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American Journal of Ophthalmology Nov 2023To describe the progression of pentosan polysulfate sodium (PPS) maculopathy after drug discontinuation qualitatively and quantitatively using multimodal imaging...
PURPOSE
To describe the progression of pentosan polysulfate sodium (PPS) maculopathy after drug discontinuation qualitatively and quantitatively using multimodal imaging assessmen.
DESIGN
Prospective case series.
METHODS
Patients with PPS maculopathy were evaluated after discontinuation of PPS. Near-infrared reflectance (NIR), fundus autofluorescence (FAF), and optical coherence tomography (OCT) were evaluated in all patients at baseline and at the final follow-up visit at least 12 months later. A qualitative and quantitative analysis of the retinal imaging findings was performed. Patterns of disease progression were evaluated. Area of disease involvement on FAF, retinal pigment epithelium (RPE) atrophy on FAF and NIR, and retinal layer thicknesses on OCT were measured at baseline and at the follow-up visit.
RESULTS
A total of 26 eyes were included, with a follow-up period ranging from 13 to 30 months. The diseased area measured on FAF showed significant expansion in all eyes from baseline to follow-up despite drug cessation (P = .03) with a median linearized rate of change of 0.42 mm/y. There was significant reduction in the central macular thickness (P = .04), inner nuclear layer thickness (P = .003), outer nuclear layer thickness (P = .02), and subfoveal choroidal thickness (P = .003) at follow-up vs baseline. New areas of RPE atrophy on FAF in the macula developed in 4 eyes while preexisting atrophic lesions increased in size in 5 eyes.
CONCLUSION
Eyes with baseline PPS maculopathy all exhibited remarkable progression with qualitative and quantitative multimodal imaging analysis despite drug discontinuation. Disease progression may be attributed to underlying inner choroidal ischemia or RPE impairment.
Topics: Humans; Pentosan Sulfuric Polyester; Fluorescein Angiography; Macular Degeneration; Retinal Diseases; Tomography, Optical Coherence; Disease Progression; Atrophy; Retinal Pigment Epithelium
PubMed: 37327961
DOI: 10.1016/j.ajo.2023.05.021 -
Retinal Cases & Brief Reports Jun 2023Pentosan polysulfate (PPS), a drug used for interstitial cystitis, has recently been detected to cause maculopathy in a dose-dependent manner. Outer retinal atrophy is...
PURPOSE
Pentosan polysulfate (PPS), a drug used for interstitial cystitis, has recently been detected to cause maculopathy in a dose-dependent manner. Outer retinal atrophy is the hallmark of this condition.
METHODS
History, examination and multimodal imaging were used to guide diagnosis and management.
RESULTS
We report a case of PPS-related maculopathy in a 77-year-old lady, who presented with florid retinal atrophy at the posterior pole in both eyes, and a concurrent macular hole in the left eye. She had been diagnosed with interstitial cystitis several years prior for which she was prescribed PPS (Elmiron). She had noticed a drop in vision 5 years following initiation of PPS and self-discontinued the drug after 24 years of use. A diagnosis of PPS-related maculopathy with a macular hole was made. She was counselled regarding the prognosis and was advised to avoid PPS. Surgery for macular hole was deferred in view of the severe retinal atrophy.
CONCLUSIONS
PPS-related maculopathy can lead to severe retinal atrophy and a subsequent degenerative macular hole. A high index of suspicion is required for early detection and cessation of drug to prevent this irreversible vision loss.
PubMed: 37321232
DOI: 10.1097/ICB.0000000000001444 -
Ophthalmic Surgery, Lasers & Imaging... Jul 2023To compare the risk factors for the development and progression of pigmentary retinopathy in patients exposed to pentosan polysulfate sodium (PPS).
BACKGROUND AND OBJECTIVE
To compare the risk factors for the development and progression of pigmentary retinopathy in patients exposed to pentosan polysulfate sodium (PPS).
MATERIALS AND METHODS
Retrospective cohort study of patients exposed to PPS with at least two follow-up visits with multimodal imaging.
