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Peter Ghosh - One of the best experts on this subject based on the ideXlab platform.
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mesenchymal progenitor cells primed with Pentosan Polysulfate promote lumbar intervertebral disc regeneration in an ovine model of microdiscectomy
The Spine Journal, 2017Co-Authors: Peter Ghosh, David Oehme, Graham Jenkin, Andrew C W Zannettino, Chris D Daly, Tanya Badal, Ronald Shimmon, Kanika JainAbstract:Abstract Background Context Neural compression associated with lumbar disc herniation is usually managed surgically by microdiscectomy. However, 10%–20% of patients re-present with debilitating back pain, and approximately 15% require further surgery. Purpose Using an ovine model of microdiscectomy, the present study investigated the relative potential of Pentosan Polysulfate-primed mesenchymal progenitor cells (pMPCs) or MPC alone implanted into the lesion site to facilitate disc recovery. Study Design An ovine model of lumbar microdiscectomy was used to compare the relative outcomes of administering MPCs or pMPCs to the injury site postsurgery. Methods At baseline 3T magnetic resonance imaging (MRI) of 18 adult ewes was undertaken followed by annular microdiscectomy at two lumbar disc levels. Sheep were randomized into three groups (n=6). The injured controls received no further treatment. Defects of the treated groups were implanted with a collagen sponge and MPC (5×105 cells) or pMPC (5×105 cells). After 6 months, 3T MRI and standard radiography were performed. Spinal columns were dissected, individual lumbar discs were sectioned horizontally, and nucleus pulposus (NP) and annulus fibrosus (AF) regions were assessed morphologically and histologically. The NP and AF tissues were dissected into six regions and analyzed biochemically for their proteoglycans (PGs), collagen, and DNA content. Results Both the MPC- and pMPC-injected groups exhibited less reduction in disc height (p Conclusions In an ovine model 6 months after administration of pMPCs to the injury site disc PG content and matrix organization were improved relative to controls, suggesting pMPCs' potential as a postsurgical adjunct for limiting progression of disc degeneration after microdiscectomy.
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mesenchymal progenitor cells combined with Pentosan Polysulfate mediating disc regeneration at the time of microdiscectomy a preliminary study in an ovine model
Journal of Neurosurgery, 2014Co-Authors: David Oehme, Peter Ghosh, Susan Shimmon, Courtney Mcdonald, John Troupis, Tony Goldschlager, Jeffrey V Rosenfeld, Graham JenkinAbstract:Object Following microdiscectomy, discs generally fail to undergo spontaneous regeneration and patients may experience chronic low-back pain and recurrent disc prolapse. In published studies, formulations of mesenchymal progenitor cells combined with Pentosan Polysulfate (MPCs+PPS) have been shown to regenerate disc tissue in animal models, suggesting that this approach may provide a useful adjunct to microdiscectomy. The goal of this preclinical laboratory study was to determine if the transplantation of MPCs+PPS, embedded in a gelatin/fibrin scaffold (SCAF), and transplanted into a defect created by microdiscectomy, could promote disc regeneration. Methods A standardized microdiscectomy procedure was performed in 18 ovine lumbar discs. The subsequent disc defects were randomized to receive either no treatment (NIL), SCAF only, or the MPC+PPS formulation added to SCAF (MPCs+PPS+SCAF). Necropsies were undertaken 6 months postoperatively and the spines analyzed radiologically (radiography and MRI), biochem...
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Pentosan Polysulfate increases affinity between adamts 5 and timp 3 through formation of an electrostatically driven trimolecular complex
Biochemical Journal, 2012Co-Authors: Linda Troeberg, Peter Ghosh, Barbara Mulloy, Menghuee Lee, Gillian Murphy, Hideaki NagaseAbstract: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.
