the 10-week treatment and the 3-month follow-up. Mean reduction of VAS/OSPI was from 8.8/26.4 before to 4/15.3 after treatment, 3.8/15.2 after 3 months, 3.8/14 after 6 months, and 3.4/12.1 after 12 months. In 21 patients, renewed instillation or maintenance therapy was necessary. Intravesical treatment with PPS reduces both the VAS and the OSPI in patients with BPS/IC.

Unlabelled: BACKGROUND, PURPOSE AND METHODS: This observational study assessed the effect of continuous intraventricular infusion of pentosan polysulphate (PPS) in seven patients at different clinical centres in the UK., Results: Complications of intraventricular catheterization were frequent. PPS was well-tolerated over a wide dose range (11-110 microg/kg/day) during the 6-month study. Four patients were assessed for the entire study period: one remained stable, two showed minimal deterioration and one progressed significantly., Conclusion: Mean survival of all patients was longer than reported values for natural history of specific prion disorders. Possible reasons for these findings are explored.

Objectives: To measure urinary epidermal growth factor (EGF) and interleukin-6 (IL-6) levels in painful bladder syndrome/interstitial cystitis (PBS/IC) patients randomized to either cyclosporine A (CyA) or pentosan polysulfate sodium (PPS) treatment for 6 months and compare the results with treatment response., Methods: Urine samples from PBS/IC patients were collected before (n = 37) and after treatment (n = 34). The concentration of EGF was determined by an in-house immunofluorometric assay and that of IL-6 by the Immulite assay. The clinical response to treatment was determined by the subjective global response analysis (GRA, scale 1 to 6). Participants who reported categories 5 (much better) or 6 (cured) were considered responders., Results: According to GRA, 72% of CyA patients and 16% of PPS patient responded to their treatment (P <0.001). In the CyA group, post-treatment urinary EGF levels were significantly reduced (from 35 +/- 15.8 to 28.3 +/- 17.9 ng/mg creatinine; P <0.034), whereas the urinary IL-6 levels were not affected by CyA or PPS treatment in the whole group. In older patients (aged more than 52 years) who had higher IL-6 levels and longer duration of disease, these were reduced by successful CyA therapy., Conclusions: Treatment of PBS/IC patients with CyA resulted in significantly decreased urinary levels of EGF. Interleukin-6 levels did not change significantly in all treated patients after either CyA or PPS treatment, but in older patients the levels were reduced after CyA treatment.