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British Journal of Clinical Pharmacology Jul 2022Recent epidemiologic studies have examined the risk of maculopathy with pentosan polysulfate sodium (PPS), a drug indicated for the treatment of interstitial cystitis....
AIMS
Recent epidemiologic studies have examined the risk of maculopathy with pentosan polysulfate sodium (PPS), a drug indicated for the treatment of interstitial cystitis. However, results have been contradictory. Thus, we quantified the risk of maculopathy with PPS with a focus on risk with duration of use.
METHODS
We used a new user, retrospective cohort study with an active comparator. We created a cohort of mutually exclusive 6221 PPS users and 89 744 amitriptyline users, a tricyclic antidepressant also used for the treatment of pain secondary to interstitial cystitis. Subjects were selected from the PharMetrics Plus database (IQVIA, Durham, NC) from 2006 to 2020. Cohort members were followed to the first event of the study outcome (maculopathy) or end of enrolment. A Cox regression model was constructed to adjust for potential confounders.
RESULTS
The mean follow-up was 3.0 years for PPS users and amitriptyline users. The adjusted hazard ratio (HR) for maculopathy in PPS users was 2.64 (95% confidence interval [CI]: 1.90-3.68). The HR for the sensitivity analysis that combined maculopathy and age-related macular degeneration (AMD) was 1.38 (95% CI: 1.16-1.65). A cumulative duration-response pattern was observed, with use greater than 3 years having a 9.5-fold risk of maculopathy (HR = 9.56, 95% CI: 3.60-25.37) compared to a 2.3-fold risk of maculopathy with use for 1 year or less (HR = 2.27, 95% CI: 1.50-3.43). The number needed to harm for the first 4 years of use was 250.
CONCLUSIONS
The results of this study suggest an increased risk of maculopathy with PPS use, particularly with longer duration of use.
Topics: Amitriptyline; Cystitis, Interstitial; Humans; Macular Degeneration; Pentosan Sulfuric Polyester; Retrospective Studies
PubMed: 35277990
DOI: 10.1111/bcp.15303 -
International Immunopharmacology May 2022Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for...
Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for chronic intestinal inflammation. This study aimed to explore the efficacy and the hematological effects of pentosan polysulfate sodium (PPS) in a dextran sulfate sodium (DSS)-induced colitis model. Forty C57BL/6 female mice were equally divided into five groups: control group, DSS-colitis group, DSS-colitis treated with 5-aminosalicylic acid, DSS-colitis treated with PPS, and DSS-colitis treated with both drugs. Disease activity index (DAI) and colon length were calculated. Colonic IL-6 and IL-35 levels were assayed by ELISA. IL-35 gene expression was evaluated by qRT-PCR. Colon tissue samples were examined by H&E stain and immunohistochemistry (IHC) of Ki67. The colitis group subjected to combined treatment showed the best outcome with significant improvement of DAI and increased colon length. Colonic IL-6 was significantly lower in both PPS- and combination-treated groups accompanied by a significantly higher IL-35 level and its EBI3 subunit mRNA expression. However, the PPS-treated colitis group showed higher gene expression of IL-35 EBI3 subunit by 1.5-fold compared with the combined group. The colon mucosa and crypts were significantly preserved in mice treated with both drugs with the best Ki67 positive cell density. PPS is a safe and promising drug in the treatment of UC as it exerted the best positive effect on the anti-inflammatory IL-35 level and gene expression. However, superior improvement of DAI was seen when PPS was added to ASA with a greater mucosal proliferation and repair.
Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Female; Interleukins; Mesalamine; Mice; Mice, Inbred C57BL; Pentosan Sulfuric Polyester; Signal Transduction
PubMed: 35247859
DOI: 10.1016/j.intimp.2022.108620 -
Pharmaceuticals (Basel, Switzerland) Feb 2022With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster,...
