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BMC Musculoskeletal Disorders Mar 2021Alphaviruses, such as Ross River (RRV) and chikungunya virus (CHIKV), cause significant global morbidity, with outbreaks of crippling joint inflammation and pain,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alphaviruses, 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.
METHODS
This 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.
RESULTS
PPS 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.
CONCLUSIONS
Overall, 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 REGISTRATION
This trial is registered at the Australian New Zealand Clinical Trials Registry # ACTRN12617000893303 .
Topics: Arthralgia; Australia; Double-Blind Method; Hand Strength; Humans; Pentosan Sulfuric Polyester; Quality of Life; Ross River virus; Treatment Outcome
PubMed: 33711991
DOI: 10.1186/s12891-021-04123-w -
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 -
Ophthalmology. Retina Mar 2022Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings.
PURPOSE
Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings.
DESIGN
Multi-institutional retrospective study.
PARTICIPANTS
Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4, 2020.
METHODS
Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics.
MAIN OUTCOME MEASURES
Pentosan polysulfate exposure characteristics and fundus imaging features.
RESULTS
There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2-18.9), with a median cumulative exposure of 1.5 kg (0.9-2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients.
CONCLUSIONS
Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.
Topics: Anticoagulants; Humans; Macula Lutea; Macular Degeneration; Pentosan Sulfuric Polyester; Retinal Diseases; Retrospective Studies
PubMed: 34298229
DOI: 10.1016/j.oret.2021.07.004 -
Biochemical Pharmacology May 2020Hepcidin peptide is crucial in the regulation of systemic iron availability controlling its uptake from the diet and its release from the body storage tissues. Hepcidin...
Hepcidin peptide is crucial in the regulation of systemic iron availability controlling its uptake from the diet and its release from the body storage tissues. Hepcidin dysregulation causes different human disorders ranging from iron overload (e.g. hemochromatosis) to iron deficiency (e.g. anemia). Hepcidin excess is common in the Anemia of Chronic Diseases or Anemia of Inflammation and in the genetic form of anemia named IRIDA; the pharmacological downregulation of hepcidin in these disorders could improve the anemia. Commercial heparins were shown to be strong inhibitors of hepcidin expression, by interfering with BMP6/SMAD pathway. The non-anti-coagulant heparins, modified to abolish the anti-thrombin binding site, were equally potent and could be used to improve iron status. To perform its anti-hepcidin activity heparin needs 2O- and 6O-sulfation and an average molecular weight (MW) up to 4000-8000 Dalton, depending on the sulfation level. The pentosane polysulfate (PPS), which shares with heparin a high degree of sulfation, is a compound with low anti-coagulant activity that is already in use for pharmaceutical treatment. In the present work we analyzed the anti-hepcidin activity of PPS in vitro and in vivo. We found that it acts as a strong inhibitor of hepcidin expression in HepG2 cells with an effect already visible after 2-3 h of treatment. It also suppressed hepcidin in mice in a dose dependent manner after 3 h and with a significant redistribution of systemic iron without evident side effects. PPS is also able to abolish the LPS dependent hepcidin upregulation similarly to that showed for heparin derivatives. These results suggest PPS as an interesting compound to control hepcidin in vivo.
Topics: Administration, Oral; Animals; Gene Expression; Hep G2 Cells; Hepcidins; Humans; Injections, Subcutaneous; Liver; Male; Mice; Mice, Inbred C57BL; Pentosan Sulfuric Polyester
PubMed: 32088260
DOI: 10.1016/j.bcp.2020.113867 -
American Journal of Ophthalmology Jul 2021To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of...
PURPOSE
To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of choroidal vascularity index (CVI) analysis.
DESIGN
Prospective cohort study Methods: Of 741 patients prescribed PPS within a large university database, 100 (13.4%) with any consumption agreed to participate in a prospective screening investigation. Multimodal retinal imaging including near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) was performed in all patients. Characteristic findings of affected patients were identified, and affected and unaffected cohorts were compared. CVI, defined as stromal choroidal area (SCA) divided by the total choroidal area, was analyzed.
