Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I.

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.

Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

Anti-inflammatory actions of Pentosan polysulfate sodium in a mouse model of influenza virus A/PR8/34-induced pulmonary inflammation.

Introduction: There is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The semi-synthetic polysaccharide, Pentosan polysulfate sodium (PPS), an inhibitor of NF-kB activation, was investigated for its systemic and local anti-inflammatory effects in a mouse model of influenza virus A/PR8/1934 (PR8 strain) mediated infection. Methods: Immunocompetent C57BL/6J mice were infected intranasally with a sublethal dose of PR8 and treated subcutaneously with 3 or 6 mg/kg PPS or vehicle. Disease was monitored and tissues were collected at the acute (8 days post-infection; dpi) or post-acute (21 dpi) phase of disease to assess the effect of PPS on PR8-induced pathology. Results: In the acute phase of PR8 infection, PPS treatment was associated with a reduction in weight loss and improvement in oxygen saturation when compared to vehicle-treated mice. Associated with these clinical improvements, PPS treatment showed a significant retention in the numbers of protective SiglecF+ resident alveolar macrophages, despite uneventful changes in pulmonary leukocyte infiltrates assessed by flow cytometry. PPS treatment in PR8- infected mice showed significant reductions systemically but not locally of the inflammatory molecules, IL-6, IFN-g, TNF-a, IL-12p70 and CCL2. In the post-acute phase of infection, PPS demonstrated a reduction in the pulmonary fibrotic biomarkers, sICAM-1 and complement factor C5b9. Discussion: The systemic and local anti-inflammatory actions of PPS may regulate acute and post-acute pulmonary inflammation and tissue remodeling mediated by PR8 infection, which warrants further investigation.

A post-trial follow-up study of pentosan polysulfate monotherapy on preventing recurrent urinary tract infection in women.

For women with recurrent urinary tract infection (UTI), previous U101 study has shown that pentosan polysulfate sodium (PPS) monotherapy for 16 weeks significantly reduced UTI episodes in the treatment group throughout the trial period. In this follow-up study, we aimed to assess whether the effects of PPS would last after completion of the trial to prevent recurrent UTIs. Conducted from 2018 to 2019, the U101 study was a multicenter, prospective, phase 2a, randomized trial, enrolling women with recurrent UTI to study the effects of a 16-week oral PPS monotherapy. After approximately two years, the follow-up was conducted by phone interview, obtaining data including self-reported UTI events, quality of life questionnaire, and adverse events. The primary endpoint of follow-up study was UTI recurrence-free survival and the secondary endpoints were quality of life and adverse events. Approximately two years after completion of the trial, the rate of recurrent UTI was 25% (3 of the 12 patients) in the PPS group and 85.7% (12 of the 14 patients) in the control group. Over the entire follow-up period, the UTI recurrence-free survival was significantly better in the PPS group than in the control group (log-rank test p < 0.001). The quality of life at two years was significantly improved in the PPS when compared to the control group (91.7 vs. 77.5, p < 0.001). No late adverse event was observed after cessation of the treatment. In this study, sixteen weeks of PPS monotherapy in women with recurrent UTI significantly reduced the numbers of recurrent UTI episodes during the 2-year follow-up.

Systematic review of pharmacological management in Creutzfeldt-Jakob disease: no options so far?

BACKGROUND: The Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that manifests as a rapidly progressive dementia syndrome. Currently, CJD has no cure, and many patients die within the first year, but some drugs are being studied as options for managing this condition. OBJECTIVE: To evaluate the effectiveness of pharmacological treatments offered to patients with CJD as a means to increase survival and reduce cognitive deterioration. METHODS: A systematic review of the literature was performed using 4 independent reviewers and 1 extra reviewer to resolve possible divergences in the search and analysis of papers indexed in MedLINE (PubMed), SciELO and Lilacs databases. The Medical Subject Heading (MeSH) terms used were: prion diseases, Creutzfeldt-Jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine, and pentosan polysulfate, with the Boolean operators AND and OR. This search included controlled clinical trials, uncontrolled clinical trials, and case series published from the year 2000 onwards, in the English language. RESULTS: A total of 85 papers were found using the descriptors used. At the end of the selection analyses, 9 articles remained, which were analyzed fully and individually. CONCLUSIONS: None of the drugs evaluated proved significantly effective in increasing survival in patients with CJD. Flupirtine appears to have a beneficial effect in reducing cognitive deterioration in patients with CJD. However, additional studies are needed to establish better evidence and therapeutic options for the management of patients with CJD.

