Pentosan Polysulfate Research Articles

Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex

The semi-synthetic sulfated polysaccharide PPS (pentosan polysulfate) increases affinity between the aggrecan-degrading ADAMTSs (adamalysins with thrombospondin motifs) and their endogenous inhibitor, TIMP (tissue inhibitor of metalloproteinases)-3. In the present study we demonstrate that PPS mediates the formation of a high-affinity trimolecular complex with ADAMTS-5 and TIMP-3. A TIMP-3 mutant that lacks extracellular-matrix-binding ability was insensitive to this affinity increase, and truncated forms of ADAMTS-5 that lack the Sp (spacer) domain had reduced PPS-binding ability and sensitivity to the affinity increase. PPS molecules composed of 11 or more saccharide units were 100-fold more effective than those of eight saccharide units, indicating the involvement of extended or multiple protein-interaction sites. The formation of a high-affinity trimolecular complex was completely abolished in the presence of 0.4 M NaCl. These results suggest that PPS enhances the affinity between ADAMTS-5 and TIMP-3 by forming electrostatically driven trimolecular complexes under physiological conditions.

Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis.

Introduction of sodium pentosan polysulfate and avoidance of urethral catheterisation: improved outcomes in children with haemorrhagic cystitis post stem cell transplant/chemotherapy

PurposeHaemorrhagic 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. MethodsA 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. ResultsFive 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). ConclusionEarly identification, avoidance of urethral catheterisation, and use of SPP significantly reduces blood transfusion requirements and mortality from HC.

Inhibitory Effects of Pentosan Polysulfate Sodium on MAP-Kinase Pathway and NF-κB Nuclear Translocation in Canine Chondrocytes &lt;i&gt;In Vitro&lt;/i&gt;

Pentosan polysulfate sodium (PPS) has a heparin-like structure and is purificated from the plant of European beech wood. PPS has been used for the treatment of interstitial cystitis for human patients. Recent years, it was newly recognised that PPS reduce pain and inflammation of OA. The molecular biological mechanism of PPS to express its clinical effects is not fully understood. The purpose of the present study is to investigate a mechanism of action of PPS on inflammatory reaction of chondrocytes in vitro. It was evaluated that effects of PPS on interleukin (IL)-1β-induced phosphorylation of mitogen-actiated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), nuclear translocation of nuclear factor-kappa B (NF-κB), and matrix metalloproteinase (MMP)-3 production in cultured articular chondrocytes. As a result, in the presence of PPS existence, IL-1β-induced phosphorylation of p38 and ERK were certainly inhibited, while JNK phosphorylation was not affected. Nuclear translocation of NF-κB and MMP-3 production were suppressed by PPS pretreatment prior to IL-1β stimulation. In conclusion, it is strongly suggested that PPS treatment prevents inflammatory intracellular responses induced by IL-1 β through inhibition of phosphorylation of certain MAPKs, p38 and ERK and then nuclear translocation of NF-κB in cultured chondrocytes. These PPS properties may contribute to suppressive consequence of catabolic MMP-3 synthesis. These data might translate the clinical efficacy as PPS treatment could inhibit the cartilage catabolism and related clinical symptoms of OA in dogs.

In vitro inhibition of influenza A virus infection by marine microalga-derived sulfated polysaccharide p-KG03

The sulfated polysaccharide, p-KG03, purified from the marine microalga, Gyrodinium impudium, is a unique compound comprising homogenous galactose units conjugated to uronic acid and sulfated groups. Although previous studies showed that p-KG03 suppresses tumor cell growth and infection by encephalomyocarditis virus, its effect against enveloped virus infection and the biological mechanism of action have not been elucidated. In this report, the inhibitory activity of p-KG03 against influenza virus was examined and compared with that of other sulfated polysaccharides (fucoidan and pentosan polysulfate) and antiviral agents (oseltamivir phosphate, oseltamivir carboxylate, amantadine, and ribavirin). The results of a cytopathic effect reduction assay using MDCK cells demonstrated that p-KG03 exhibited the 50% effective concentration (EC50) values of 0.19–0.48μg/ml against influenza type A virus infection (selectivity index >200) but not all influenza type B viruses. Mechanism studies showed that inhibition of influenza virus replication was maximized when p-KG03 was added during or within 6h after viral infection, suggesting that mainly the viral adsorption and internalization steps are targeted by this compound. The results of influenza virus binding assay to p-KG03 and fluorescence microscopy indicate that the antiviral activity of p-KG03 is directly associated with its interaction with viral particles. The sulfated polysaccharide p-KG03 is a potent and specific influenza A viral entry inhibitor and may be a candidate for antiviral drug development.