RESULTS
The prevalence of PPS maculopathy was 16%. NIR illustrated punctate hyperreflective lesions with early presentation. FAF illustrated a speckled macular network of hypo- and hyperautofluorescence colocalized with multifocal hyperreflective retinal pigment epithelial lesions on SD-OCT. Advanced cases demonstrated varying degrees of atrophy. The affected cohort exhibited significantly greater mean PPS therapy duration, mean daily dosage, and mean cumulative dosage (19.5±5.5 years, 433.9±137.6 mg, 3,103.1±1,402.2 g) compared with the unaffected cohort (7.1±6.6 years, 291.6±177.6 mg, 768.4±754.8 g). SCA was significantly lower and CVI was significantly greater in the affected vs the unaffected group.
CONCLUSIONS
This prospective cohort study identified a prevalence of PPS maculopathy of 15%-20% among PPS users who agreed to participate. A spectrum of findings may be observed with multimodal retinal imaging. Significant choroidal abnormalities associated with this characteristic maculopathy may provide surrogate markers of macular toxicity.
Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Body Mass Index; Choroid; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Multimodal Imaging; Optical Imaging; Pentosan Sulfuric Polyester; Perfusion Index; Prevalence; Prospective Studies; Retina; Retinal Diseases; Retinal Pigment Epithelium; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 33651989
DOI: 10.1016/j.ajo.2021.02.025 -
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 -
Ophthalmology Oct 2019
Topics: Aged; Cystitis, Interstitial; Female; Humans; Macular Degeneration; Male; Middle Aged; Pentosan Sulfuric Polyester; Retinal Pigment Epithelium
PubMed: 31004677
DOI: 10.1016/j.ophtha.2019.04.024 -
Seminars in Arthritis and Rheumatism Feb 1999Structure-modifying osteoarthritis (OA) drugs (SMOADs) may be defined as agents that reverse, retard, or stabilize the underlying pathology of OA, thereby providing... (Review)
Review
OBJECTIVES
Structure-modifying osteoarthritis (OA) drugs (SMOADs) may be defined as agents that reverse, retard, or stabilize the underlying pathology of OA, thereby providing symptomatic relief in the long-term. The objective of this review was to evaluate the literature on sodium pentosan polysulfate (NaPPS) and calcium pentosan polysulfate (CaPPS), with respect to the pathobiology of OA to ascertain whether these agents should be classified as SMOADs.
METHODS
Published studies on NaPPS and CaPPS were selected on the basis of their relevance to the known pathobiology of OA, which also was reviewed.
RESULTS
Both NaPPS and CaPPS exhibit a wide range of pharmacological activities. Of significance was the ability of these agents to support chondrocyte anabolic activities and attenuate catabolic events responsible for loss of components of the cartilage extracellular matrix in OA joints. Although some of the anti-catabolic activities may be mediated through direct enzyme inhibition, NaPPS and CaPPS also have been shown to enter chondrocytes and bind to promoter proteins and alter gene expression of matrix metalloproteinases and possibly other mediators. In rat models of arthritis, NaPPS and CaPPS reduced joint swelling and inflammatory mediator levels in pouch fluids. Moreover, synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS and CaPPS or after intraarticular injection of NaPPS into arthritic joints. In rabbit, canine, and ovine models of OA, NaPPS and CaPPS preserved cartilage integrity, proteoglycan synthesis, and reduced matrix metalloproteinase activity. NaPPS and CaPPS stimulated the release of tissue plasminogen activator (t-PA), superoxide dismutase, and lipases from vascular endothelium while concomitantly decreasing plasma levels of the endogenous plasminogen activator inhibitor PAI-1. The net thrombolytic and lipolytic effects exhibited by NaPPS and CaPPS may serve to improve blood flow through subchondral capillaries of OA joints and improve bone cell nutrition. In geriatric OA dogs, NaPPS and CaPPS reduced symptoms, as well as normalized their thrombolytic status, threshold for platelet activation, and plasma triglyceride levels. These hematologic parameters were shown to be abnormal in OA animals before drug treatment. Similar outcomes were observed in OA patients when CaPPS or NaPPS were given orally or parenterally in both open and double-blind trials.