ANTECEDENTES: A doença de Creutzfeldt-Jakob (DCJ) é uma encefalopatia espongiforme que se manifesta como síndrome demencial rapidamente progressiva. Atualmente, a DCJ não possui cura e muitos pacientes morrem no primeiro ano de doença, mas alguns medicamentos vêm sendo estudados como opções no manejo desta condição. OBJETIVO: Avaliar a eficácia dos tratamentos farmacológicos oferecidos aos pacientes com DCJ no aumento de sobrevida e na redução da deterioração cognitiva. MéTODOS: Foi realizada uma revisão sistemática da literatura utilizando 4 revisores independentes e 1 extra para resolver divergências eventuais na busca e na análise de trabalhos indexados nas bases de dados MedLINE (via PubMed), SciELO e Lilacs. Os termos Medical Subjects Heading (MeSH) utilizados foram: prion diseases, creutzfeldt jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine e pentosan polysulfate, com os operadores booleanos AND e OR. Essa pesquisa incluiu ensaios clínicos controlados, não controlados e séries de casos, publicados a partir do ano 2000 no idioma inglês. RESULTADOS: Ao todo, foram encontrados 85 trabalhos através dos descritores utilizados. Ao final das análises de seleção, restaram 9 artigos, que foram analisados na íntegra individualmente. CONCLUSõES: Nenhuma das drogas avaliadas se mostrou significativamente eficaz no aumento da sobrevida dos pacientes com DCJ. A flupirtina parece ter um efeito benéfico na redução da deterioração cognitiva dos pacientes com DCJ. Entretanto, estudos adicionais são necessários para o estabelecimento de melhores evidências e opções terapêuticas para o manejo dos pacientes com DCJ.

Role of oral pentosan polysulfate in Bacillus Calmette-Guérin therapy in patients with non-muscle-invasive bladder cancer.

PURPOSE: Intravesical Bacillus Calmette-Guérin (BCG) instillation, although an important treatment for non-muscle-invasive bladder cancer, exerts local and systemic adverse effects. Pentosan polysulfate (PPS) is a bladder mucosal protective drug that acts by replacing mucus in the glycosaminoglycan layer of the damaged urothelium. We hypothesized that co-administration of oral PPS with BCG instillation would relieve BCG-related adverse effects without affecting its efficacy. MATERIALS AND METHODS: A total of 217 patients receiving BCG instillation were enrolled. They were placed in two groups and analyzed retrospectively: group A (n=122) received BCG instillation only and group B (n=95) received 100 mg of PPS thrice daily during the BCG treatment. RESULTS: After BCG instillation, the rate of BCG-treatment discontinuation owing to adverse effects was 15.6% in group A and 6.3% in group B (p=0.034). The proportion of patients with bacteriuria after BCG was higher in group B; however, no statistical difference was observed (28.7% vs. 41.1%; p=0.057). The proportion of patients with pyuria was significantly higher in group B (81.1% vs. 91.6%; p=0.029). The proportion of patients using antibiotics was significantly higher in group A (73.8% vs. 43.2%; p=0.001). The recurrence rate within 1 year was 29 (23.8%) in group A vs. 19 (20.0%) in group B (p=0.507). Univariate and multivariate analyses showed that antibiotic use had a statistically significant effect on BCG discontinuation. CONCLUSIONS: Oral PPS effectively decreased the discontinuation rate and antibiotic use without affecting the BCG efficacy.

[Protective properties of urothelium and possibilities of targeted pathogenetic therapy of chronic pelvic pain: sodium pentosan polysulfate].

The review article is devoted to the possibilities of using targeted therapy for urothelial diseases, namely painful bladder syndrome (BPS). The protective structural components of the bladder mucosa, as well as their chemical features, are described in detail. Pentosanpolysulfate (PPS), being an oral heparinoid, can be used as part of pathogenetic therapy to restore the mucous membrane of the bladder. The efficacy and safety of this drug has been proven by us in a multicenter, randomized, double-blind, placebo-controlled trial. An additional assessment of the effectiveness and safety of the use of PPS in BPS was confirmed as part of our systematic review and meta-analysis. Thus, PPS is a pathogenetically sound tool in the treatment of patients with painful bladder syndrome.

Pentosan polysulfate for the treatment of hemorrhagic cystitis after allogeneic hematopoietic cell transplant.

