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The Journal of Veterinary Medical... Aug 2020Pentosan polysulfate (PPS) is a semi-synthetic sulfated polysaccharide compound which has been shown the benefits on therapeutic treatment for osteoarthritis (OA) and...
Pentosan polysulfate (PPS) is a semi-synthetic sulfated polysaccharide compound which has been shown the benefits on therapeutic treatment for osteoarthritis (OA) and has been proposed as a disease modifying osteoarthritis drugs (DMOADs). This study investigated the effects of PPS on cell proliferation, particularly in cell cycle modulation and phenotype promotion of canine articular chondrocytes (AC). Canine AC were treated with PPS (0-80 µg/ml) for 24, 48 and 72 hr. The effect of PPS on cell viability, cell proliferation and cell cycle distribution were analyzed by MTT assay, DNA quantification and flow cytometry. Chondrocyte phenotype was analyzed by quantitative real-time PCR (qPCR) and glycosaminoglycan (GAG) quantification. PPS significantly reduced AC proliferation through cell cycle modulation particularly by maintaining a significantly higher proportion of chondrocytes in the G1 phase and a significantly lower proportion in the S phase of the cell cycle in a concentration- and time-dependent manner. While the proportion of chondrocytes in G1 phase corresponded with the significant downregulation of cyclin-dependent kinase (CDK) 1 and 4. Furthermore, the study confirms that PPS promotes a chondrogenic phenotype of AC through significant upregulation of collagen type II (Col2A1) mRNA and GAG synthesis. The effect of PPS on the inhibition of chondrocyte proliferation while promoting a chondrocyte phenotype could be beneficial in the early stages of OA treatment, which transient increase in proliferative activity of chondrocytes with subsequent phenotypic shift and less productive in an essential component of extracellular matrix (ECM) is observed.
Topics: Animals; Cartilage, Articular; Cell Cycle; Cell Proliferation; Cell Survival; Cells, Cultured; Chondrocytes; Chondrogenesis; Cyclin-Dependent Kinases; Dogs; Gene Expression Regulation; Osteoarthritis; Pentosan Sulfuric Polyester
PubMed: 32641601
DOI: 10.1292/jvms.20-0091 -
Stem Cell Research May 2020We evaluated the synergistic effects of pentosan polysulfate sodium (PPS) and mesenchymal stem cells (MSCs) in an interstitial cystitis (IC) rat model. After generation...
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.
Topics: Adipose Tissue; Animals; Cystitis, Interstitial; Inflammation; Mesenchymal Stem Cells; Pentosan Sulfuric Polyester; Rats
PubMed: 32334368
DOI: 10.1016/j.scr.2020.101801 -
Carbohydrate Polymers Apr 2020Rapid advances have been made in developing analytical technologies for characterization of highly heterogeneous active ingredients of complex drugs, such as pentosan...
Rapid advances have been made in developing analytical technologies for characterization of highly heterogeneous active ingredients of complex drugs, such as pentosan polysulfate (PPS), active ingredient of the drug Elmiron®, approved by the Food and Drug Administration and marketed in the United States to treat interstitial cystitis. PPS sulfated polysaccharides comprise of a repeat unit of β(1-4)-D-xylopyranoses randomly substituted by 4-O-methyl-glucopyranosyluronic acid. To define the critical quality attributes (CQAs) of such a complex drug, it is critical to develop an approach that integrates data from orthogonal analytical methodologies. Here, we developed an approach integrating diverse analytical tools including gel permeation chromatography, LC/ESI-MS and NMR to measure CQAs of PPS. The proposed mathematical framework integrates the data from these diverse analytical methods as function of PPS chain length and building blocks. Our approach would facilitate in establishing a scientific foundation for comparative characterization of drug products with complex active ingredients.
Topics: Carbohydrate Conformation; Chromatography, Gel; Cystitis, Interstitial; Humans; Magnetic Resonance Spectroscopy; Molecular Weight; Pentosan Sulfuric Polyester; Spectrometry, Mass, Electrospray Ionization
PubMed: 32070534
DOI: 10.1016/j.carbpol.2020.115913 -
American Journal of Ophthalmology Case... Mar 2020To describe a patient with a past diagnosis of Stargardt disease that was later determined to be pentosan polysulfate (PPS) maculopathy.
PURPOSE
To describe a patient with a past diagnosis of Stargardt disease that was later determined to be pentosan polysulfate (PPS) maculopathy.
OBSERVATIONS
The patient had clinical and imaging findings uncharacteristic of Stargardt disease. Rather, her fundus resembled the recently described maculopathy ascribed to PPS. After genetic testing was found to be negative for pathologic variants, the patient was asked to cease usage of PPS.
CONCLUSIONS AND IMPORTANCE
This case emphasizes the importance of reviewing patient medication profiles prior to rendering a diagnosis of a retinal dystrophy. It is essential that ophthalmologists catch drug toxicities as early as possible, to minimize risk of further irreversible vision loss due to continued medication exposure.
PubMed: 32043016
DOI: 10.1016/j.ajoc.2020.100604 -
Canadian Urological Association Journal... Feb 2020
PubMed: 31999543
DOI: 10.5489/cuaj.6401 -
Diagnostics (Basel, Switzerland) Dec 2019Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative...
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.
PubMed: 31861164
DOI: 10.3390/diagnostics9040226 -
Journal of the Formosan Medical... Aug 2020Pentosan polysulfate sodium (PPS), a semi-synthetic polysaccharide that adheres to bladder mucosa, is effective in treating interstitial cystitis. We evaluated the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND/PURPOSE
Pentosan polysulfate sodium (PPS), a semi-synthetic polysaccharide that adheres to bladder mucosa, is effective in treating interstitial cystitis. We evaluated the clinical benefit of PPS for the prevention of recurrent urinary tract infection (UTI) in women.