Ketamine-snorting associated cystitis

Ketamine hydrochloride, commonly used as a pediatric anesthetic agent, is an N-methyl-D-aspartic (NMDA) acid receptor antagonist with rapid onset and short duration of action. It produces a cataleptic-like state where the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. It has emerged as an increasingly popular choice among young drug users, especially within dance club venues. Cases of bladder dysfunction among recreational ketamine users were reported since Shahani et al first reported nine cases of ketamine-associated ulcerative cystitis in 2007. We report on four patients who had history of ketamine abuse, presenting with dysuria, fluctuating lower urinary tract symptoms (LUTS), lower abdominal or perineal pain, and impaired functional bladder capacities. Urinalysis showed pyuria and microhematuria. Urine culture was sterile. Bladder ulceration with severe diffuse hemorrhage and low bladder capacity were noted under anesthetized cystoscopic examination. Transurethral bladder mucosa biopsy was consistent with chronic cystitis. Cessation of ketamine abuse was the milestone of treatment, followed by the administration of mucosal protective agents, such as pentosan polysulphate or hyaluronic acid. Suprapubic pain was improved in three patients during follow-up. However, the outcome of treatment depends on the severity of the disease process, similar to that of interstitial cystitis (IC).

Noncovalent PEGylation by Polyanion Complexation as a Means To Stabilize Keratinocyte Growth Factor-2 (KGF-2)

Repifermin, a truncated form of fibroblast growth factor-10 (FGF-10) also known as keratinocyte growth factor-2 (KGF-2), is a heparin-binding protein with potent regenerative properties. The protein unfolds and aggregates at relatively low temperature (~37 °C). Electrostatic interactions between polyanions and several FGFs have been reported to enhance the thermal stability of these proteins. Polyethylene glycol (PEG) was grafted to the polyanions pentosan polysulfate (PPS) and dextran sulfate (DS) as an alternative means to stabilize and noncovalently PEGylate KGF-2. Physical characteristics of KGF-2:polyanion-PEG complexes were examined using a variety of methods including circular dichroism (CD), intrinsic tryptophan fluorescence, differential scanning calorimetry, and dynamic light scattering. When compared to KGF-2 alone, subtle changes in CD spectra and fluorescence emission maxima were found when KGF-2 was formulated with the synthetic PEG-polyanions. Highly PEGylated polyanions (DS-PEG5) did not bind KGF-2 as well as conjugates with fewer PEG chains. The molecular weight of PEG did not have a noticeable effect on KGF-2 binding to the various PEG-polyanion conjugates. At optimal molar ratios, PPS-PEG and DS-PEG conjugates were able to stabilize KGF-2 by increasing the melting temperature by approximately 9-17 °C. Thus, polyanion-PEG conjugates improved the stability of KGF-2 and also offered a new electrostatic PEGylation scheme that may be extrapolated to other heparin-binding proteins.

Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice

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.

Ketamine‐Induced Uropathy: A New Clinical Entity Causing Lower Urinary Tract Symptoms

Ketamine abuse can damage the urinary tract and cause lower urinary tract symptoms (LUTS). This report presents our observations and management on urinary tract damage caused by ketamine abuse. From November 2006 to February 2009, 20 patients visited Taipei Veterans General Hospital due to ketamine-related lower urinary tract symptoms. We analyzed the clinical presentations, daily ketamine dose, interval between ketamine usage to develop LUTS, urodynamic studies, radiological image findings, cystoscopic and ureterorenoscopic findings, histological findings, urinary ketamine levels and treatment responses. Of these 20 patients, all had moderate to severe LUTS, including frequency, urgency, dysuria and hematuria. The mean daily consumption of ketamine was 3.2 ± 2.0 g. The mean interval from consumption to the development of LUTS was 12.7 months (range, 2-36 months). Eight patients underwent video urodynamic studies, with a mean cystometric capacity of 70.8 mL. Eight patients had hydronephrosis and six of them underwent ureterorenoscopy. All patients underwent cystoscopy with hydrodistention. Mean bladder capacity under anesthesia was 289.9 mL, and 14 (70%) patients showed significant symptomatic improvement after hydrodistention. Ten patients quit ketamine and nine (90%) experienced symptomatic relief. The response rates of symptomatic improvement to each treatment were 75% (12/16) for oral pentosan polysulfate sodium with prednisolone, 40% (2/5) intravesical instillation of xylocaine and heparin, and 0% (0/2) for intravesical instillation of hyaluronic acid. Ketamine abuse causes damage to the upper and lower urinary tracts. While ketamine abuse is an illicit drug problem, it is also associated with serious urological damage.