With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate (HS) on the surface of host cells plays an important role as a co-receptor for this viral pathogen-host cell interaction. Our previous studies demonstrated that many sulfated glycans, such as heparin, fucoidans, and rhamnan sulfate have anti-SARS-CoV-2 activities. In the current study, a small library of sulfated glycans and highly negatively charged compounds, including pentosan polysulfate (PPS), mucopolysaccharide polysulfate (MPS), sulfated lactobionic acid, sulodexide, and defibrotide, was assembled and evaluated for binding to the S-proteins and inhibition of viral infectivity in vitro. These compounds inhibited the interaction of the S-protein receptor-binding domain (RBD) (wild type and different variants) with immobilized heparin, a highly sulfated HS, as determined using surface plasmon resonance (SPR). PPS and MPS showed the strongest inhibition of interaction of heparin and S-protein RBD. The competitive binding studies showed that the IC of PPS and MPS against the S-protein RBD binding to immobilized heparin was ~35 nM and ~9 nM, respectively, much lower than the IC for soluble heparin (IC = 56 nM). Both PPS and MPS showed stronger inhibition than heparin on the S-protein RBD or spike pseudotyped lentiviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, PPS and MPS exhibited strong antiviral activities against pseudotyped viral particles of SARS-CoV-2 containing wild-type or Delta S-proteins.
PubMed: 35215371
DOI: 10.3390/ph15020258 -
Stem Cells and Development Aug 2022This review highlights the attributes of pentosan polysulfate (PPS) in the promotion of intervertebral disc (IVD) repair processes. PPS has been classified as a... (Review)
Review
Pentosan Polysulfate, a Semisynthetic Heparinoid Disease-Modifying Osteoarthritic Drug with Roles in Intervertebral Disc Repair Biology Emulating the Stem Cell Instructive and Tissue Reparative Properties of Heparan Sulfate.
This review highlights the attributes of pentosan polysulfate (PPS) in the promotion of intervertebral disc (IVD) repair processes. PPS has been classified as a disease-modifying osteoarthritic drug (DMOAD) and many studies have demonstrated its positive attributes in the countering of degenerative changes occurring in cartilaginous tissues during the development of osteoarthritis (OA). Degenerative changes in the IVD also involve inflammatory cytokines, degradative proteases, and cell signaling pathways similar to those operative in the development of OA in articular cartilage. PPS acts as a heparan sulfate (HS) mimetic to effect its beneficial effects in cartilage. The IVD contains small cell membrane HS proteoglycans (HSPGs) such as syndecan, and glypican and a large multifunctional HS/chondroitin sulfate (CS) hybrid proteoglycan (HSPG2/perlecan), that have important matrix-stabilizing properties and sequester, control, and present growth factors from the FGF, VEGF, PDGF, and BMP families to cellular receptors to promote cell proliferation, differentiation, and matrix synthesis. HSPG2 also has chondrogenic properties and stimulates the synthesis of extracellular matrix (ECM) components and expansion of cartilaginous rudiments, and has roles in matrix stabilization and repair. Perlecan is a perinuclear and nuclear proteoglycan (PG) in IVD cells with roles in chromatin organization and control of transcription factor activity, immunolocalizes to stem cell niches in cartilage, promotes escape of stem cells from quiescent recycling, differentiation and attainment of pluripotency and migratory properties. These participate in tissue development and morphogenesis, ECM remodeling and repair. PPS also localizes in the nucleus of stromal stem cells, promotes development of chondroprogenitor cell lineages, ECM synthesis and repair and discal repair by resident disc cells. The availability of recombinant perlecan and PPS offers new opportunities in repair biology. These multifunctional agents offer welcome new developments in repair strategies for the IVD.
Topics: Cartilage, Articular; Extracellular Matrix Proteins; Heparan Sulfate Proteoglycans; Heparinoids; Heparitin Sulfate; Humans; Intervertebral Disc; Pentosan Sulfuric Polyester; Stem Cells
PubMed: 35102748
DOI: 10.1089/scd.2022.0007 -
JAMA Ophthalmology Mar 2022
Topics: Humans; Pentosan Sulfuric Polyester; Retinal Diseases
PubMed: 35084438
DOI: 10.1001/jamaophthalmol.2021.5972 -
Ophthalmic Epidemiology Feb 2023We describe a retrospective cohort study investigating the prevalence of pentosan polysulfate sodium (PPS) maculopathy in patients with PPS exposure, as well as the...