RESULTS
A total of 97 patients were included (33 with PPS-associated retinopathy and 64 without). The average follow-up was 29.4 months, overall cumulative dose was 1,220 ± 910 g (1,730 ± 870 vs 959 ± 910; < 0.0001), and total PPS duration was 12.1 ± 7.1 years (16.0.2 ± 6.1 vs 10.1 ± 6.9; < 0.0001). The best-corrected visual acuity remained stable during follow-up. At presentation, the average area of the retinopathy in the worse eye was 54.1 ± 50 mm in the PPS-retinopathy group, worsening at a rate of 6.10 ± 10 mm/year. Patients who developed choroidal neovascular membranes (CNVMs) had faster rates of retinopathy progression (11.6 ± 12 vs 3.53 ± 7.6 mm/year, = 0.036). No patient had the exact same gene mutation.
CONCLUSION
PPS-associated pigmentary retinopathy can continue to progress over time, even after discontinuing the medication. CNVM development may be associated with faster rates of retinopathy progression. .
Topics: Humans; Pentosan Sulfuric Polyester; Follow-Up Studies; Retrospective Studies; Retinal Diseases; Retinitis Pigmentosa; Sodium
PubMed: 37310751
DOI: 10.3928/23258160-20230522-02 -
Retina (Philadelphia, Pa.) Sep 2023To refine the retinal phenotypes of suspected pentosan polysulfate sodium toxicity using ultra-widefield imaging.
PURPOSE
To refine the retinal phenotypes of suspected pentosan polysulfate sodium toxicity using ultra-widefield imaging.
METHODS
Patients with complete dosing profiles who visited the ophthalmology department and with ultra-widefield and optical coherence tomography imaging records were identified using electronic health records at a large academic center. Retinal toxicity was initially identified using previously published imaging criteria, while grading was categorized using both previously reported and new classification systems.
RESULTS
One hundred and four patients were included in this study. Twenty-six (25%) were identified as having toxicity from PPS. The mean duration of exposure and cumulative dose between the retinopathy group (162.7 months, 1,803.2 g) were longer and higher compared with the nonretinopathy group (69.7 months, 972.6 g) (both P < 0.001). There was variability of extramacular phenotype in the retinopathy group, with four eyes having only peripapillary involvement and six eyes having far peripheral extension.
CONCLUSION
Retinal toxicity in the setting of prolonged exposure and increased cumulative dosing from PPS therapy produces phenotypic variability. Providers should be aware of the extramacular component of toxicity when screening patients. Understanding the different retinal phenotypes may prevent continued exposure and reduce the risk of vision-threatening foveal-involving disease.
Topics: Humans; Pentosan Sulfuric Polyester; Fluorescein Angiography; Retina; Retinal Diseases; Tomography, Optical Coherence; Phenotype
PubMed: 37229759
DOI: 10.1097/IAE.0000000000003844 -
The Journal of Veterinary Medical... Jun 2023Pentosan polysulfate sodium (PPS) is a heparin-like polysaccharide that is applied as a therapeutic treatment for osteoarthritis (OA) in animals. This study investigated...
Pentosan polysulfate sodium promotes redifferentiation to the original phenotype in micromass-cultured canine articular chondrocytes and exerts molecular weight-dependent effects.
Pentosan polysulfate sodium (PPS) is a heparin-like polysaccharide that is applied as a therapeutic treatment for osteoarthritis (OA) in animals. This study investigated the efficacy of different molecular weights PPS (1,500-7,000 Da) on the phenotype regulatory and chondrogenic properties of canine articular chondrocytes. The cytotoxicity of PPS on chondrocytes was assessed using flow cytometry and 3-(4,5-dimehylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. After 72 hr of exposure, PPS did not induce chondrocyte apoptosis, regardless of molecular weight. In addition, chondrogenic properties were determined according to the mRNA and protein levels in micromass-cultured chondrocytes. Quantitative polymerase chain reaction analysis confirmed that PPS promotes a chondrogenic phenotype in chondrocytes in a molecular weight-dependent manner, with significant upregulation of collagen type II alpha 1 chain, aggrecan, and SRY-box transcription factor 9 (SOX9) mRNA levels relative to those in the control. However, the collagen type I alpha 2 chain mRNA level simultaneously increased after 7,000 Da PPS treatment. PPS exposure also increased collagen type II and SOX9 protein production in a molecular weight-dependent manner and inhibited Akt phosphorylation in chondrocytes. Alcian blue staining indicated that PPS treatment enhanced proteoglycan deposition in micromass cultures, with stronger effects observed in 5,000 and 7,000 Da groups. Overall, these results indicate that PPS exerts protective effects on the chondrocyte phenotype and may represent a potential therapeutic target for OA treatment. Increasing the molecular weight of PPS could enhance these anabolic effects.
