Screening practices and risk assessment for maculopathy in pentosan polysulfate users across different exposure levels.

In this population-based cohort study, we investigated screening practices for maculopathy and incidences of specific macular/retinal conditions in pentosan polysulfate (PPS) users and assessed the relationship between these outcomes and drug exposure levels. Using a health claims database that covers approximately 50 million Koreans, we identified 138,593 individuals who were prescribed PPS between 2010 and 2021. For the 133,762 PPS users who initiated therapy between 2012 and 2021, the cumulative PPS dose for each participant was evaluated, and based on their cumulative PPS dose, patients were categorized into the high-risk (≥ 500 g), low-risk (50-500 g), and minimal exposure (< 50 g) groups. We analyzed the performance and methods of these examination methods used between 2018 and 2021 and compared them among cumulative dose groups to determine whether high-risk users underwent maculopathy screening more frequently or appropriately. We assessed the cumulative incidence of overall macular degeneration and maculopathy excluding common macular diseases following PPS therapy initiation. Most PPS users (99.7%) received a cumulative PPS dose < 500 g and the high- and low-risk groups comprised 445 (0.3%) and 22,185 (16.6%) patients, respectively. During the study period, monitoring examinations were conducted in 52.6% and 49.4% of high- and low-risk patients, respectively, revealing no significant difference between the two groups (P = 0.156). No significant differences were observed in the annual percentages of patients receiving ophthalmic examinations between the high- and low-risk groups (all P > 0.05). The cumulative incidences of overall macular degeneration and maculopathy excluding common macular diseases in high-risk users were 19.3% and 9.0%, respectively, which were significantly different from those of low-risk users (both P < 0.001). Multivariate Cox regression analysis revealed significantly higher risks of maculopathy excluding common macular diseases in the low- (Hazard ratio [HR] of 1.55 [95% CI 1.13-2.12]) and high-risk groups (HR of 1.66 [95% CI 1.22-2.27]) compared to the minimal exposure group. Our findings suggest a need for increased emphasis on PPS maculopathy screening in high-risk patients, highlighting raising awareness regarding exposure-dependent risks and the establishment of screening guidelines.

Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial.

INTRODUCTION: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia. METHODS AND ANALYSIS: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

Fluorescence Lifetime Imaging of Human Retinal Pigment Epithelium in Pentosan Polysulfate Toxicity Using Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration. Methods: AOFLIO was performed on three subjects with PPS toxicity (57-67 years old) and six age-matched controls (50-64 years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls. Results: Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps. Conclusions: Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.

Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I.

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.

[The interpretation of the updated American Urological Association guideline of interstitial cystitis/bladder pain syndrome in 2022].

In 2022, American Urological Association updated the guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). A significant change has been made in treatment recommendations. The updated guideline no longer divided treatments into first-line through sixth-line tiers. Instead, treatment is categorized into behavioral/non-pharmacologic, oral medicines, bladder instillations, procedures, and major surgery. This change emphasizes the heterogeneity of IC/BPS patients and the importance of individualized treatment, overturns traditional unreasonable ideas about hierarchical and progressive treatment, and encourages patients and physicians to make treatment decisions together. At the same time, the panel emphasized the importance of early implementation of cystoscopy in patients suspected of Hunner lesions and warned against the possibility of pentosan polysulfate causing a unique retinal pigmentary maculopathy. Urinary reconstruction surgery was considered to only be used as a last resort for the treatment of IC/BPS, and there is uncertainty about the overall balance between benefits and risks/burdens. The updated guideline provides a new understanding and decision-making basis for the diagnosis and treatment of IC/BPS. However, it should be noted that the clinical characteristics of Chinese patients should be considered in practice and the application of the guideline should be localized.

Pentosan Polysulfate Sodium Causes Diminished Function and Subtle Morphological Changes in Retina and RPE of Mice.

Purpose: There are numerous reports of a distinctive maculopathy in adults exposed to pentosan polysulfate sodium (PPS), a drug prescribed to treat bladder discomfort associated with interstitial cystitis. We tested whether PPS treatment of mice injures RPE or retina to provide insight into the etiology of the human condition. Methods: Mice were fed PPS-supplemented chow over 14 months. RPE and retinal function was assessed by electroretinography (ERG) regularly. Following euthanasia, one eye was used for sagittal sectioning and histology, the contralateral for RPE flatmounting. ZO-1 positive RPE cell borders were imaged using confocal microscopy and cell morphology was analyzed using CellProfiler. Results: After 10 months of PPS treatment, we observed diminution of mean scotopic c-wave amplitudes. By 11 months, we additionally observed diminutions of mean scotopic a- and b-wave amplitudes. Analysis of flatmounts revealed altered RPE cell morphology and morphometrics in PPS-treated mice, including increased mean en face cell area and geometric eccentricity, decreased RPE cell solidity and extent, and cytosolic translocation of alpha-catenin, all markers of RPE cell stress. Sex and regional differences were seen in RPE flatmount measures. Shortened photoreceptor outer segments were also observed. Conclusions: PPS treatment reduced RPE and later retina function as measured by ERG, consistent with a primary RPE injury. Post-mortem analysis revealed extensive RPE pleomorphism and polymegathism and modest photoreceptor changes. We conclude that PPS treatment of mice causes slowly progressing RPE and photoreceptor damage and thus may provide a useful model for some retinal pathologies.