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cervical motion preservation using mesenchymal progenitor cells and Pentosan Polysulfate a novel chondrogenic agent preliminary study in an ovine model
Neurosurgical Focus, 2010Co-Authors: Tony Goldschlager, Peter Ghosh, Jeffrey V Rosenfeld, Andrew C W Zannettino, Stan Gronthos, Silviu Itescu, Graham JenkinAbstract: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. (DOI: 10.3171/2010.3.FOCUS1050) key w ords • anterior cervical discectomy • Pentosan Polysulfate • mesenchymal stem cell • tissue engineering • sheep • Gelfoam
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calcium Pentosan Polysulfate is a multifaceted exosite inhibitor of aggrecanases
The FASEB Journal, 2008Co-Authors: Linda Troeberg, Peter Ghosh, Kazunari Fushimi, Rama Khokha, Herve Emonard, Hideaki NagaseAbstract:Degradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show that calcium Pentosan Polysulfate (CaPPS), a chemically sulfated xylanopyranose from beechwood, is a multifaceted exosite inhibitor of the aggrecanases and protects cartilage against aggrecan degradation. CaPPS interacts with the noncatalytic spacer domain of ADAMTS-4 and the cysteine-rich domain of ADAMTS-5, blocking activity against their natural substrate aggrecan with inhibitory concentration 50 values of 10-40 nM but only weakly inhibiting hydrolysis of a nonglycosylated recombinant protein substrate. In addition, CaPPS increased cartilage levels of tissue inhibitor of metalloproteinases-3 (TIMP-3), an endogenous inhibitor of ADAMTS-4 and -5. This was due to the ability of CaPPS to block endocytosis of TIMP-3 mediated by low-density lipoprotein receptor-related protein. CaPPS also increased the affinity of TIMP-3 for ADAMTS-4 and -5 by more than 100-fold, improving the efficacy of TIMP-3 as an aggrecanase inhibitor. Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis.
Calogera M. Simonaro - One of the best experts on this subject based on the ideXlab platform.
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safety study of sodium Pentosan Polysulfate for adult patients with mucopolysaccharidosis type ii
Diagnostics (Basel Switzerland), 2019Co-Authors: Kenji E Orii, Calogera M. Simonaro, Edward H. Schuchman, Shunji Tomatsu, Alaena Lim, Molly Stapleton, Yasuyuki Suzuki, Toshiyuki Fukao, Tadashi MatsumotoAbstract:Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan Polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers.
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Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice.
JIMD reports, 2018Co-Authors: Victor Deangelis, Edward H. Schuchman, Calogera M. SimonaroAbstract:Overall Goal: This study was designed to evaluate the impact of Pentosan Polysulfate (PPS) treatment on mice with mucopolysaccharidosis (MPS) type IIIA (Sanfilippo A syndrome; OMIM 252900).
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Dose Responsive Effects of Subcutaneous Pentosan Polysulfate Injection in Mucopolysaccharidosis Type VI Rats and Comparison to Oral Treatment
2016Co-Authors: Michael Frohbergh, Edward H. Schuchman, Alon Lai, Fanli Meng, Nesrin Karabul, Er Solyom, James Iatridis, Calogera M. SimonaroAbstract: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 (sc) 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 sc 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 sc 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 sc 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, sc. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of sc PPS administration. Conclusions: Once weekly sc administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily ora
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Pentosan Polysulfate oral versus subcutaneous injection in mucopolysaccharidosis type i dogs
PLOS ONE, 2016Co-Authors: Calogera M. Simonaro, Shunji Tomatsu, Tracey Sikora, Francyne Kubaski, Michael Frohbergh, Johana Guevara, Raymond Y Wang, Moin VeraAbstract: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.
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dose responsive effects of subcutaneous Pentosan Polysulfate injection in mucopolysaccharidosis type vi rats and comparison to oral treatment
PLOS ONE, 2014Co-Authors: Michael Frohbergh, Edward H. Schuchman, Alon Lai, James C Iatridis, Fanli Meng, Nesrin Karabul, Alexander Solyom, Calogera M. SimonaroAbstract: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.
Nieraj Jain - One of the best experts on this subject based on the ideXlab platform.
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expanded clinical spectrum of Pentosan Polysulfate maculopathy a macula society collaborative study
Ophthalmology Retina, 2021Co-Authors: Nieraj Jain, Albert Liao, Sunir J Garg, Samir N Patel, Charles C Wykoff, Nikolas J S London, Rahul N Khurana, David N Zacks, Audina M Berrocal, Brandon J LujanAbstract:Purpose Explore the spectrum of clinical manifestations of Pentosan Polysulfate (PPS) maculopathy observed across a range of practice settings. Design Multi-institutional retrospective study. Subjects, Participants, and/or Controls Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019 through December 4, 2020. Methods Members of The Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics. Main Outcome Measures Pentosan Polysulfate exposure characteristics and fundus imaging features. Results There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2 to 18.9), with a median cumulative exposure of 1.5 kg (0.9 – 2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients, and a prominent vitelliform maculopathy in 2 patients. Conclusions Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.
