Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation.
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SUBMITTER: Rudd PA
PROVIDER: S-EPMC8423248 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeIndividuals with pentosan polysulfate sodium (PPS) maculopathy commonly report symptoms of prolonged dark adaptation and difficulty reading. We hypothesize that PPS maculopathy causes degradation of visual function not fully captured with visual acuity testing.MethodsSubjects with PPS maculopathy underwent multimodal evaluation of retinal structure and function. Structural changes were graded as moderate or advanced. Patient-reported visual function was assessed with the National Eye Institute Visual Function Questionnaire 39 (NEI-VFQ-39) and Low Luminance Questionnaire (LLQ). Objective functional evaluations included Early Treatment of Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), Pelli-Robson contrast sensitivity, mesopic microperimetry, and dark adaptometry. Functional testing results were correlated with structural disease category.ResultsThirteen patients (26 eyes), median age 62 years (range, 37-76), completed the study. Median ETDRS letter score was 82 (Snellen equivalent 20/25). Median NEI-VFQ-39 and LLQ composite scores were 65 (range, 33-88) and 41 (range, 20-92), respectively. Median contrast sensitivity was 1.65 (range, 0.15-1.95), and median mesopic microperimetry average thresholds and percent reduced thresholds were 26 decibels (range, 0.4-28.6) and 21.6% (range, 0-100%), respectively. Median rod intercept time was 14.1 minutes (range, 4.4-20.0). Eyes with advanced disease based on retinal structure had significantly worse retinal function for several testing modalities.ConclusionsPPS maculopathy causes considerable visual function degradation that is not fully captured with BCVA testing. There was good correlation between other measures of visual function and disease severity. These findings deepen our concern regarding this patient safety issue.
| S-EPMC7691795 | biostudies-literature
Project description:ImportanceCase series have identified a macular condition hypothesized to be associated with the use of pentosan polysulfate sodium (PPS). Observational studies seeking to quantify this association have yielded equivocal results.ObjectiveTo estimate the association between PPS exposure and maculopathy.Design, setting, and participantsThis disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System from January 2013 through June 2020.ExposureAdverse event reports for pentosan polysulfate were selected and compared with adverse event reports associated with drugs taken for the following indications: interstitial cystitis, cystitis, bladder disorder, or bladder pain.Main outcome measuresRetinal adverse events were identified using the retinal disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query, which includes conditions associated with retinal damage attributable to blockage of its blood supply, nutritional deficiencies, toxins, and diseases affecting the retina.ResultsThere were 2775 reports available for analysis in the PPS group (of which 1966 were for women [70.9%]) and 6833 reports in the other drugs group (of which 4036 [59.1%] were for women). The proportion of adverse events for any macular event relative to all other events was elevated for the users of PPS compared with those using other interstitial cystitis and bladder pain drugs (proportionate reporting ratio [PRR], 1.21 [95% CI, 1.01-1.44]). With respect to specific retinal conditions, macular degeneration (20 [0.8%] vs 15 [0.2%]), maculopathy (83 [3.4%] vs 2 [0.03%]), retinal dystrophy (3 [0.1%] vs 0), retinal injury (5 [0.2%] vs 0), and retinal toxicity (3 [0.1%] vs 0) were proportionately more common among users of PPS compared with those using other interstitial cystitis and bladder pain drugs, respectively.Conclusions and relevanceThe results of the current study add to the growing evidence that PPS use is associated with an increased risk of maculopathy. Studies that rule out prevalent retinal abnormalities prior to the initiation of PPS would strengthen the current body of literature.
| S-EPMC8603224 | biostudies-literature
Project description:ImportanceA 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.ObjectiveTo characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy.Design, setting, and participantsIn 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 measuresDrug exposure, visual acuity, and retinal imaging characteristics.ResultsOf 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 relevanceThese 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.
| S-EPMC6735406 | biostudies-literature
Project description:ImportanceRecent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).ObjectiveTo evaluate the disease course in PPS-associated maculopathy after drug cessation.Design, setting, and participantsIn this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019.Main outcomes and measuresChange in visual acuity and retinal imaging characteristics over time.ResultsOf the 11 included patients, all were female, and the median (interquartile range [IQR]) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year.Conclusions and relevanceThese retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.
| S-EPMC7349079 | biostudies-literature
Project description:BackgroundPentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats.Methodology/principal findingsTreatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP-1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS-treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues.ConclusionsBased on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies.