METHODS
We conducted a multicenter, open-label, prospective, phase II, randomized controlled trial enrolling women with recurrent UTI ≥ 2 times in the past 6 months or ≥ 3 times in the past 12 months. Patients received oral PPS monotherapy for 16 weeks in treatment group. All patients were followed every 28 days until UTI recurrence or up to 112 days. The primary endpoint was the UTI recurrence-free survival. Adverse events were recorded as secondary endpoint.
RESULTS
A total of 26 women were eligible for analysis. In the PPS group, none (0%) of the 12 patients had UTI recurrence during the study period. However, 9 (64%) of 14 patients had UTI recurrence in the control group. The UTI recurrence-free survival was significantly higher in the PPS group than in the control group (log-rank test p = 0.0004). One adverse event which led to discontinuation of the trial regimen was regarded as irrelevance of PPS treatment. The limitation was the small number of cases.
CONCLUSION
Among women with recurrent UTI, 16-week PPS monotherapy significantly reduced UTI recurrence when compared with the control group.
Topics: Administration, Oral; Anticoagulants; Cystitis, Interstitial; Female; Humans; Pentosan Sulfuric Polyester; Prospective Studies; Urinary Tract Infections
PubMed: 31813658
DOI: 10.1016/j.jfma.2019.11.007 -
The British Journal of Ophthalmology Aug 2020A series at a single clinical centre recently demonstrated an association between the interstitial cystitis drug pentosan polysulfate sodium (PPS) and a...
BACKGROUND/AIMS
A series at a single clinical centre recently demonstrated an association between the interstitial cystitis drug pentosan polysulfate sodium (PPS) and a vision-threatening pigmentary maculopathy. The aim of this study was to determine if an association exists between PPS use and macular disease in a large national cohort.
METHODS
A retrospective, matched cohort study using data from a large US medical claims database from 2002 to 2016 was performed. A total of 3012 and 1604 PPS users were compared with 15 060 and 8017 matched controls at 5 and 7 years, respectively. The primary outcome measures included (1) any new diagnosis of a hereditary or secondary pigmentary maculopathy (atypical maculopathy outcome), and (2) any new diagnosis of dry age-related macular degeneration (AMD) or drusen in addition to the aforementioned diagnoses (atypical maculopathy+AMD outcome).
RESULTS
At the 5-year and 7-year follow-up, 9 (0.3%) and 10 (0.6%) PPS patients progressed to the atypical maculopathy outcome compared with 32 (0.2%) and 25 (0.3%) control patients, respectively. 103 (3.4%) and 87 (5.4%) PPS patients developed the atypical maculopathy+AMD outcome compared with 440 (2.9%) and 328 (4.1%) control patients at 5 and 7 years, respectively. At 5 years, multivariate analysis showed no significant association (p>0.13). At 7 years, PPS users had significantly increased odds of having the atypical maculopathy+AMD outcome (OR=1.41, 95% CI 1.09 to 1.83, p=0.009).
CONCLUSIONS
PPS exposure was associated with a new diagnosis of macular disease at the 7-year follow-up in a large national cohort.
Topics: Adult; Aged; Anticoagulants; Cohort Studies; Databases, Factual; Female; Follow-Up Studies; Geographic Atrophy; Humans; Male; Middle Aged; Pentosan Sulfuric Polyester; Retinal Drusen; Retinal Pigment Epithelium; Retrospective Studies; United States
PubMed: 31694837
DOI: 10.1136/bjophthalmol-2019-314765 -
PloS One 2019Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in...
Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in this context is unknown. We hypothesised that the osteocyte, being the principal cell type in the sub-chondral bone, was capable of expressing the pain mediator Nerve Growth Factor (NGF), and that this may be altered in the presence of PPS. We tested the expression of NGF and the response to PPS in the presence or absence of the proinflammatory cytokine tumour necrosis factor-alpha (TNFα), in human osteocytes. For this we differentiated human primary osteoblasts grown from subchondral bone obtained at primary knee arthroplasty for KOA to an osteocyte-like stage over 28d. We also tested NGF expression in fresh osteocytes obtained by sequential digestion from KOA bone and by immunofluorescence in KOA bone sections. We demonstrate for the first time the production and secretion of NGF/proNGF by this cell type derived from patients with KOA, implicating osteocytes in the pain response in this pathological condition and possibly others. PPS inhibited TNFα-induced levels of proNGF secretion and TNFα induced NGF mRNA expression. Together, this provides evidence that PPS may act to suppress the release of NGF in the subchondral bone to ameliorate pain associated with knee osteoarthritis.
Topics: Aged; Arthralgia; Female; Humans; Nerve Growth Factor; Osteoarthritis, Knee; Osteocytes; Pentosan Sulfuric Polyester; Transcriptome; Tumor Necrosis Factor-alpha
PubMed: 31557169
DOI: 10.1371/journal.pone.0222602 -
JAMA Ophthalmology Nov 2019A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for...
IMPORTANCE
A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.
OBJECTIVE
To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy.
DESIGN, SETTING, AND PARTICIPANTS
In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019.
MAIN OUTCOMES AND MEASURES
Drug exposure, visual acuity, and retinal imaging characteristics.
RESULTS
Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (-0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes [53%]) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes [23%]; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities.
CONCLUSIONS AND RELEVANCE
These findings suggest that PPS-associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium-photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.
PubMed: 31486843
DOI: 10.1001/jamaophthalmol.2019.3392