PURPOSE
We describe a retrospective cohort study investigating the prevalence of pentosan polysulfate sodium (PPS) maculopathy in patients with PPS exposure, as well as the relationship between cumulative PPS exposure and the presence of PPS-maculopathy.
METHODS
Patients were identified through review of the electronic medical record system. Available diagnostic imaging was reviewed for signs of PPS-maculopathy. Patients were also contacted to determine cumulative exposure.
RESULTS
Of the 335 identified eligible patient records, 84 had sufficient diagnostic imaging. Sixteen patients had definitive signs of PPS-maculopathy, 6 had likely signs of PPS-maculopathy, and 62 had no signs. The mean cumulative PPS exposure and standard error of the mean (SEM) for patients with any signs of PPS-maculopathy was 1946.0 g (396.0 g), significantly higher than the mean cumulative PPS exposure for patients without such signs of 782.3 g (105.3 g). No significant difference in BCVA was noted. The odds ratio (OR, 95% confidence interval (95% CI)) of PPS-maculopathy was significantly elevated in patients with cumulative PPS exposures of 1500-2000 g [OR 4.72 (0.856-26.02 95% CI)] and greater than 2000 g [OR 28.33 (2.388-336.1, 95% CI)]. Logistic regression analysis confirmed a positive dose response relationship.
CONCLUSIONS
We describe the concerning incidence of PPS-maculopathy in a multispecialty ophthalmology practice's patient population and investigate the dose-dependency of PPS-maculopathy. Patients with PPS-maculopathy were shown to have a higher average exposure to PPS than those without the maculopathy. Patients with cumulative PPS exposures greater than 1500 g were shown to have an increased risk of PPS-maculopathy.
Topics: Humans; Pentosan Sulfuric Polyester; Prevalence; Retrospective Studies; Retinal Diseases; Macular Degeneration
PubMed: 35081852
DOI: 10.1080/09286586.2022.2031227 -
Biomedicines Dec 2021As with many other pathogens, SARS-CoV-2 cell infection is strongly dependent on the interaction of the virus-surface Spike protein with the glycosaminoglycans of target...
As with many other pathogens, SARS-CoV-2 cell infection is strongly dependent on the interaction of the virus-surface Spike protein with the glycosaminoglycans of target cells. The SARS-CoV-2 Spike glycoprotein was previously shown to interact with cell-surface-exposed heparan sulfate and heparin in vitro. With the aim of using Enoxaparin as a treatment for COVID-19 patients and as prophylaxis to prevent interpersonal viral transmission, we investigated GAG binding to the Spike full-length protein, as well as to its receptor binding domain (RBD) in solution by isothermal fluorescence titration. We found that Enoxaparin bound to both protein variants with similar affinities, compared to the natural GAG ligand heparan sulfate (with Kd-values in the range of 600-680 nM). Using size-defined Enoxaparin fragments, we discovered the optimum binding for dp6 or dp8 for the full-length Spike protein, whereas the RBD did not exhibit a significant chain-length-dependent affinity for heparin oligosaccharides. The soluble ACE2 receptor was found to interact with unfractionated GAGs in the low µM Kd range, but with size-defined heparins with clearly sub-µM Kd-values. Interestingly, the structural heparin analogue, pentosan polysulfate (PPS), exhibited high binding affinities to both Spike variants as well as to the ACE2 receptor. In viral infection experiments, Enoxaparin and PPS both showed a strong inhibition of infection in a concentration range of 50-500 µg/mL. Both compounds were found to retain their inhibitory effects at 500 µg/mL in a natural biomatrix-like human sputum. Our data suggest the early topical treatment of SARS-CoV-2 infections with inhaled Enoxaparin; some clinical studies in this direction are already ongoing, and they further imply an oral or nasal prophylactic inactivation of the virus by Enoxaparin or PPS for the prevention of inter-personal viral transmission.
PubMed: 35052728
DOI: 10.3390/biomedicines10010049 -
Journal of Pharmaceutical and... Mar 2022Pentosan Polysulfate Sodium (PPS) is a semi-synthetic polysulfated xylan sourced from beechwood tree barks. PPS, which is mainly composed of a xylose chain with branched...