| S-EPMC3554761 | biostudies-literature
Project description: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). Protocol: Three groups of MPS IIIA mice were evaluated: 1-week-old mice treated with subcutaneous (subQ) PPS at 25 mg/kg once weekly for 31 weeks (group 1); 5-month-old mice treated with subQ PPS once weekly at 50 mg/kg for 12 weeks (group 2); and 5-week-old mice treated by continual intracerebroventricular (ICV) PPS infusion for 11 weeks (60 μg/kg/day). Treated MPS IIIA mice and controls were assessed by measuring plasma cytokine levels, histologic analyses of systemic organs, and analyses of various neuroinflammatory, neurodegenerative, and lysosomal disease markers in their brains. Neurobehavioral testing also was carried out. Results: As seen in other MPS animal models, subQ PPS treatment reduced plasma cytokine levels and macrophage infiltration in systemic tissues. ICV administration did not elicit these systemic effects. SubQ PPS administration also significantly impacted brain neuropathology, inflammation, and behavior. The effect of early subQ treatment was more significant than dose. Surprisingly, ICV PPS treatment had intermediate effects on most of these brain markers, perhaps due to the limited dose and/or duration of treatment. Consistent with these neuropathological findings, we also observed significant improvements in the hyperactivity/anxiety and learning behaviors of the MPS IIIA mice treated with early subQ PPS.
| S-EPMC6323024 | biostudies-literature
Project description:Background/aimsA 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.MethodsA 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).ResultsAt 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).ConclusionsPPS exposure was associated with a new diagnosis of macular disease at the 7-year follow-up in a large national cohort.
| S-EPMC7288845 | biostudies-literature
Project description:BackgroundAlphaviruses, such as Ross River (RRV) and chikungunya virus (CHIKV), cause significant global morbidity, with outbreaks of crippling joint inflammation and pain, leaving patients incapacitated for months to years. With no available vaccine or specific therapeutic for any alphaviral disease, and a growing economic and public health burden, there is a serious need for the development of specific therapies.MethodsThis study evaluated the safety and efficacy of pentosan polysulfate sodium (PPS) in subjects with RRV-induced arthralgia in a double-blind, placebo-controlled trial. Twenty subjects were randomized 2:1 to subcutaneous PPS (2 mg/kg) or placebo (sodium chloride 0.9%) twice weekly for 6 weeks. Safety evaluation included physical examination, concomitant medications, and laboratory findings. Efficacy assessments included change from baseline in joint function (hand grip strength and RAPID3) and quality of life (SF-36) at Days 15, 29, 39 and 81 after treatment initiation. Inflammatory and cartilage degradation biomarkers were exploratory endpoints.ResultsPPS was well tolerated, with a similar proportion of subjects reporting at least one treatment-emergent adverse event (TEAE) in the treatment and placebo groups. Injection site reactions were the most common TEAE and occurred more frequently in the PPS group. Dominant hand grip strength and SF-36 scores improved with PPS at all time points assessed, with hand grip strength improvement of 6.99 kg (p = 0.0189) higher than placebo at Day 15. PPS showed significant improvements versus placebo in adjusted mean relative change from baseline for RAPID3 Pain (p = 0.0197) and Total (p = 0.0101) scores at Day 15. At the conclusion of the study overall joint symptoms, assessed by RAPID3, showed near remission in 61.5% of PPS subjects versus 14.3% of placebo subjects. Additionally, PPS treatment improved COMP, CTX-II, CCL1, CXCL12, CXCL16 and CCL17 biomarker levels versus placebo.ConclusionsOverall, the improvements in strength and joint symptoms warrant further evaluation of PPS as a specific treatment for RRV-induced and other forms of arthritis.Trial registrationThis trial is registered at the Australian New Zealand Clinical Trials Registry # ACTRN12617000893303 .
| S-EPMC7955617 | biostudies-literature
Project description:BackgroundWe 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.Methodology/principal findingsMPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed.ConclusionsPPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.
| S-EPMC4827827 | biostudies-literature
Project description:IntroductionThere is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The semi-synthetic polysaccharide, Pentosan polysulfate sodium (PPS), an inhibitor of NF-kB activation, was investigated for its systemic and local anti-inflammatory effects in a mouse model of influenza virus A/PR8/1934 (PR8 strain) mediated infection.MethodsImmunocompetent C57BL/6J mice were infected intranasally with a sublethal dose of PR8 and treated subcutaneously with 3 or 6 mg/kg PPS or vehicle. Disease was monitored and tissues were collected at the acute (8 days post-infection; dpi) or post-acute (21 dpi) phase of disease to assess the effect of PPS on PR8-induced pathology.ResultsIn the acute phase of PR8 infection, PPS treatment was associated with a reduction in weight loss and improvement in oxygen saturation when compared to vehicle-treated mice. Associated with these clinical improvements, PPS treatment showed a significant retention in the numbers of protective SiglecF+ resident alveolar macrophages, despite uneventful changes in pulmonary leukocyte infiltrates assessed by flow cytometry. PPS treatment in PR8- infected mice showed significant reductions systemically but not locally of the inflammatory molecules, IL-6, IFN-g, TNF-a, IL-12p70 and CCL2. In the post-acute phase of infection, PPS demonstrated a reduction in the pulmonary fibrotic biomarkers, sICAM-1 and complement factor C5b9.DiscussionThe systemic and local anti-inflammatory actions of PPS may regulate acute and post-acute pulmonary inflammation and tissue remodeling mediated by PR8 infection, which warrants further investigation.
| S-EPMC9947849 | biostudies-literature