Nationwide Usage of Pentosan Polysulfate and Practice Patterns of Pentosan Polysulfate Maculopathy Screening in South Korea.

OBJECTIVE: To investigate the nationwide use of pentosan polysulfate (PPS) and screening practices for PPS maculopathy (PPM), with a focus on the timing and modalities used. DESIGN: Population-based cohort study. PARTICIPANTS: For evaluation of nationwide usage, 133 762 individuals who received PPS prescriptions between 2012 and 2021 were included. To investigate practice patterns, 55 487 individuals (referred to as overall users) who initiated PPS therapy between 2018 and 2020 were identified using the Health Insurance Review and Assessment database. After excluding patients with ophthalmic diseases before PPS administration, 34 857 PPS users without prior ophthalmic diseases were identified. METHODS: Ophthalmic examinations performed after initiating PPS therapy were categorized as baseline and subsequent monitoring examinations. The timing and modalities employed for these examinations were analyzed. The annual trends in PPS utilization and maculopathy screening were evaluated by assessing the number of PPS users and determining the proportion of patients receiving retinal/macular examinations among these users. MAIN OUTCOME MEASURES: Performance of baseline and subsequent monitoring examinations and timing and modalities used for screening. RESULTS: The number of PPS users dramatically increased annually over the study period from 5494 in 2012 to 40 451 in 2021. However, the majority of PPS users did not undergo baseline or subsequent monitoring examinations for PPM. Only 27.2% and 12.4% of PPS users without prior ophthalmic disease underwent baseline and monitoring examinations, respectively. Funduscopy/fundus photography was the most commonly utilized, whereas OCT and fundus autofluorescence (FAF) were performed in only 45.2% and 5.3% of the PPS users without prior ophthalmic diseases for monitoring, respectively. The performance of the screening examinations differed significantly across the 3 different daily dose and duration groups (all P < 0.05). CONCLUSIONS: This study highlights the lack of performance of baseline and monitoring examinations for maculopathy in most patients taking PPS in South Korea. The limited use of OCT and FAF suggests potential insensitivity in detecting PPM. These findings emphasize the need for improvements in screening practices, including increased awareness and referrals to ophthalmologists, utilization of more sensitive modalities, and regular monitoring to enable early detection of PPM. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Characterization of pentosan polysulfate patients for development of an alert and screening system for ophthalmic monitoring.

OBJECTIVE: Pentosan polysulfate (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, NJ) is a U.S. Food and Drug Administration-approved oral medication for interstitial cystitis. Numerous reports have been published detailing retinal toxicity with the use of PPS. Studies characterizing this condition are primarily retrospective, and consequently, alert and screening systems need to be developed to actively screen for this disease. The goal of this study was to characterize ophthalmic monitoring trends of a PPS-using patient sample to construct an alert and screening system for monitoring this condition. METHODS: A single-institution retrospective chart review was conducted between January 2005 and November 2020 to characterize PPS use. An electronic medical record (EMR) alert was constructed to trigger based on new PPS prescriptions and renewals offering ophthalmology referral. RESULTS: A total of 1407 PPS users over 15 years was available for characterization, with 1220 (86.7%) being female, the average duration of exposure being 71.2 ± 62.6 months, and the average medication cumulative exposure being 669.7 ± 569.2 g. A total of 151 patients (10.7%) had a recorded visit with an ophthalmologist, with 71 patients (5.0%) having optical coherence tomography imaging. The EMR alert fired for 88 patients over 1 year, with 34 patients (38.6%) either already being screened by an ophthalmologist or having been referred for screening. CONCLUSIONS: An EMR support tool can improve referral rates of PPS maculopathy screening with an ophthalmologist and may serve as an efficient method for longitudinal screening of this condition with the added benefit of informing pentosan polysulfate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.

Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.