Pharmacotherapy for Osteoarthritis: A Review

Osteoarthritis (OA) is a leading cause of disability in the elderly. The goal of OA treatment is to control symptoms, prevent disease progression, minimize disability, and improve quality of life. The management can be divided into non pharmacologic interventions, pharmacologic interventions, and surgical options. Pharmacologic interventions can be further subdivided into symptomatic therapy and potential structureor disease-modifying therapy. There are, at present, no specific pharmacologic therapies that can prevent the progression of joint damage due to OA. Acetaminophen is the first line of therapy, although most of the patient requires NSAIDs. Risk of gastrointestinal (GI) bleeding and cardiovascular risk need to be considered, especially for elderly. With inflammatory components, intra-articular glucocorticoid injection gives short term benefit. Compared with corticosteroid injections, hyaluronan injections have similar clinical effects. But it is more costly. So far research with potential structure- and disease-modifying drugs in osteoarthritis includes tetracyclines, glycosaminoglycan polysulfuric acid, pentosan polysulfate, diacerein, glucosamine and others. Scientists are looking for new therapeutic targets like IL-1 receptor antagonist (IL-1Ra), mitogen-activated protein (MAP) kinases inhibitors, NF-kappaB inhibitors. Gene therapy, Chondrocyte and stem cell transplants showed some promise in animal models. Keyword: Osteoarthritis, pharmacologic therapy, disease modifying therapy DOI: http://dx.doi.org/10.3329/jom.v12i2.7690 JOM 2011; 12(2): 142-148

Protease‐resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion

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.

A Survey of Antiprion Compounds Reveals the Prevalence of Non-PrP Molecular Targets

Prion diseases are fatal neurodegenerative diseases caused by the accumulation of the misfolded isoform (PrP(Sc)) of the prion protein (PrP(C)). Cell-based screens have identified several compounds that induce a reduction in PrP(Sc) levels in infected cultured cells. However, the molecular targets of most antiprion compounds remain unknown. We undertook a large-scale, unbiased, cell-based screen for antiprion compounds and then investigated whether a representative subset of the active molecules had measurable affinity for PrP, increased the susceptibility of PrP(Sc) to proteolysis, or altered the cellular localization or expression level of PrP(C). None of the antiprion compounds showed in vitro affinity for PrP or had the ability to disaggregate PrP(Sc) in infected brain homogenates. These observations suggest that most antiprion compounds identified in cell-based screens deploy their activity via non-PrP targets in the cell. Our findings indicate that in comparison to PrP conformers themselves, proteins that play auxiliary roles in prion propagation may be more effective targets for future drug discovery efforts.

The risk for cross-reactions after a cutaneous delayed-type hypersensitivity reaction to heparin preparations is independent of their molecular weight: a systematic review

Heparins are a widely used class of drugs known to cause delayed-type hypersensitivity (DTH) reactions. Recent publications indicate that the incidence of these may be higher than previously thought. To date, patient-related but no drug-related risk factors for the development of DTH reactions to heparins have been identified, although molecular weight is discussed as a potentially relevant parameter. To address this, a systematic review was conducted on the frequency of cross-reactions after DTH reactions to heparin preparations. We electronically searched MEDLINE and EMBASE, hand-searched selected journals and references, and contacted experts for unpublished data. Sixty-six publications and unpublished data of 14 patients resulted in 198 patients with 1084 tests for cross-reactivity. The primary causative agents were mostly unfractionated heparin (50%) and low molecular weight heparins (49.5%). Cross-reactions were more likely after an initial DTH reaction to unfractionated heparin than after an initial DTH reaction to low molecular weight heparin. Our findings also indicate that molecular weight does not correlate with the risk for cross-reactivity, which is in line with recent observations, indicating that different heparins have to be individually considered. The available data demonstrated the lowest overall risk for cross-reactions for pentosan polysulfate (36.4%) and fondaparinux (10.4%). In the clinical context, fondaparinux is recommended as the current best alternative when a DTH reaction occurs.