INTRODUCTION: Hemorrhagic cystitis can commonly occur following an allogeneic hematopoietic cell transplant and treatment options are currently limited. Pentosan polysulfate, a heparin-like, sulfated polysaccharide, is used to relieve bladder pain and discomfort associated with interstitial cystitis. Initial reports in patients with hemorrhagic cystitis demonstrate that pentosan polysulfate may hasten hemorrhagic cystitis resolution and control symptoms. METHODS AND RESULTS: This report includes a retrospective case series of six patients who received pentosan polysulfate for the treatment of hemorrhagic cystitis following an allogeneic hematopoietic cell transplant. Pentosan polysulfate was initiated at a median of 4.5 days (range: 3-18) following hemorrhagic cystitis onset and continued for a median duration of 17.5 days (range: 7-64). Four patients were tested for BK virus and all were found to have BK viremia and viruria around the time of pentosan polysulfate initiation. The median number of red blood cell transfusions seemed to decrease in the patients initiated on pentosan polysulfate. All patients received a multi-agent treatment regimen, which included pentosan polysulfate, and half the patients had symptom resolution. The median time to symptom resolution from pentosan polysulfate initiation was 9 days (range: 7-10). CONCLUSION: Pentosan polysulfate was well-tolerated and seemed to assist with symptom resolution. Future studies are needed to confirm the impact of pentosan polysulfate on the treatment of hemorrhagic cystitis.

Pentosan polysulfate induces low-level persistent prion infection keeping measurable seeding activity without PrP-res detection in Fukuoka-1 infected cell cultures.

Each prion strain has its own characteristics and the efficacy of anti-prion drugs varies. Screening of prion disease therapeutics is typically evaluated by measuring amounts of protease-resistant prion protein (PrP-res). However, it remains unclear whether such measurements correlate with seeding activity, which is evaluated by real-time quaking-induced conversion (RT-QuIC). In this study, the effects of anti-prion compounds pentosan polysulfate (PPS), Congo red, and alprenolol were measured in N2a58 cells infected with Fukuoka-1 (FK1) or 22L strain. The compounds abolished PrP-res and seeding activity, except for N2a58/FK1 treated with PPS. Interestingly, the seeding activity of N2a58/FK1, which was reduced in the presence of PPS, was not lost and remained at low levels. However, upon removal of PPS, both were gradually restored to their original levels. These results indicate that low-level persistent prion infection keeping measurable seeding activity is induced by PPS in a strain-dependent manner. Furthermore, for protein misfolding cyclic amplification (PMCA), the anti-prion effect of PPS decreased in FK1 compared to 22L, suggesting that the differences occur at the level of the direct conversion. Our findings demonstrate that the advantages of RT-QuIC and PMCA can be exploited for more accurate assessment of therapeutic drug screening, reflecting strain differences.

Pentosan polysulfate exerts anti-inflammatory effect and halts albuminuria progression in diabetic nephropathy: Role of combined losartan.

Pentosan polysulfate sodium (PPS) is a polysulfated glycosaminoglycan approved for the treatment of interstitial cystitis. It also showed renoprotective effects in chronic kidney injury models, for example, 5/6 nephrectomy and diabetic nephropathy (DN). In the present study, we addressed to evaluate the therapeutic value of PPS in DN of rats in combination with losartan (LSR). Sixty male Sprague-Dawley rats were randomly divided into six groups: control group, untreated diabetic groups (8 and 16 weeks after diabetes induction by streptozotocin "STZ", 60 mg/kg, intraperitoneal [I.P.]), LSR-treated diabetic group (10 mg/kg/day, P.O.), PPS-treated diabetic group (25 mg/kg/day, P.O.), and combination-treated diabetic group. Drug treatment was started 8 weeks after induction of diabetes and continued for a further 8 weeks. Renal functions, albuminuria, renal IL-6, oxidative stress, and renal histopathology were evaluated. STZ-treated diabetic rats developed progressive albuminuria, renal dysfunction, and significant glomerular change 16 weeks after induction of diabetes. Administration of PPS, alone or in combination with LSR, showed some beneficial effects on DN evolution and significantly decreased renal inflammation as detected by IL-6 level. The best beneficial effect on DN evolution was obtained by PPS sole therapy based on albuminuria evaluation and renal histopathology. However, the combination of PPS and LSR did not show additive benefits. This study reported that the renoprotection of PPS in the setting of DN is evident by exerting anti-inflammatory and antioxidant effects, but this effect could be masked when combined with an angiotensin receptor blocker.

Pharmacologic Management of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as persistent or chronic discomfort perceived to be related to the urinary bladder accompanied by urinary urgency or frequency. Pharmacotherapies used to treat IC/BPS include oral and intravesical agents. Oral therapies include amitriptyline, hydroxyzine, cyclosporine A, and pentosan polysulfate sodium (PPS), although the recent finding of pigmented maculopathy with chronic PPS is very concerning and must be discussed with patients, many of whom will choose to either come off this medicine or not even start it. Certolizumab pegol is a pharmacologic therapy that is currently in clinical development for treatment of IC/BPS symptoms.

Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?

OBJECTIVE: To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. METHODS: We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. RESULTS: There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. CONCLUSIONS: Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.

Pentosan Polysulfate Sodium augments the therapeutic effect of 5-Aminosalicylic Acid in DSS colitis model; the role of IL-35 expression.

Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for chronic intestinal inflammation. This study aimed to explore the efficacy and the hematological effects of pentosan polysulfate sodium (PPS) in a dextran sulfate sodium (DSS)-induced colitis model. Forty C57BL/6 female mice were equally divided into five groups: control group, DSS-colitis group, DSS-colitis treated with 5-aminosalicylic acid, DSS-colitis treated with PPS, and DSS-colitis treated with both drugs. Disease activity index (DAI) and colon length were calculated. Colonic IL-6 and IL-35 levels were assayed by ELISA. IL-35 gene expression was evaluated by qRT-PCR. Colon tissue samples were examined by H&E stain and immunohistochemistry (IHC) of Ki67. The colitis group subjected to combined treatment showed the best outcome with significant improvement of DAI and increased colon length. Colonic IL-6 was significantly lower in both PPS- and combination-treated groups accompanied by a significantly higher IL-35 level and its EBI3 subunit mRNA expression. However, the PPS-treated colitis group showed higher gene expression of IL-35 EBI3 subunit by 1.5-fold compared with the combined group. The colon mucosa and crypts were significantly preserved in mice treated with both drugs with the best Ki67 positive cell density. PPS is a safe and promising drug in the treatment of UC as it exerted the best positive effect on the anti-inflammatory IL-35 level and gene expression. However, superior improvement of DAI was seen when PPS was added to ASA with a greater mucosal proliferation and repair.

PENTOSAN POLYSULFATE AND VISION: Findings from an International Survey of Exposed Individuals.

PURPOSE: To investigate patient-reported visual function among individuals taking pentosan polysulfate (PPS) for interstitial cystitis. METHODS: A 27-item online survey was distributed to an international mailing list of individuals with interstitial cystitis in November 2018. Demographic characteristics, PPS exposure history, subjective visual function, and previous macular diagnoses were queried. The impact of PPS use, grouped by tertile of cumulative exposure, on visual function and macular diagnoses was assessed with multivariate logistic regression. RESULTS: The survey was completed by 912 respondents. Eight hundred and sixty-one (96.4%) were women, and the median age was 55 [interquartile range (IQR), 45-64 years]. Among PPS users, the median exposure was 547.5 g (IQR, 219-1,314 g). Respondents in the highest PPS exposure tertile were more likely to report difficulty with reading small print [adjusted odds ratio 2.29, 95% confidence interval (CI) 1.15-4.57] and to have a diagnosis of macular degeneration and/or pigmentary maculopathy (adjusted odds ratio 2.41, 95% CI 1.44-4.03) than unexposed respondents. CONCLUSION: In this large sample of individuals with interstitial cystitis, those in the highest PPS exposure category were more likely to have difficulties reading small print and to report a previous diagnosis of macular disease. Further study of objective measures of visual function in PPS users is warranted.

Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis.