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Pentosan Polysulfate and vision findings from an international survey of exposed individuals
Retina-the Journal of Retinal and Vitreous Diseases, 2021Co-Authors: Ogul E Uner, Megha K Shah, Nieraj JainAbstract: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.
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Pentosan Polysulfate maculopathy
Survey of Ophthalmology, 2021Co-Authors: Aaron Lindekemyers, Adam M Hanif, Nieraj JainAbstract:Pentosan Polysulfate sodium (PPS), a semisynthetic sulfated polysaccharide, is the only FDA-approved oral therapy for interstitial cystitis. Recent studies have described a progressive, vision-threatening macular condition associated with long-term PPS use. We reviewed all publications concerning PPS maculopathy to consolidate known clinical features and to evaluate the strength of this association. Current literature supports a strong dose-dependent association between PPS exposure and a progressive maculopathy impacting the retinal pigment epithelium (RPE) and RPE-photoreceptor interface that may worsen even after drug cessation. Initial symptoms may include prolonged dark adaptation and difficulty reading with relative visual acuity preservation. Fundus examination often shows macular pigment clumps corresponding to lesions of focal RPE thickening. Fundus autofluorescence most clearly depicts the condition, with a distinctive pattern of hypo- and hyperautofluorescent spots in the posterior pole that sometimes extends to the retinal periphery. Many cases also show a characteristic peripapillary hypoautofluorescent halo. Near infrared reflectance may aid in early detection. RPE atrophy, cystoid macular edema, and macular neovascularization may also occur, potentially resulting in loss of central acuity. This newly described association implies significant public health risk. Ophthalmologists should screen PPS users with multimodal retinal imaging, and prescribers should minimize dose and duration of PPS use.
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Pentosan Polysulfate maculopathy versus age related macular degeneration comparative assessment with multimodal imaging
Canadian Journal of Ophthalmology-journal Canadien D Ophtalmologie, 2021Co-Authors: Joseph S Christiansen, Alexander C Barnes, Duncan E Berry, Nieraj JainAbstract:OBJECTIVE To evaluate whether Pentosan Polysulfate maculopathy manifests distinctive imaging features that can be differentiated from those found in age-related macular degeneration (AMD). METHODS Local databases were queried to identify patients with a diagnosis of interstitial cystitis who were seen at the Emory Eye Center between May 2014 and January 2019 and who had fundus imaging available for review. Ninety patients met the eligibility criteria. Masked graders categorized patients based on imaging characteristics as follows: category 1: Pentosan Polysulfate maculopathy; category 2: AMD or drusen; category 3: neither; and category 4: unsure. Pentosan Polysulfate exposure characteristics were compared among groups. RESULTS Of the 90 subjects evaluated, 79 (88%) were female and the median age was 61.5 years (range, 30-89). Seventeen patients were placed in category 1; 25 in category 2; 47 in category 3, and; 1 in category 4. Among categories 1 to 4, respectively, 17 (100%), 15 (60%), 28 (60%), and 0 patients had exposure to Pentosan Polysulfate (p = 0.007). Mean cumulative exposure to Pentosan Polysulfate across the four categories was 2.1, 0.36, 0.34, and 0 kg, respectively (p < 0.00001). Eyes with Pentosan Polysulfate maculopathy did not have typical drusen in the macula. CONCLUSION Although Pentosan Polysulfate maculopathy resembles some aspects of AMD, the 2 conditions can be differentiated with the use of multimodal fundus imaging.
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potential new onset clinically detectable Pentosan Polysulfate maculopathy years after drug cessation
Retinal Cases & Brief Reports, 2020Co-Authors: Joshua M Barnett, Nieraj JainAbstract:Purpose To describe a potential case of Pentosan Polysulfate maculopathy that appeared to manifest nearly three years after drug cessation. Methods Complete ophthalmic examination including multimodal fundus imaging, electroretinography, automated perimetry, and molecular testing were performed. Results A 44-year-old female with a 435g cumulative exposure to Pentosan Polysulfate sodium presented 38-months after drug cessation with six months of worsening metamorphopsia and prolonged dark adaptation. Fundus exam and multimodal fundus imaging demonstrated characteristic features of Pentosan Polysulfate maculopathy, and molecular testing was unremarkable. In contrast, color fundus photos of the same patient acquired at an outside facility 25 months prior did not display features consistent with PPS maculopathy. Conclusion This case suggests that new onset clinically detectable Pentosan Polysulfate maculopathy may develop years after drug cessation. If corroborated, this finding has important ramifications for PPS dosing and surveillance guidelines.
