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Fundamental & Clinical Pharmacology Oct 2022Pentosan polysulfate sodium (PPS) is a polysulfated glycosaminoglycan approved for the treatment of interstitial cystitis. It also showed renoprotective effects in...
Pentosan polysulfate sodium (PPS) is a polysulfated glycosaminoglycan approved for the treatment of interstitial cystitis. It also showed renoprotective effects in chronic kidney injury models, for example, 5/6 nephrectomy and diabetic nephropathy (DN). In the present study, we addressed to evaluate the therapeutic value of PPS in DN of rats in combination with losartan (LSR). Sixty male Sprague-Dawley rats were randomly divided into six groups: control group, untreated diabetic groups (8 and 16 weeks after diabetes induction by streptozotocin "STZ", 60 mg/kg, intraperitoneal [I.P.]), LSR-treated diabetic group (10 mg/kg/day, P.O.), PPS-treated diabetic group (25 mg/kg/day, P.O.), and combination-treated diabetic group. Drug treatment was started 8 weeks after induction of diabetes and continued for a further 8 weeks. Renal functions, albuminuria, renal IL-6, oxidative stress, and renal histopathology were evaluated. STZ-treated diabetic rats developed progressive albuminuria, renal dysfunction, and significant glomerular change 16 weeks after induction of diabetes. Administration of PPS, alone or in combination with LSR, showed some beneficial effects on DN evolution and significantly decreased renal inflammation as detected by IL-6 level. The best beneficial effect on DN evolution was obtained by PPS sole therapy based on albuminuria evaluation and renal histopathology. However, the combination of PPS and LSR did not show additive benefits. This study reported that the renoprotection of PPS in the setting of DN is evident by exerting anti-inflammatory and antioxidant effects, but this effect could be masked when combined with an angiotensin receptor blocker.
Topics: Albuminuria; Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Interleukin-6; Kidney; Losartan; Male; Pentosan Sulfuric Polyester; Rats; Rats, Sprague-Dawley; Streptozocin
PubMed: 35434832
DOI: 10.1111/fcp.12781 -
The Urologic Clinics of North America May 2022Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as persistent or chronic discomfort perceived to be related to the urinary bladder accompanied by urinary... (Review)
Review
Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as persistent or chronic discomfort perceived to be related to the urinary bladder accompanied by urinary urgency or frequency. Pharmacotherapies used to treat IC/BPS include oral and intravesical agents. Oral therapies include amitriptyline, hydroxyzine, cyclosporine A, and pentosan polysulfate sodium (PPS), although the recent finding of pigmented maculopathy with chronic PPS is very concerning and must be discussed with patients, many of whom will choose to either come off this medicine or not even start it. Certolizumab pegol is a pharmacologic therapy that is currently in clinical development for treatment of IC/BPS symptoms.
Topics: Cystitis, Interstitial; Female; Humans; Male; Pentosan Sulfuric Polyester; Urinary Bladder
PubMed: 35428433
DOI: 10.1016/j.ucl.2022.01.003 -
Neurourology and Urodynamics Jun 2022To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current...
OBJECTIVE
To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines.
METHODS
We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression.
RESULTS
There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression.
CONCLUSIONS
Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.
Topics: Amitriptyline; Chronic Pain; Cystitis, Interstitial; Drug Prescriptions; Female; Humans; Hydroxyzine; Pelvic Pain; Pentosan Sulfuric Polyester
PubMed: 35391498
DOI: 10.1002/nau.24923 -
Retinal Cases & Brief Reports Nov 2023The purpose of this study was to report a unique case of pentosan polysulfate sodium (PPS) maculopathy with remarkable rapid progression over 2 years. These findings...
PURPOSE
The purpose of this study was to report a unique case of pentosan polysulfate sodium (PPS) maculopathy with remarkable rapid progression over 2 years. These findings show the importance of early detection of macular disease to limit toxic exposure and reduce the risk of progression.
METHODS
Multimodal retinal imaging including fundus autofluorescence, near-infrared reflectance with pseudocolor, and spectral domain optical coherence tomography was performed in an elderly patient with a history of PPS therapy (cumulative dose of 1,205 g) at baseline and 2 years later.
RESULTS
Baseline multimodal retinal imaging failed to show significant macular findings of PPS toxicity in either eye, but on repeat evaluation 2 years later, advanced features of PPS maculopathy were detected in both eyes with fundus autofluorescence, near-infrared reflectance, pseudocolor, and spectral domain optical coherence tomography.
CONCLUSION
This report describes a remarkable case of rapid progression of PPS maculopathy as documented with multimodal retinal imaging. The dramatic progression of macular findings over just 2 years underscores the importance of early detection and prompt withdrawal of therapy, if systemically feasible, to retard the development and rate of progression of PPS maculopathy.