CONCLUSIONS
The data presented in this review support the contention that NaPPS and CaPPS should be classified as SMOADs. However, additional long-term clinical studies employing methods of assessing joint structural changes will be needed to confirm this view.
Topics: Animals; Cartilage, Articular; Cells, Cultured; Clinical Trials as Topic; DNA; Disease Models, Animal; Dogs; Enzyme Inhibitors; Humans; Mice; Osteoarthritis; Pentosan Sulfuric Polyester; Rabbits; Rats; Synovitis; Treatment Outcome
PubMed: 10073500
DOI: 10.1016/s0049-0172(99)80021-3 -
Journal of Virology Aug 2019Human T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical...
Human T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The underlying mechanism for the pathogenesis of HAM/TSP remains unclear. According to a recent clinical trial, a humanized antibody that targets CCR4 cells ameliorates inflammation by reducing the number of infected cells in the central nervous system; this result suggests that the transmigration of HTLV-1-infected cells plays a crucial role in HAM/TSP. Partly due to the blood-brain barrier, current treatments for HAM/TSP are mostly palliative. Pentosan polysulfate (PPS), a semisynthetic glycosaminoglycan, has recently been used to treat HAM/TSP and was found to alleviate the symptoms. In this study, we investigated the effect of PPS on HTLV-1-infected cells and provide evidence for its efficacy in HAM/TSP. PPS was cytotoxic to certain HTLV-1-infected cells and significantly suppressed HTLV-1 virion production. PPS also efficiently inhibited HTLV-1 cell-cell transmission in T cells. In addition, PPS blocked HTLV-1 infection of primary endothelial cells (human umbilical vascular endothelial cells) and suppressed the subsequent induction of proinflammatory cytokine expression. Furthermore, PPS was found to inhibit the adhesion and transmigration of HTLV-1-infected cells. We also confirmed the anti-HTLV-1 effect of PPS using two mouse models. PPS blocked HTLV-1 infection in a mouse model with peripheral blood mononuclear cell (PBMC)-humanized NOD-scid IL2Rgamma (huPBMC NSG) mice. PPS was also found to suppress the development of dermatitis and lung damage in HTLV-1 bZIP factor (HBZ)-transgenic (HBZ-Tg) mice, an HTLV-1 transgenic mouse model in which the mice develop systemic inflammation. HTLV-1 is the first human retrovirus to have been identified and is endemic in certain areas worldwide. HTLV-1 infection leads to the development of an inflammatory disease called HAM/TSP, a myelopathy characterized by slowly progressive spastic paraparesis. There have been no effective therapeutics available for HAM/TSP, but recently, a semisynthetic glycosaminoglycan, named pentosan polysulfate (PPS), has been found to alleviate the symptoms of HAM/TSP. Here we conducted a comprehensive study on the effect of PPS both and PPS demonstrated anti-HTLV-1 potential in infected cell lines, as shown by its suppressive effects on HTLV-1 replication and transmission and on the transmigration of infected T cells. Moreover, results obtained from two HTLV-1 mouse models demonstrate that PPS inhibits HTLV-1 infection and inflammation development Our work offers insights into the treatment of HAM/TSP by PPS and also suggests its possible use for treating other HTLV-1-induced inflammatory diseases.
Topics: Animals; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Disease Models, Animal; Endothelial Cells; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Leukocytes, Mononuclear; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Pentosan Sulfuric Polyester; T-Lymphocytes; Virus Replication
PubMed: 31167921
DOI: 10.1128/JVI.00413-19 -
Ophthalmology Apr 2020To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy.
PURPOSE
To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy.
DESIGN
Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA).
PARTICIPANTS
Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database.
METHODS
Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure.
MAIN OUTCOME MEASURES
The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy.
RESULTS
The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus.
CONCLUSIONS
In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy.
Topics: Adult; Aged; Anticoagulants; Cystitis, Interstitial; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insurance, Health; Macula Lutea; Male; Middle Aged; Pentosan Sulfuric Polyester; Proportional Hazards Models; Retinal Diseases; Retrospective Studies; Risk Factors; United States
PubMed: 31899034
DOI: 10.1016/j.ophtha.2019.10.036