BACKGROUND: Bladder pain syndrome (BPS), which includes the condition of interstitial cystitis, is a poorly understood clinical condition for which patients present with varying symptoms. Management of BPS is challenging for both patients and practitioners. At present, there is no universally accepted diagnosis and diverse causes have been proposed. This is reflected in wide-ranging treatment options, used alone or in combination, with limited evidence. A network meta-analysis (NMA) simultaneously comparing multiple treatments may help to determine the best treatment options for patients with BPS. OBJECTIVES: To conduct a network meta-analysis to assess the effects of interventions for treating people with symptoms of bladder pain syndrome (BPS). SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and handsearched journals and conference proceedings (searched 11 May 2018) and the reference lists of relevant articles. We conducted a further search on 5 June 2019, which yielded four small studies that were screened for eligibility but were not incorporated into the review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of interventions for treating adults with BPS. All types of interventions (including conservative, pharmacological and surgical) were eligible. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies using Cochrane's 'Risk of bias' tool. Primary outcomes were the number of people cured or improved, pain, frequency and nocturia. For each outcome, random-effects NMA models were fitted using WinBUGS 1.4. We monitored median odds ratios (ORs) for binary outcomes and mean differences (MDs) for continuous outcomes with 95% credible intervals (Crls). We compared results of the NMA with direct evidence from pairwise meta-analysis of head-to-head trials. We used the CINeMA tool to assess the certainty of evidence for selected treatment categories. MAIN RESULTS: We included 81 RCTs involving 4674 people with a median of 38 participants (range 10 to 369) per RCT. Most trials compared treatment against control; few trials compared two active treatments. There were 65 different active treatments, and some comparisons were informed by direct evidence from only one trial. To simplify, treatments were grouped into 31 treatment categories by mode of action. Most studies were judged to have unclear or high risk of bias for most domains, particularly for selection and detection bias. Overall, the NMA suggested that six (proportion cured/improved), one (pain), one (frequency) and zero (nocturia) treatment categories were effective compared with control, but there was great uncertainty around estimates of effect. Due to the large number of intervention comparisons in this review, we focus on three interventions: antidepressants, pentosan polysulfate (PPS) and neuromuscular blockade. We selected these interventions on the basis that they are given 'strong recommendations' in the EAU Guidelines for management of BPS (EAU Guidelines 2019). We found very low-certainty evidence suggesting that antidepressants were associated with greater likelihood of cure or improvement compared with control (OR 5.91, 95% CrI 1.12 to 37.56), but it was uncertain whether they reduced pain (MD -1.27, 95% CrI -3.25 to 0.71; low-certainty evidence), daytime frequency (MD -2.41, 95% CrI -6.85 to 2.05; very low-certainty evidence) or nocturia (MD 0.01, 95% CrI -2.53 to 2.50; very low-certainty evidence). There was no evidence that PPS had improved cure/improvement rates (OR 0.14, 95% CrI 0.40 to 3.35; very low-certainty evidence) or reduced pain (MD 0.42, 95% CrI -1.04 to 1.91; low-certainty evidence), frequency (MD -0.37, 95% CrI -5.00 to 3.44; very low-certainty evidence) or nocturia (MD -1.20, 95% CrI -3.62 to 1.28; very low-certainty evidence). There was evidence that neuromuscular blockade resulted in greater cure or improvement (OR 5.80, 95% CrI 2.08 to 18.30) but no evidence that it improved pain (MD -0.33, 95% CrI -1.71 to 1.03), frequency (MD -0.91, 95% CrI -3.24, 1.29) or nocturia (MD -0.04, 95% CrI -1.35 to 1.27). The certainty of this evidence was always very low. AUTHORS' CONCLUSIONS: We are uncertain whether some treatments may be effective in treating patients with BPS because the certainty of evidence was generally low or very low. Data were available for a relatively large number of trials, but most had small sample sizes and effects of treatments often could not be estimated with precision. An NMA was successfully conducted, but limited numbers of small trials for each treatment category hampered our ability to fully exploit the advantages of this analysis. Larger, more focused trials are needed to improve the current evidence base.

Efficacy of combination therapy with pentosan polysulfate sodium and adipose tissue-derived stem cells for the management of interstitial cystitis in a rat model.

We evaluated the synergistic effects of pentosan polysulfate sodium (PPS) and mesenchymal stem cells (MSCs) in an interstitial cystitis (IC) rat model. After generation of the IC rat model, the rats were divided into 4 groups according to the treatment they received: phosphate-buffered saline injection into bladder submucosa, daily oral PPS feeding, MSC injection into bladder submucosa, or MSC injection into bladder submucosa with daily oral PPS feeding. After treatment, conscious cystometry and pain scale measurement were performed and their bladders were obtained for histological and proinflammatory-related gene expression analysis. On cystometric analysis, all treatment groups showed significantly increased intercontraction intervals and lower pain scores compared to those of the control group. Histological analysis revealed regenerated urothelium, less fibrosis, and decreased mast cell infiltration in all treatment groups compared to the control group. Significantly lower expression of TNF-α, IFN-γ, MCP, IL-6, TLR2, and TLR11 was observed in the PPS with MSC group compared to the other groups. Combination therapy with PPS and MSCs showed histological and functional effects in an IC rat model, including synergistic effects leading to increased intercontraction interval and decreased inflammatory reactions.

Retinal Toxicity in a Patient on Pentosan Polysulfate Sodium.

Pentosan Polysulfate Sodium (PPS) is commonly used in the treatment of interstitial cystitis/bladder pain syndrome. Recently there have been reported cases of retinal toxicity associated with long-term PPS use. We present a case of a 42-year-old female taking PPS for the last 10 years who was found to have signs of retinal toxicity, but was completely asymptomatic. PPS was discontinued after these retinal findings were discovered.