Spectrophotometric determination of various polyanions with polymeric film optodes using microtiter plate reader

Polycation-sensitive membrane optodes based on the chromoionophore 2′,7′-dichlorofluorescein octadecylester (DCFOE) have previously been developed and used for determination of heparin via a titrimetric method. In this study, it is shown that some other important polyanions such as PPS (pentosan polysulfate), DNA, xanthan, Na-alginate, and carrageenan (food additive) can also be readily determined by using DCFOE-based microtiter plate-format optodes (MPOs) and polycationic titrants that bind these polyanionic species. The optical sensors are prepared with poly(vinyl chloride) (PVC), polyurethane (PU), bis(2-ethylhexyl)sebacate (DOS), and 2′,7′-dichlorofluorescein octadecylester (DCFOE) and exhibit reproducible and sensitive absorbance changes in response to the varying polycationic titrant concentrations. Three different polycations; protamine, poly- l-lysine and poly- l-arginine, are employed as titrants. The method has a detection limit of 1 μg mL −1, and a dynamic range of 1–40 μg mL −1. After the quantitative determinations are successfully demonstrated in buffered solutions, similar titrations are also performed in real samples. The method is validated by recovery studies in these samples. The average polyanion recoveries were quantitative [99.7(±1.3) % for pastry cream with vanillin (protamine titrant); 100.4 (±3.3) % for pastry gel with strawberry(PLA titrant), and 102.9(±2.0) % for pastry gel with strawberry (PLL titrant)].

Heparin enhances the cell-protein misfolding cyclic amplification efficiency of variant Creutzfeldt–Jakob disease

Highly sensitive in vitro screening tests are required to prevent the iatrogenic spread of variant Creutzfeldt–Jakob disease (vCJD). Protein misfolding cyclic amplification (PMCA) is a candidate for such a test, but the sensitivity of this method is insufficient. Polyanions were reported to enhance PMCA efficiency, but their effects on vCJD are unclear. We developed a cell-PMCA of vCJD, wherein cell lysate containing exogenously expressed human PrP was used as substrates, to investigate the effects of various sulfated polysaccharides on amplification efficiency. PrP res amounts after cell-PMCA were analyzed by western blotting. Heparin, dermatan sulfate, and dextran sulfate (average molecular weight [MW] 1400 kDa) enhanced efficiency, but dextran sulfate (average MW 8 kDa) and a heparin pentasaccharide analog had no effect. Pentosan polysulfate inhibited cell-PMCA reaction. The amplification efficiency of cell-PMCA of vCJD increased to >100-fold per round with heparin. The enhancing effects of heparin on cell-PMCA were seed dependent: it was high for vCJD, low for sporadic Creutzfeldt–Jakob disease, and low to negligible for hamster-adapted scrapie-derived 263 K. In multi-round PMCA, signals were detected at earlier rounds with heparin than without heparin, and PrP Sc in 10 −10 diluted vCJD brain was detected by the sixth round. Heparin-assisted cell-PMCA of vCJD represents a significant step toward detecting very minute amounts of PrP Sc in the body fluids of asymptomatic vCJD patients.

What is BPS and how should it be managed in real life clinical practice?

What is “bladder pain syndrome (BPS)”? This report published in this month’s CUAJ describes the long-term clinical results of pentosan polysulfate sodium (PPS) for BPS.1 No one had even heard of this diagnostic entity until 2008, when the syndrome was first proposed by the European Society for the Study of Painful Bladder Syndrome/Interstitial Cystitis.2 This same group previously proposed and championed the term “painful bladder syndrome (PBS)” for what we all believed was the same condition. Prior to that time, most of us called this syndrome “interstitial cystitis (IC).”3 Many still do. Based on the years that these authors reported their results, I strongly suspect that they were treating patients that they diagnosed with IC, not PBS or BPS. While the research community struggles with nomenclature, there is no doubt that women with pelvic pain perceived to be bladder related and concomitant urinary storage symptoms are difficult to manage. The literature surrounding the only oral medication approved for this condition (approved for IC not BPS, a term not recognized by any regulatory organization) clearly shows that the benefits of PPS compared to placebo are at best modest in the short term,3 however the longer the duration of exposure, the greater the predicted response rate.4 Some problems and limitations with this study include that it was retrospective, patients who discontinued PPS prior to 3 months were not included, other treatments were not documented and the primary outcome measure was global response assessment which has not be validated for long-term studies and is likely very inaccurate after 3 months. The strengths of this study were that it provides real-life clinical observations on the safety and efficacy of this treatment in Canadian urology outpatients. And what were those observations? The results corroborated that of a large multicentre, long-term, prospective study that clearly showed that response increased with duration of therapy.4 However, is PPS an appropriate long-term monotherapy? Despite the suggestion from this study that it is, many patients did not achieve the desired beneficial response and it is very likely that many of those that did had other forms of specific and nonspecific IC directed therapy. So how do these results affect clinical practice? To start with, PPS is an appropriate intervention, but duration of therapy remains a key point in efficacy considerations. Many of these patients are not a homogenous group, but present with various but identifiable clinical phenotypes that predict different responses to different therapies. We have addressed this issue by describing the UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, and tenderness domains) phenotypic classification system for patients with chronic urologic pain syndromes,5 including IC/PBS/BPS,6 that differentiates patients according to their clinical phenotype, allowing individually directed therapy according to the various phenotype classifications diagnosed. Multimodal therapy is the key to better management of this condition, no matter whether you call it IC, PBS or BPS.