Re: Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

How should a conscientious physician advise patients with Interstitial Cystitis /Bladder Pain Syndrome (IC/BPS) when they want to know if taking Pentosan Polysulfate Sodium (PPS) will lead to loss of vision? Ever since the initial report from Pearce et al in 2018 suggesting that PPS usage can lead to the development of pigmented maculopathy (PM), my patients have been inundated with solicitations from attorneys looking to sign up clients for class action lawsuits.1 While there have been additional reports suggesting a relationship between PPS exposure and the development of PM, Ludwig et al found that there was no difference in the rate of macular disease between patients with documented IC/BPS who had taken PPS and those with IC/BPS with no history of PPS use.2 The large size of Ludwig's study certainly suggests that PPS may not cause PM to develop, and if the rate of PM in the IC population is higher than in controls, it may be due to the disease itself and not from the medication. In this manuscript, Proctor clearly describes the immune inflammatory response that is responsible for the development of the bladder damage seen with IC/BPS. Also, he describes how inflammatory mediators can enter the blood stream and might be a potential cause for the development of PM.3 This is a thought-provoking hypothesis that demands further evaluation. I have prescribed PPS since its approval and have many patients who feel it is an essential part of their IC treatment regimen. There is no other prescription medication that functions in the same fashion. I require them to follow the FDA recommendations for annual eye exams to look for PM development. I also advise patients that as they improve, we will discuss dose reduction and even discontinuation if their IC symptoms have abated. By following these suggestions, one should be able to continue to prescribe PPS for appropriate patients while carefully monitoring them for PM. I found this article extremely informative and will refer to it when counseling patients about IC/BPS and PPS.

Further advances in identification of pentosan polysulfate monosaccharide composition by NMR.

Several publications have recently proposed NMR spectroscopy to evaluate the critical quality attributes (CQA) of pentosan polysulfate sodium (PPS), the active ingredient of Elmiron™ approved to treat interstitial cystitis. PPS is a polymer of sulfated ß(1-4)-d-xylopyranose residues randomly substituted by 4-O-methyl-glucopyranosyluronic acid, containing, beyond the main xylose-2,3-O-disulfate repetitive unit, some minor residues that can be marker of both the starting material and preparation process. In the present study we assigned some previously unknown cross-peaks in 1H-13C HSQC NMR of PPS related to its minor sequences adding additional details to its CQA. Four anomeric cross-peaks related to glucuronate-branched xylose and different sulfation pattern as well as the preceding xyloses were identified. Two minor process-related signals of monosulfated xyloses (unsubstituted in position 2 or 3) were also assigned. The isolation of a disaccharide fraction allowed the assignment of the reducing end xylose-α/ß as well as the preceding xylose residues to be corrected. Additionally, the oversulfation of PPS allowed detection of the reducing end xylose-tri-1,2,3-O-sulfate. The newly identified cross-peaks were integrated into an updated quantitative NMR method. Finally, we demonstrated that an in-depth PPS analysis can be obtained using NMR instruments at medium magnetic fields (500 MHz/600 MHz), commonly available in pharmaceutical industries.

VISUAL AND ANATOMICAL CHANGES AFTER DRUG CESSATION IN PENTOSAN POLYSULFATE SODIUM-ASSOCIATED MACULOPATHY.

PURPOSE: The purpose of this study was to describe a case of development of pentosan polysulfate sodium (PPS)-related maculopathy that exhibited potential improvement in imaging findings after drug cessation. METHODS: This study is a case report. RESULTS: A 66-year-old woman presented with progressive pigmentary maculopathy associated with long-term PPS usage, including development of a choroidal neovascular membrane in her right eye. After discontinuation of PPS, her clinical course was notable for partial subjective and objective improvement in visual acuity, as well as partial improvement in outer retinal architecture on ocular coherence tomography, but persistence of retinal pigment epithelium atrophy and autofluorescence changes. CONCLUSION: The course of retinopathy after discontinuation of PPS has yet to be fully determined and has so far been suggested to be progressive. Anatomical improvements seen in our case suggest that further investigations are warranted to determine whether there is potential for partial reversal of some changes in PPS maculopathy.

Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

Progression of Pentosan-Polysulfate Sodium-Associated Retinopathy: Intermediate Follow-Up.

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; P < 0.0001), and total PPS duration was 12.1 ± 7.1 years (16.0.2 ± 6.1 vs 10.1 ± 6.9; P < 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 mm2 in the PPS-retinopathy group, worsening at a rate of 6.10 ± 10 mm2/year. Patients who developed choroidal neovascular membranes (CNVMs) had faster rates of retinopathy progression (11.6 ± 12 vs 3.53 ± 7.6 mm2/year, P = 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. [Ophthalmic Surg Lasers Imaging Retina 2023;54:388-394.].

Progression of Pentosan Polysulfate Sodium Maculopathy in a Prospective Cohort.

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.

REFINING THE RETINAL PHENOTYPE OF PATIENTS WITH SUSPECTED PENTOSAN POLYSULFATE SODIUM RETINOPATHY.

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.

A Precise qNMR Method for the Rapid Quantification of Lot-to-Lot Variations in Multiple Quality Attributes of Pentosan Polysulfate Sodium.

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.