Curtis J Nickel - One of the best experts on this subject based on the ideXlab platform.
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Pentosan Polysulfate sodium for treatment of interstitial cystitis bladder pain syndrome insights from a randomized double blind placebo controlled study
The Journal of Urology, 2015Co-Authors: Curtis J Nickel, Sender Herschorn, Kristene Whitmore, John B Forrest, Andrew Friedman, Alan BasemanAbstract: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 ...
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time to initiation of Pentosan Polysulfate sodium treatment after interstitial cystitis diagnosis effect on symptom improvement
Urology, 2008Co-Authors: Curtis J Nickel, David M Kaufman, Huabin F Zhang, George J Wan, Peter K SandAbstract:Objectives Interstitial cystitis (IC) is a chronic, debilitating condition that is often associated with late diagnosis and a delay in initiation of appropriate IC-specific therapy. The purpose of this study was to determine whether the length of time from initial diagnosis to start of treatment impacts subsequent symptom improvement. Methods A retrospective analysis was conducted in 128 patients with IC who had been treated with Pentosan Polysulfate sodium (PPS) 300 mg/day for 32 weeks in a multicenter, randomized, double-blind, parallel-group clinical trial. Outcome measures included the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and the O’Leary-Sant Interstitial Cystitis Problem Index (ICPI). Early treatment was defined as treatment initiation 6 months or less after IC diagnosis, whereas late treatment was defined as treatment initiation 24 months or more after IC diagnosis. Efficacy data were analyzed by using the intent-to-treat, last-observation-carried-forward population. Results At the end of the study, mean changes from baseline in total ICSI and ICPI scores (± SEM) for early treatment (6 months or less) versus late treatment (24 months or more) were 3.97 ± 0.59 versus 2.15 ± 0.70 ( P = 0.0472) and 3.94 ± 0.56 versus 1.77 ± 0.63 ( P = 0.0117), respectively. Similar trends for both measures were observed when examining other times from IC diagnosis (3 months or less versus 24 months or more, 3 months or less versus 36 months or more, and 6 months or less versus 36 months or more). Conclusions Initiation of PPS treatment within 6 months of establishing the diagnosis of IC may be associated with greater improvement in patient symptoms and symptom bother.
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Pentosan Polysulfate sodium therapy for men with chronic pelvic pain syndrome a multicenter randomized placebo controlled study
The Journal of Urology, 2005Co-Authors: Curtis J Nickel, John B Forrest, Kevin M Tomera, Jose M Hernandezgraulau, Timothy D Moon, Anthony J Schaeffer, John N Krieger, Scott I Zeitlin, Robert J Evans, Daniel J LamaAbstract:ABSTRACT Purpose: We evaluated the efficacy and tolerability of Pentosan Polysulfate sodium (PPS) for the treatment of men with chronic pelvic pain syndrome (CPPS), National Institutes of Health (NIH) category III. Materials and Methods: In a 16-week double-blind study 100 men with a clinical diagnosis of CPPS were randomized to receive 300 mg PPS or placebo 3 times daily. Clinical Global Improvement (CGI) was the primary outcome measure. Additional outcome measures were the NIH-Chronic Prostatitis Symptom Index (CPSI), Subjective Global Assessment and Symptom Severity Index assessment tools. Results: Significantly more patients receiving PPS experienced moderate to marked improvement based on CGI assessment (18 or 37% vs 8 or 18%, p = 0.04). However, mean CGI scores were not significantly different between the PPS group (1.0) and placebo groups (1.0 vs 0.6, p = 0.107). All NIH-CPSI domains suggested a positive effect for PPS and for total NIH-CPSI the difference approached statistical significance (−5.9 or 22% vs −3.2 or 12%, p = 0.068). The PPS group showed significantly greater improvement in NIH-CPSI quality of life domain scores than the placebo group (−2.0 or 22% vs −1.0 or 12%, p = 0.031). Of patients receiving PPS 67% and 80% of those receiving placebo completed the 16-week study. Diarrhea, nausea and headache were the most common adverse events. Conclusions: Pentosan Polysulfate (900 mg daily) was more likely than placebo to provide relief for CPPS symptoms.