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

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

810 CYCLOSPORINE A FOR REFRACTORY INTERSTITIAL CYSTITIS: EXPERIENCE OF TWO TERTIARY CENTERS

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Interstitial Cystitis1 Apr 2011810 CYCLOSPORINE A FOR REFRACTORY INTERSTITIAL CYSTITIS: EXPERIENCE OF TWO TERTIARY CENTERS John Forrest, Deborah Erickson, and Monica Cardona John ForrestJohn Forrest Tulsa, OK More articles by this author , Deborah EricksonDeborah Erickson Lexington, KY More articles by this author , and Monica CardonaMonica Cardona Tulsa, OK More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.628AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although many treatments are used for bladder pain syndrome/interstitial cystitis (BPS/IC), some patients remain debilitated. Cyclosporine A (CyA) was effective in a single-arm trial and was more effective than pentosan polysulfate in a randomized trial.1,2 Based on these reports, we offer CyA off-label to refractory IC patients. This is a retrospective review of our experience. METHODS Charts were reviewed with the IRB approval. At University of Kentucky (KU) and Urologic Specialists of Oklahoma, Inc, eligible patients had failed oral and/or instillation therapy Risks and off-label nature of the treatment were explained. Initial dose was 2 to 3 mg/kg/day divided into twice daily doses. Afer symptoms improved, dose was decreased gradually as tolerated. Dose also was adjusted based on side effects and serum CyA levels. The first visit was 1 month, then every 3 months, with symptom assessment, physical exam, comprehensive metabolic panel, complete blood count, serum magnesium, uric acid, and CyA levels. RESULTS Nineteen patients were evaluated including 12 women and 7 men with an age range of 44 to 71. Average follow up was 1 year. Fourteen of nineteen patients reported a 70% average global improvement in their symptoms. The remainder were non-responders or discontinued therapy early secondary to side effects including fatigue, muscle cramping, or lab abnormalities. Associated clinical findings include Hunner's ulcers in 13 of 19 patients and collagen vascular disease in 6 of 19 patients. CONCLUSIONS CyA was effective in the majorify of our refractory IC patients. Potential clinical markers to perdict a cyclosporine response include the presence of Hunner's ulcer or associated collagen vascular disease. CyA was generally well tolerated but requires careful monitoring.1,2 Sairanen, J J Urol 2005 and 2005 © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e326 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Forrest Tulsa, OK More articles by this author Deborah Erickson Lexington, KY More articles by this author Monica Cardona Tulsa, OK More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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

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

Modulation of cytokine-induced prostaglandin E2 production in cultures of articular chondrocytes obtained from carpal joints of camels (Camelus dromedarius)

To determine whether camel articular chondrocytes can be maintained in tissue culture without phenotype loss and whether the response to cytokine stimulation can be modulated. Cartilage from 4 carpal joints of healthy adult dromedary camels (Camelus dromedarius). Chondrocytes were evaluated for type II collagen and aggrecan production They were incubated with control media or with 2 test mixtures (alone and then in combination) that have anti-inflammatory activity (avocado-soybean unsaponifiables, glucosamine, and chondroitin sulfate [ie, ASU + GLU + CS] and pentosan polysulfate and N-acetyl glucosamine [ie, PPS + NG]). Cells were then stimulated with interleukin-1β and tumor necrosis factor-α to determine prostaglandin (PG) E₂ production and nuclear factor (NF)-κB activation. Chondrocytes proliferated in media used for propagating equine chondrocytes; they produced type II collagen and aggrecan. Cytokine stimulation induced PGE₂ production and translocation of NF-κB. Incubation with each test mixture significantly inhibited PGE₂ production. The combination of ASU + GLU + CS and PPS + NG significantly potentiated PGE₂ inhibition and disrupted NF-κB translocation, compared with effects for either mixture alone. Chondrocytes proliferated without loss of the cartilage phenotype. Responses to cytokines were significantly inhibited by the mixtures of ASU + GLU + CS and PPS + NG, which indicated that this response can be modulated. This culture technique can be used to study the functional properties of camel chondrocytes and identify agents that may potentially be used to treat and manage joint inflammation.