Topics: Humans; Aged; Pentosan Sulfuric Polyester; Retinal Diseases; Macular Degeneration; Retina; Tomography, Optical Coherence; Fluorescein Angiography
PubMed: 35385434
DOI: 10.1097/ICB.0000000000001273 -
Thrombosis and Haemostasis Jun 2022
Topics: Heparin; Humans; Pentosan Sulfuric Polyester; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35373312
DOI: 10.1055/a-1815-2142 -
Retinal Cases & Brief Reports Nov 2023The purpose of this study was to describe the characteristic pattern of progression of pentosan polysulfate (PPS) maculopathy with multimodal retinal imaging in two...
BACKGROUND/PURPOSE
The purpose of this study was to describe the characteristic pattern of progression of pentosan polysulfate (PPS) maculopathy with multimodal retinal imaging in two patients, including one with over 9 years of follow-up.
METHODS
Two patients with PPS maculopathy were sequentially evaluated with near-infrared reflectance (NIR) and optical coherence tomography.
RESULTS
Near-infrared reflectance showed characteristic centrifugal progression of the parafoveal hyperreflective lesions toward the vascular arcades with the development of hyporeflective areas in both cases. Optical coherence tomography demonstrated focal retinal pigment epithelium (RPE) thickening that corresponded to the hyperreflective lesions on NIR. On subsequent optical coherence tomography scans, the hyperreflective areas resolved with the development of ellipsoid zone attenuation, RPE disruption, and atrophy, which colocalized with hyporeflectivity on NIR.
CONCLUSION
This report describes the progression of pentosan polysulfate maculopathy over almost 10 years of PPS treatment and highlights the importance of NIR as a tool for the diagnosis and monitoring of PPS maculopathy. Pentosan polysulfate lesions present as areas of focal RPE thickening with ensuing development of ellipsoid zone loss and RPE drop-out. The pathophysiology of PPS toxicity is unknown and may either result from primary RPE or choroidal toxicity.
Topics: Humans; Pentosan Sulfuric Polyester; Retina; Retinal Diseases; Macular Degeneration; Retinal Pigment Epithelium; Tomography, Optical Coherence; Fluorescein Angiography
PubMed: 35344532
DOI: 10.1097/ICB.0000000000001276 -
Ophthalmology. Retina Sep 2022There is growing evidence of a direct association between pentosan polysulfate (PPS) therapy and the development of macular changes. Using standardized visual acuity...
PURPOSE
There is growing evidence of a direct association between pentosan polysulfate (PPS) therapy and the development of macular changes. Using standardized visual acuity (VA) testing and multimodal imaging, we investigated the impact of PPS therapy on vision and described an expanded spectrum of imaging findings among PPS users.
DESIGN
Cross-sectional screening study.
PARTICIPANTS
Thirty-nine patients who were current or recent users of PPS.
METHODS
The participants underwent a brief eye examination and answered a comprehensive medical and ophthalmic history questionnaire. Color fundus photography, fundus autofluorescence (FAF), and spectral-domain OCT (SD-OCT) were performed. The images were evaluated by expert graders at Wisconsin Reading Center. Abnormalities were categorized as definite toxicity (DT) if seen on both FAF and SD-OCT and as questionable toxicity (QT) if seen on either FAF or SD-OCT.
MAIN OUTCOME MEASURES
ETDRS and Snellen VA, the dosage and duration of PPS exposure, and the prevalence of retinal toxicity on imaging.
RESULTS
The mean ETDRS and Snellen VA of the study cohort were 85 letters and 20/22, respectively. The mean PPS daily dose was 282 mg (range, 88-400 mg), whereas the mean cumulative dose was 915 g (range, 19-3650 g) over a mean period of 8.8 years (range, 2 months-25 years). There was evidence of retinopathy in 41% of the eyes; DT was identified in 24 eyes (31%) and QT in 8 eyes (10%). Retinal pigment epithelium (RPE) abnormalities (thickening or thinning or both) were present in all eyes with DT. Retinal pigment epithelium atrophy was seen in 7 eyes (9%). In addition to well-established findings, the unique SD-OCT features of this cohort included interdigitation zone abnormalities and the presence of a flying saucer-type defect. Fundus autofluorescence abnormalities were seen in 24 eyes (30.8%), with 20 (66.7%) of these exhibiting abnormalities located outside the central subfield and extending beyond the arcades.
CONCLUSIONS
Findings from the masked grading of multimodal imaging at a centralized reading center suggest a wider phenotypic spectrum of structural abnormalities among patients taking PPS. Macular changes selectively involve the RPE and outer retina, with a range of findings often seen beyond the arcades. The subtle and atypical findings in this cohort should prompt clinicians to consider lowering the threshold for diagnosing PPS retinopathy.