Topics: Animals; Dogs; Chondrocytes; Pentosan Sulfuric Polyester; Molecular Weight; Collagen Type II; Phenotype; Osteoarthritis; Cells, Cultured; RNA, Messenger; Cartilage, Articular; Cell Differentiation; SOX9 Transcription Factor; Dog Diseases
PubMed: 37150611
DOI: 10.1292/jvms.22-0567 -
The AAPS Journal May 2023Pentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to...
Pentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to yield a mixture of 4-6 kDa polysaccharides. The chain is mainly composed of sulfated xylose (Xyl) with branched 4-O-methyl-glucuronate (MGA). During generic drug development, the quality attributes (QAs) including monosaccharide composition, modification, and length need to be comparable to those found in the reference list drug (RLD). However, the range of QA variation of the RLD PPS has not been well characterized. Here, multiple PPS RLD lots were studied using quantitative NMR (qNMR) and diffusion ordered spectroscopy (DOSY) to quantitate the components in the mixture and to probe both inter- and intra-lot precision variability. The DOSY precision assessed using coefficient of variation (CV) was 6%, comparable to PPS inter-lot CV of 5%. The QAs obtained from 1D qNMR were highly precise with a precision CV < 1%. The inter-lot MGA content was 4.8 ± 0.1%, indicating a very consistent botanical raw material source. Other process-related chemical modification including aldehyde at 0.51 ± 0.04%, acetylation at 3.3 ± 0.2% and pyridine at 2.08 ± 0.06%, varied more than MGA content. The study demonstrated that 1D qNMR is a quick and precise method to reveal ranges of variation in multiple attributes of RLD PPS which can be used to assess equivalency with generic formulations. Interestingly, the synthetic process appeared to introduce more variations to the PPS product than the botanical source of the material.
Topics: Pentosan Sulfuric Polyester; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging
PubMed: 37147461
DOI: 10.1208/s12248-023-00815-4 -
Frontiers in Molecular Biosciences 2023The unexpected surge of respiratory syncytial virus (RSV) cases following pandemic phase of COVID-19 has drawn much public attention. Drawing on the latest antiviral...
The unexpected surge of respiratory syncytial virus (RSV) cases following pandemic phase of COVID-19 has drawn much public attention. Drawing on the latest antiviral research, revisiting this heightened annual outbreak of respiratory disease could lead to new treatments. The ability of sulfated polysaccharides to compete for a variety of viruses binding to cell surface heparan sulfate, suggests several drugs that might have therapeutic potential for targeting RSV-glycosaminoglycan interactions. In the current study, the binding affinity and kinetics of two RSV glycoproteins (RSV-G protein and RSV-F protein) to heparin were investigated by surface plasmon resonance. Furthermore, solution competition studies using heparin oligosaccharides of different lengths indicated that the binding of RSV-G protein to heparin is size-dependent, whereas RSV-F protein did not show any chain length preference. The two RSV glycoproteins have slightly different preferences for heparin sulfation patterns, but the -sulfo group in heparin was most critical for the binding of heparin to both RSV-G protein and RSV-F protein. Finally, pentosan polysulfate and mucopolysaccharide polysulfate were evaluated for their inhibition of the RSV-G protein and RSV-F protein-heparin interaction, and both highly negative compounds showed strong inhibition.
PubMed: 37122559
DOI: 10.3389/fmolb.2023.1151174 -
MedRxiv : the Preprint Server For... Apr 2023We describe a novel colopathy associated with pentosan polysulfate (PPS) use and measure the strength of the drug-disease association.
INTRODUCTION
We describe a novel colopathy associated with pentosan polysulfate (PPS) use and measure the strength of the drug-disease association.
METHODS
Two-part investigation. In the cohort study of individuals with a history of prior long-term PPS use, case histories were obtained and gastrointestinal disease course was followed with review of endoscopy records and histopathology specimens. Findings were summarized with descriptive statistics. In the cross-sectional study of individuals with interstitial cystitis, drug exposure and medical histories were obtained for patients seen at a single clinical center. Strength of association between PPS use and diagnoses of inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS) was measured with multivariate logistic regression.