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randomized double blind dose ranging study of Pentosan Polysulfate sodium for interstitial cystitis
Urology, 2005Co-Authors: Curtis J Nickel, John B Forrest, Jose M Hernandezgraulau, Robert J Evans, Lowell C Parsons, Jack Barkin, Phillip G Mosbaugh, David M Kaufman, Keith Lloyd, Linda E AtkinsonAbstract:Abstract Objectives To compare the current recommended dose of Pentosan Polysulfate sodium (PPS) with doses two to three times higher. Methods We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, double-dummy, parallel-group, multicenter, 32-week study. Adults (n = 380) with a diagnosis of interstitial cystitis (IC) as determined by a positive cystoscopic examination combined with bladder pain and urgency or a history of IC symptoms for at least 6 months were enrolled. Participants completed the Patient’s Overall Rating of Symptom Index (PORIS) and the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) at baseline (ICSI only) and during follow-up visits at 4, 8, 12, 16, 24, and 32 weeks. Results Mean ICSI scores improved significantly during the 32 weeks for all dosages (baseline 11.2, 11.9, and 11.9 to endpoint 8.2, 8.1, 8.6 for 300, 600, and 900 mg, respectively; P Conclusions For all three dosages of PPS, a clinically significant but similar response was demonstrated. The duration of therapy appears to be more important than the dosage.
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effect of Pentosan Polysulfate therapy on intravesical potassium sensitivity
Urology, 2002Co-Authors: Lowell C Parsons, Curtis J Nickel, John B Forrest, Jose M Hernandezgraulau, Robert Evans, Keith L Lloyd, Jack Barkin, Phillip G Mosbaugh, David M Kaufman, Linda E AtkinsonAbstract:Abstract Objectives. To evaluate further the intravesical potassium sensitivity test (PST) as an indicator of the epithelial leak of interstitial cystitis (IC) and determine whether successful Pentosan Polysulfate (PPS; Elmiron) treatment is associated with a change in PST results. Most individuals with IC appear to have an abnormally permeable epithelium that allows urinary solutes such as potassium to penetrate to the bladder interstitium, provoking symptoms. Methods. Data were from an optimal dose trial of PPS in IC. Patients underwent a PST before and after a 32-week trial of 300, 600, or 900 mg PPS/day. The response to PPS treatment was measured using the Patient Overall Rating of Improvement in Symptoms scale. The before and after treatment PSTs and Patient Overall Rating of Improvement of Symptoms scores were compared. Results. Of 377 patients with IC at 28 centers, 302 (80%) had a positive PST at entry. Of the 198 patients who completed the study, 153 were PST positive at entry and 92 (60%) showed clinical improvement at exit. Clinically improved patients had significant improvement on the PST analog pain and urgency scales (3.2 to 1.3 and 3.6 to 1.9, respectively; P Conclusions. PST shows abnormal epithelial permeability in most patients with IC and a significant reduction in this permeability after successful PPS therapy. PST appears to be a valid indicator of epithelial abnormality and a reliable test in the diagnosis of IC.
Hideaki Nagase - One of the best experts on this subject based on the ideXlab platform.
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Pentosan Polysulfate increases affinity between adamts 5 and timp 3 through formation of an electrostatically driven trimolecular complex
Biochemical Journal, 2012Co-Authors: Linda Troeberg, Peter Ghosh, Barbara Mulloy, Menghuee Lee, Gillian Murphy, Hideaki NagaseAbstract: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.
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calcium Pentosan Polysulfate is a multifaceted exosite inhibitor of aggrecanases
The FASEB Journal, 2008Co-Authors: Linda Troeberg, Peter Ghosh, Kazunari Fushimi, Rama Khokha, Herve Emonard, Hideaki NagaseAbstract:Degradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show that calcium Pentosan Polysulfate (CaPPS), a chemically sulfated xylanopyranose from beechwood, is a multifaceted exosite inhibitor of the aggrecanases and protects cartilage against aggrecan degradation. CaPPS interacts with the noncatalytic spacer domain of ADAMTS-4 and the cysteine-rich domain of ADAMTS-5, blocking activity against their natural substrate aggrecan with inhibitory concentration 50 values of 10-40 nM but only weakly inhibiting hydrolysis of a nonglycosylated recombinant protein substrate. In addition, CaPPS increased cartilage levels of tissue inhibitor of metalloproteinases-3 (TIMP-3), an endogenous inhibitor of ADAMTS-4 and -5. This was due to the ability of CaPPS to block endocytosis of TIMP-3 mediated by low-density lipoprotein receptor-related protein. CaPPS also increased the affinity of TIMP-3 for ADAMTS-4 and -5 by more than 100-fold, improving the efficacy of TIMP-3 as an aggrecanase inhibitor. Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis.