Pentosan Polysulfate Sodium (PPS) is a semi-synthetic polysulfated xylan sourced from beechwood tree barks. PPS, which is mainly composed of a xylose chain with branched O-methyl-glucuronate (MGA), can have heterogeneity in monosaccharide species, sequence and chemical modifications including sulfation and acetylation. The monosaccharide composition in polysaccharide therapeutics is a frequently quoted quality attribute (QA), which has been assessed using two-dimensional (2D) H-C HSQC NMR. However, the sensitivity of 2D NMR for the assessment of PPS inter-lot variability from the same manufacturer was unclear and questions remained whether 2D NMR had sufficient sensitivity to distinguish normal batch to batch variations in this QA. Here, a 2D peak profile method was applied to compare high-resolution semi-quantitative (semi-q) HSQC spectra with the inclusion of intermediate precision spectra collected on two PPS drug lots released 29 months apart (where one of the lots was expired). The semi-q HSQC NMR confirmed the mass equivalence of total polysaccharides, O-Methyl and acetyl groups between the two lots. The 2D spectral peak profile results readily identified significant lot-to-lot differences (p < 0.05) in relative distribution among most monosaccharide species, in addition to heterogeneity in MGA distribution and acetyl transfer from PPS to free acetate in the expired lot. Precisely measured chemical QAs are prerequisites to establish normal batch variation in the innovator product, providing important reference ranges for complex generic drug developers. Overall, high-resolution semi-q HSQC NMR may provide a sensitive tool to measure fine chemical differences in polysaccharide therapeutics needed to establish chemical QAs and compare batches without concerns of intrinsic NMR method variation.
Topics: Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pentosan Sulfuric Polyester
PubMed: 35038672
DOI: 10.1016/j.jpba.2022.114589 -
Clinical Ophthalmology (Auckland, N.Z.) 2021To evaluate the risk factors and fundus findings of patients with potential PPS-associated retinopathy.
PURPOSE
To evaluate the risk factors and fundus findings of patients with potential PPS-associated retinopathy.
PATIENTS AND METHODS
A retrospective chart review was performed of patients exposed to PPS who had a dilated fundus examination at a large retina-only practice from 2018-21. Multimodal images were evaluated by masked reviewers.
RESULTS
A total of 148 patients were included, of whom 33 (22%) had PPS-associated retinopathy, and 115 (78%) did not. The mean age was 60.3 years old, and the mean follow-up was 11.8 months. The PPS-associated retinopathy group had higher mean cumulative doses of PPS (1600g±849 vs 864g±852, < 0.0001, Mann-Whitney test) and longer duration of PPS use (13.6 years vs 7.48, < 0.0001). There was no statistically significant difference based on a history of kidney or liver disease or the dosage per day for the weight, body mass index, body surface area, or lean body weight. Of the patients with PPS-associated retinopathy whose genetic results were available, 15 of 16 (93%) were heterozygous for variants of uncertain significance.
CONCLUSION
A longer duration of PPS use and higher cumulative dosage of PPS were associated with an increased risk of developing PPS-associated pigmentary retinopathy. The role of genetic mutations in patients exposed to PPS is still to be determined.
PubMed: 34992341
DOI: 10.2147/OPTH.S340041 -
European Journal of Ophthalmology Dec 2021Pentosan polysulfate-related maculopathy is a recently described clinical entity, related to dose and long term use of this medication, and may progress despite drug...
BACKGROUND
Pentosan polysulfate-related maculopathy is a recently described clinical entity, related to dose and long term use of this medication, and may progress despite drug cessation. Cystoid macular oedema (CMO) has been reported in some cases, but there are few reports of treatment outcomes in the literature.
AIMS
We present the case of a 55 year old female, with CMO secondary to pentosan polysulfate maculopathy, that was responsive to treatment with both intravitreal anti-VEGF and steroid injections, stabilising vision over a four year follow up period.
CONCLUSIONS
This is the first report, to our knowledge, of CMO related to pentosan polysulfate maculopathy responding to intravitreal steroid injections, broadening the therapeutic options for preserving vision in these patients.
PubMed: 34866437
DOI: 10.1177/11206721211066387