RESULTS
In the cohort study of 13 participants, median PPS exposure was 2.04 kg (0.99-2.54). Eleven (84.6%) developed symptoms suggestive of IBD and/or IBS after initiation of PPS therapy. Of the 10 participants whose endoscopic and histopathologic findings we reviewed, six had abnormal-appearing colonic mucosa on endoscopy and all 10 had abnormal mucosal changes on histology. Clinical and histologic improvement was observed after PPS cessation. In the cross-sectional study of 219 subjects with interstitial cystitis, PPS use was a statistically significant predictor of both the IBD [adjusted odds ratio=3.3 (95% confidence interval, 1.2-8.8, p=0.02)] and the composite IBD+IBS [adjusted odds ratio=3.3 (95% confidence interval, 1.5-7.3, p=0.002)] outcomes.
DISCUSSION
We describe a strong association between PPS use and a clinical diagnosis of IBD and/or IBS. Histopathologic findings suggest a novel drug-associated colopathy, with some subjects requiring colectomy for dysplasia.
PubMed: 37066211
DOI: 10.1101/2023.04.03.23288071 -
Journal of Vitreoretinal Diseases 2023To describe a patient initially diagnosed with age-related macular degeneration (AMD) who was ultimately determined to have progressing pentosan polysulfate sodium...
PURPOSE
To describe a patient initially diagnosed with age-related macular degeneration (AMD) who was ultimately determined to have progressing pentosan polysulfate sodium (PPS)-associated maculopathy leading to secondary cystoid macular edema (CME) 10 years after cessation of PPS.
METHODS
An interventional case report is presented.
RESULTS
A 57-year-old woman diagnosed with AMD presented with unilateral worsening vision and metamorphopsia from CME. A detailed history showed a 3-year course of PPS, which had been discontinued 10 years previously. This led to the diagnosis of PPS-associated maculopathy. After topical NSAID and corticosteroid treatment failed, intravitreal bevacizumab resolved the symptoms. CME developed in the fellow eye 5 months later and also responded to bevacizumab.
CONCLUSIONS
This case emphasizes the importance of a thorough review of past medication and medical histories in patients with pigmentary retinopathy and supports the use of antivascular endothelial growth factor therapy as an option to treat CME secondary to PPS-associated maculopathy.
PubMed: 37008392
DOI: 10.1177/24741264221136907 -
Retina (Philadelphia, Pa.) Jul 2023To assess genetic associations for pentosan polysufate sodium maculopathy.
PURPOSE
To assess genetic associations for pentosan polysufate sodium maculopathy.
METHODS
Genetic testing for inherited retinal dystrophy genes using exome testing and for 14 age-related macular degeneration-associated single nucleotide polymorphisms (SNPs) using panel testing were performed. In addition, full-field electroretinograms (ffERG) were obtained to identify any cone-rod dystrophy.
RESULTS
Eleven of 15 patients were women, with a mean age of 69 (range 46-85). Inherited retinal dystrophy exome testing in five patients revealed six pathogenic variants, but failed to confirm inherited retinal dystrophy in any patient genetically. FfERG performed in 12 patients demonstrated only nonspecific a- and b-wave abnormalities in 11 cases and was normal in one case. For age-related macular degeneration single nucleotide polymorphisms, CFH rs3766405 ( P = 0.003) and CETP ( P = 0.027) were found to be statistically significantly associated with pentosan polysulfate maculopathy phenotype compared with the control population.
CONCLUSION
Pentosan polysulfate maculopathy is not associated with Mendelian inherited retinal dystrophy genes. However, several age-related macular degeneration risk alleles were identified to be associated with maculopathy compared with their frequency in the normal population. This suggests a role for genes in disease pathology, particularly the alternative complement pathway. These findings would benefit from further investigation to understand the risk of developing maculopathy in taking pentosan polysulfate.
Topics: Female; Male; Humans; Pentosan Sulfuric Polyester; Cystitis, Interstitial; Macular Degeneration; Retinal Dystrophies; Cone-Rod Dystrophies
PubMed: 36996461
DOI: 10.1097/IAE.0000000000003794