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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 -
JAMA Ophthalmology Mar 2023Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan...
IMPORTANCE
Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan polysulfate (PPS).
OBJECTIVE
To evaluate the 2-year evolution of maculopathy associated with PPS use after drug cessation.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study prospectively evaluated the natural history of patients with maculopathy associated with PPS use. Participants seen at the Emory Eye Center were enrolled between December 1, 2018, and December 1, 2019, and data were collected through November 30, 2021.
MAIN OUTCOMES AND MEASURES
The main outcomes were changes in visual function and structure. Visual function was assessed annually with refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), mesopic microperimetry, and dark adaptometry. Structural outcomes included presence and extent of complete retinal pigment epithelium and outer retinal atrophy (cRORA), macular central subfield thickness (CST), and subfoveal choroidal thickness (SFCT).
RESULTS
Of the 12 participants (23 eyes), 11 (91.7%) were female (1 [8.3%] male), 11 (91.7%) were White (1 [8.3%] Black), and median (IQR) age at enrollment was 58 (47-64) years. Median (IQR) time from PPS discontinuation to initial visit was 0.6 (0.4-1.9) years. Median baseline ETDRS BCVA letter score was 83 (Snellen equivalent, 20/20) (IQR, 80-86.5 [20/25-20/20]), with a median 2-year change of -3 (IQR, -6 to -0.5; P = .08). Four eyes (17.4%) had a letter score decline of 15 or more, all associated with progressive cRORA. Median change in microperimetry average threshold was -3.5 dB (IQR, -4.1 to -2.5 dB; P = .001), and percent reduced threshold was 32.5% (IQR, 20.3%-52.8%; P = .004). Nine eyes (39%) had macular cRORA at baseline, with a median linearized growth rate of 0.23 mm/y (IQR, 0.22-0.25 mm/y). Two eyes (8.7%) without atrophy at baseline developed new-onset cRORA. Median baseline CST was 284 μm (IQR, 253-291 μm), with a median 2-year change of -5 μm (IQR, -13 to 0.5 μm; P = .0497). Median 2-year change in SFCT was 1 μm (IQR, -18 to 16 μm; P = .91).
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest that functional and structural deficits continue to progress in PPS-associated maculopathy even after drug cessation. Additional study is needed to determine whether these findings can be generalized to other patients with PPS-associated maculopathy and whether longer follow-up could determine subsequent disease course.
Topics: Humans; Male; Female; Middle Aged; Pentosan Sulfuric Polyester; Cohort Studies; Retrospective Studies; Tomography, Optical Coherence; Macular Degeneration; Diabetic Retinopathy; Retinal Degeneration; Atrophy
PubMed: 36729449
DOI: 10.1001/jamaophthalmol.2022.6093 -
Poultry Science Feb 2015Different F5 recombinant inbred lines from the cross Yumai 34×Ukrainka were grown in replicated trials on a single site in one harvest year at Rothamsted Research. A... (Randomized Controlled Trial)
Randomized Controlled Trial
Different F5 recombinant inbred lines from the cross Yumai 34×Ukrainka were grown in replicated trials on a single site in one harvest year at Rothamsted Research. A total of 10 samples from those lines were harvested and used in a broiler experiment. Twenty nutritionally complete meal-form diets that had 630 g/kg of wheat with different amounts of pentosan, with and without exogenous xylanase supplementation, were used to compare broiler growth performance and determine apparent metabolizable energy corrected for N retention (AMEn). We examined the relationship between the nutritive value of the wheat samples and their chemical compositions and results of quality tests. The amounts of total and water soluble pentosans in wheat samples ranged from 36.7 to 48.0 g/kg DM, and 6.7 to 11.6 g/kg DM, respectively. The mean crude oil and protein contents of the wheat samples were 10.5 and 143.9 g/kg DM, respectively. The average determined value for the kinematic viscosity was 0.0018 mPa.s, and 2.1 mPa.s for the dynamic viscosity. The AMEn of the wheat-based diets had a maximum range of 0.47 MJ/kg DM within the ten wheat samples that were tested. Xylanase supplementation improved (P<0.05) dietary AMEn, dry matter, and fat digestibility coefficients. There was a positive (P<0.05) relationship between in vitro kinematic viscosity of the wheat samples and the total pentosan content. There was a negative relationship between the total pentosan content in the wheat and broiler growth performance. An increase by 10 g of pentosan per kg of wheat reduced (P<0.001) daily feed intake and weight gain by 2.9 g and 3.5 g, respectively. The study shows that the feeding quality of wheat samples can be predicted by their total pentosan content. Supplementary xylanase improved energy and nutrient availability of all wheat samples that was independent of differences in pentosan content.
Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chickens; Diet; Dietary Supplements; Endo-1,4-beta Xylanases; Energy Metabolism; Gene Expression Regulation, Plant; Male; Pentosan Sulfuric Polyester; Polysaccharides; Triticum
PubMed: 25595480
DOI: 10.3382/ps/peu059 -
Pakistan Journal of Medical Sciences 2019In the present study, we investigated the efficacy of bladder hydrodistension combined with pentosan polysulfate (PPS) treatment in interstitial cystitis (IC)/bladder...
OBJECTIVE
In the present study, we investigated the efficacy of bladder hydrodistension combined with pentosan polysulfate (PPS) treatment in interstitial cystitis (IC)/bladder pain syndrome (BPS).
METHODS
In this study, 339 patients diagnosed with IC/BPS were categorized into two groups. The first group only received 300 mg/day PPS, while the second group received 300 mg/day PPS following bladder hydrodistension. The results were evaluated at the 3rd, 6th, and 12th months after the first dose using the interstitial cystitis symptom index (ICSI), international cystitis problem index (ICPI), visual analog scale (VAS), and female sexual function index (FSFI).
RESULTS
PPS treatment started just after hydrodistension was significantly more effective than PPS treatment alone and combined treatment significantly reduced the rate of non-compliance such that, at the end of the 3rd month, 12.1% patients in Group-1 did not continue their treatment whereas only 1.9% of patients in Group-2 did not continue.
CONCLUSIONS
The study results indicate that PPS treatment started just after hydrodistension yields significantly better results in terms of both symptom improvement and treatment compliance in patients with IC/BPS.
PubMed: 30881421
DOI: 10.12669/pjms.35.1.172 -
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 -
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 -
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 -
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