Topics: Cross-Sectional Studies; Fluorescein Angiography; Humans; Multimodal Imaging; Pentosan Sulfuric Polyester; Retinal Degeneration; Tomography, Optical Coherence
PubMed: 35339727
DOI: 10.1016/j.oret.2022.03.016 -
Thrombosis and Haemostasis Jun 2022Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs...
Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
Topics: Animals; Anticoagulants; Chlorocebus aethiops; Heparin; Pentosan Sulfuric Polyester; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vero Cells; Virus Attachment
PubMed: 35322395
DOI: 10.1055/a-1807-0168 -
PloS One 2022Hepcidin which is the crucial regulator of iron homeostasis, produced in the liver in response to anemia, hypoxia, or inflammation. Recent studies have suggested that...
Hepcidin which is the crucial regulator of iron homeostasis, produced in the liver in response to anemia, hypoxia, or inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis by inhibiting osteoblast function and promoting osteoclastogenesis. Pentosan polysulfate (PPS) is a heparin analogue and promising novel therapeutic for osteoarthritis (OA). This study was undertaken to determine whether PPS inhibits hepcidin-facilitated osteoclast (OC) differentiation and iron overload. Canine (n = 3) bone marrow mononuclear cells were differentiated to OC by macrophage colony-stimulating factor and receptor-activator of nuclear factor kappaB ligand with the treatment of hepcidin1 (200, 400, 800, 1200 nmol/L) and PPS (1, 5, 10, 20, 40 μg/mL). Differentiation and function of OC were accessed using tartrate-resistant acid phosphate staining and bone resorption assay while monitoring ferroportin1 (FPN1) and iron concentration by immunocytochemistry. Gene expression of OC for cathepsin K (CTK), matrix metallopeptidase-9, nuclear factor of activated-T-cells cytoplasmic 1 and FPN1 was examined. Hepcidin1 showed significant enhancement of OC number at 800 nmol/L (p<0.01). PPS impeded hepcidin-facilitated OC at 1, 5 and 10 μg/mL and reduction of resorption pits at 5 and 10 μg/mL (p< 0.01). All OC specific genes were downregulated with PPS, specifically in significant manner with CTK at higher concentrations. However, heparin induced FPN1 internalization and degradation was inhibited at higher concentrations of PPS while restoring iron-releasing capability of OC. We demonstrate for the first time that PPS is a novel-inhibitor of hepcidin-facilitated OC formation/function which might be beneficial for treatment of OA and osteoporosis.
Topics: Animals; Bone Marrow; Bone Resorption; Cell Differentiation; Dogs; Heparin; Hepcidins; Iron; Osteoarthritis; Osteoclasts; Osteoporosis; Pentosan Sulfuric Polyester; RANK Ligand
PubMed: 35299233
DOI: 10.1371/journal.pone.0265596 -
BMC Nephrology Mar 2022Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no...
BACKGROUND
Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no effective therapies for renal fibrosis. The present study aimed to determine whether pentosan polysulphate sodium (PPS), a FDA approved medication for interstitial cystitis, protects diabetic renal fibrosis.
METHODS
Cell viability and apoptosis were evaluated in mouse mesangial cells (SV40-MES13) after incubating with the advanced glycation end products (AGEs), which play important roles in the pathogenesis of DN. Western blot and ELISA were performed to determine the expression of transforming growth factor-beta1 (TGF-β1) and fibronectin (FN), two biomarkers of renal fibrosis, as well as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), two biomarkers of inflammation. The miRNA-mRNA regulatory network involved in the phosphatidylinositol 3-kinase (PI3K)/Ser and Thr Kinase (AKT) signalling was investigated by miRNA deep sequencing and validated by RT-PCR and miRNA transfection.
RESULTS
AGEs significantly inhibited cell proliferation and promoted cell apoptosis, which was associated with the overexpression of TGF-β1, FN, IL-6, and TNFα. PPS almost completely reversed AGEs-induced biomarkers of fibrosis and inflammation, and significantly altered the miRNA expression profile in AGEs-treated cells. Notably, the PI3K/AKT signalling was one of the most significantly enriched pathways targeted by PPS-related differentially expressed miRNAs. PPS significantly up-regulated miR-466a-3p, which was shown to target PIK3CA, and mediated the inhibitory effect of PPS on AGEs-induced activation of PI3K/AKT pathway.
CONCLUSIONS
The treatment of PPS protected against AGEs-induced toxicity in SV40 MES13 cells via miR-466a-3p-mediated inhibition of PI3K/AKT pathway.
Topics: Animals; Biomarkers; Diabetic Nephropathies; Fibrosis; Inflammation; Interleukin-6; Mice; MicroRNAs; Pentosan Sulfuric Polyester; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha
PubMed: 35291969
DOI: 10.1186/s12882-022-02732-8