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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 -
Thrombosis and Haemostasis Jun 2022
Topics: Heparin; Humans; Pentosan Sulfuric Polyester; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35373312
DOI: 10.1055/a-1815-2142 -
Scientific Reports Mar 2021Creutzfeldt-Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the...
Creutzfeldt-Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the availability of human cell-based models of prion disease. Recently, an induced pluripotent stem cell derived human cerebral organoid model was shown to take up and propagate human CJD prions. This model offers new opportunities to screen drug candidates for the treatment of human prion diseases in an entirely human genetic background. Here we provide the first evidence that human cerebral organoids can be a viable model for CJD drug screening by using an established anti-prion compound, pentosan polysulfate (PPS). PPS delayed prion propagation in a prophylactic-like treatment paradigm and also alleviated propagation when applied following establishment of infection in a therapeutic-like treatment paradigm. This study demonstrates the utility of cerebral organoids as the first human 3D cell culture system for screening therapeutic drug candidates for human prion diseases.
Topics: Cell Culture Techniques; Cell Line; Cerebral Ventricles; Creutzfeldt-Jakob Syndrome; Drug Discovery; Drug Evaluation, Preclinical; Humans; Organoids; Pentosan Sulfuric Polyester
PubMed: 33727594
DOI: 10.1038/s41598-021-84689-6 -
FEBS Letters Jan 2020Extracellular levels of soluble TIMP-3 are low, reflecting its binding by extracellular matrix (ECM) components including sulfated glycosaminoglycans (SGAGs) and...
Extracellular levels of soluble TIMP-3 are low, reflecting its binding by extracellular matrix (ECM) components including sulfated glycosaminoglycans (SGAGs) and endocytosis via low density lipoprotein receptor-related protein 1. Since TIMP-3 inhibits ECM degradation, the ability of SGAGs to elevate extracellular TIMP-3 is significant for osteoarthritis treatment. Previous studies of such interactions have utilized immobilized TIMP-3 or ligands. Here, we report the thermodynamics of the interactions of the sGAG-binding N-domain of TIMP-3 with chondroitin sulfate, pentosan polysulfate, and suramin in solution using isothermal titration calorimetry. All three interactions are driven by a favorable negative enthalpy change combined with an unfavorable decrease in entropy. The heat capacity changes (ΔC ) for all of the interactions are zero, indicating an insignificant contribution from hydrophobic interactions.
Topics: Binding Sites; Chondroitin Sulfates; Humans; Molecular Docking Simulation; Pentosan Sulfuric Polyester; Protein Binding; Suramin; Tissue Inhibitor of Metalloproteinase-3
PubMed: 31359422
DOI: 10.1002/1873-3468.13556 -
Scientific Reports Oct 2022For women with recurrent urinary tract infection (UTI), previous U101 study has shown that pentosan polysulfate sodium (PPS) monotherapy for 16 weeks significantly... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Female; Follow-Up Studies; Humans; Pentosan Sulfuric Polyester; Prospective Studies; Quality of Life; Urinary Tract Infections
PubMed: 36202908
DOI: 10.1038/s41598-022-21100-y -
Journal of Vitreoretinal Diseases 2024To describe a case of pentosan polysulfate maculopathy progression with 13 years of follow-up imaging. A case was analyzed and a literature review performed. A...
To describe a case of pentosan polysulfate maculopathy progression with 13 years of follow-up imaging. A case was analyzed and a literature review performed. A 65-year-old woman was referred to the retina service for a second opinion of a bilateral progressive pigmentary maculopathy. Her medical history was significant for interstitial cystitis that was actively treated with daily pentosan polysulfate since 2003. Multimodal imaging and fundus examination were consistent with pentosan polysulfate maculopathy. A review of records showed previous fundus imaging dating back 13 years that permitted longitudinal assessment of the disease course. Imaging findings were more prominent than the fundus examination findings. There was a 5-year period from the onset of parafoveal atrophy to foveal involvement. A pseudopodial pattern of disease expansion was seen on fundus autofluorescence. To our knowledge, this case represents the longest documented follow-up imaging of the progression of pentosan polysulfate maculopathy in the literature.
PubMed: 38770071
DOI: 10.1177/24741264241228375 -
Journal of Ophthalmology 2020This chart review of a quaternary academic medical center electronic medical record (EMR) aimed to identify patients at risk of development of maculopathy with exposure...
AIMS
This chart review of a quaternary academic medical center electronic medical record (EMR) aimed to identify patients at risk of development of maculopathy with exposure to pentosan polysulfate sodium (PPS).
METHODS
A review of electronic medical records of a quaternary medical center of patients with either documented exposure to PPS or diagnosis of interstitial cystitis (IC) from 2007 to 2019 was performed for retinal imaging and visual acuity; the study was conducted in August of 2019.
RESULTS
216 charts were included for analysis, of which 96 had documented eye exams and 24 had retinal imaging done. We identified three patients with maculopathy in the context of long-term exposure to PPS via chart review, and one additional patient was identified by referral. The median PPS exposure duration was 11 years (range 7 to 19 years). Median logMAR BCVA OD 0.6 range was 0.0-1.9 (approximate Snellen equivalent 20/80 range (20/20-20/1600)) and OS 0.7 range was 0.1-1.9 (approximate Snellen equivalent 20/100 range (20/25-20/1600)). Ultrawidefield color fundus imaging and fundus autofluorescence revealed findings of pigmentary changes and patchy macular atrophy. Optical coherence tomography (OCT) demonstrated outer retinal thinning and increased choroidal transmission coincident with areas of atrophy seen on fundus imaging.
CONCLUSIONS
Less than half of patients at risk for development of maculopathy due to exposure to PPS had received eye examinations, suggesting that those at risk are not receiving adequate screening. We found two patients with PPS maculopathy who had relatively preserved central vision, one patient with bitemporal vision loss, and one patient who developed vision loss in both eyes.
PubMed: 33489347
DOI: 10.1155/2020/8866961 -
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 -
Viruses Feb 2024Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus with high contagion and mortality rates. Heparan sulfate proteoglycans (HSPGs) are...
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus with high contagion and mortality rates. Heparan sulfate proteoglycans (HSPGs) are ubiquitously expressed on the surface of mammalian cells. Owing to its high negatively charged property, heparan sulfate (HS) on the surface of host cells is used by many viruses as cofactor to facilitate viral attachment and initiate cellular entry. Therefore, inhibition of the interaction between viruses and HS could be a promising target to inhibit viral infection. In the current study, the interaction between the receptor-binding domain (RBD) of MERS-CoV and heparin was exploited to assess the inhibitory activity of various sulfated glycans such as glycosaminoglycans, marine-sourced glycans (sulfated fucans, fucosylated chondroitin sulfates, fucoidans, and rhamnan sulfate), pentosan polysulfate, and mucopolysaccharide using Surface Plasmon Resonance. We believe this study provides valuable insights for the development of sulfated glycan-based inhibitors as potential antiviral agents.
Topics: Animals; Heparin; Middle East Respiratory Syndrome Coronavirus; Sulfates; Glycosaminoglycans; Heparitin Sulfate; Mammals
PubMed: 38400013
DOI: 10.3390/v16020237 -
Investigative Ophthalmology & Visual... Apr 2024
PubMed: 38687494
DOI: 10.1167/iovs.65.4.47