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Frontiers in Molecular Biosciences 2023The unexpected surge of respiratory syncytial virus (RSV) cases following pandemic phase of COVID-19 has drawn much public attention. Drawing on the latest antiviral...
The unexpected surge of respiratory syncytial virus (RSV) cases following pandemic phase of COVID-19 has drawn much public attention. Drawing on the latest antiviral research, revisiting this heightened annual outbreak of respiratory disease could lead to new treatments. The ability of sulfated polysaccharides to compete for a variety of viruses binding to cell surface heparan sulfate, suggests several drugs that might have therapeutic potential for targeting RSV-glycosaminoglycan interactions. In the current study, the binding affinity and kinetics of two RSV glycoproteins (RSV-G protein and RSV-F protein) to heparin were investigated by surface plasmon resonance. Furthermore, solution competition studies using heparin oligosaccharides of different lengths indicated that the binding of RSV-G protein to heparin is size-dependent, whereas RSV-F protein did not show any chain length preference. The two RSV glycoproteins have slightly different preferences for heparin sulfation patterns, but the -sulfo group in heparin was most critical for the binding of heparin to both RSV-G protein and RSV-F protein. Finally, pentosan polysulfate and mucopolysaccharide polysulfate were evaluated for their inhibition of the RSV-G protein and RSV-F protein-heparin interaction, and both highly negative compounds showed strong inhibition.
PubMed: 37122559
DOI: 10.3389/fmolb.2023.1151174 -
MedRxiv : the Preprint Server For... Apr 2023We describe a novel colopathy associated with pentosan polysulfate (PPS) use and measure the strength of the drug-disease association.
INTRODUCTION
We describe a novel colopathy associated with pentosan polysulfate (PPS) use and measure the strength of the drug-disease association.
METHODS
Two-part investigation. In the cohort study of individuals with a history of prior long-term PPS use, case histories were obtained and gastrointestinal disease course was followed with review of endoscopy records and histopathology specimens. Findings were summarized with descriptive statistics. In the cross-sectional study of individuals with interstitial cystitis, drug exposure and medical histories were obtained for patients seen at a single clinical center. Strength of association between PPS use and diagnoses of inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS) was measured with multivariate logistic regression.
RESULTS
In the cohort study of 13 participants, median PPS exposure was 2.04 kg (0.99-2.54). Eleven (84.6%) developed symptoms suggestive of IBD and/or IBS after initiation of PPS therapy. Of the 10 participants whose endoscopic and histopathologic findings we reviewed, six had abnormal-appearing colonic mucosa on endoscopy and all 10 had abnormal mucosal changes on histology. Clinical and histologic improvement was observed after PPS cessation. In the cross-sectional study of 219 subjects with interstitial cystitis, PPS use was a statistically significant predictor of both the IBD [adjusted odds ratio=3.3 (95% confidence interval, 1.2-8.8, p=0.02)] and the composite IBD+IBS [adjusted odds ratio=3.3 (95% confidence interval, 1.5-7.3, p=0.002)] outcomes.
DISCUSSION
We describe a strong association between PPS use and a clinical diagnosis of IBD and/or IBS. Histopathologic findings suggest a novel drug-associated colopathy, with some subjects requiring colectomy for dysplasia.
PubMed: 37066211
DOI: 10.1101/2023.04.03.23288071 -
Journal of Vitreoretinal Diseases 2023To describe a patient initially diagnosed with age-related macular degeneration (AMD) who was ultimately determined to have progressing pentosan polysulfate sodium...
PURPOSE
To describe a patient initially diagnosed with age-related macular degeneration (AMD) who was ultimately determined to have progressing pentosan polysulfate sodium (PPS)-associated maculopathy leading to secondary cystoid macular edema (CME) 10 years after cessation of PPS.
METHODS
An interventional case report is presented.
RESULTS
A 57-year-old woman diagnosed with AMD presented with unilateral worsening vision and metamorphopsia from CME. A detailed history showed a 3-year course of PPS, which had been discontinued 10 years previously. This led to the diagnosis of PPS-associated maculopathy. After topical NSAID and corticosteroid treatment failed, intravitreal bevacizumab resolved the symptoms. CME developed in the fellow eye 5 months later and also responded to bevacizumab.
CONCLUSIONS
This case emphasizes the importance of a thorough review of past medication and medical histories in patients with pigmentary retinopathy and supports the use of antivascular endothelial growth factor therapy as an option to treat CME secondary to PPS-associated maculopathy.
PubMed: 37008392
DOI: 10.1177/24741264221136907 -
Pharmaceuticals (Basel, Switzerland) Mar 2023Pentosan polysulfate (PPS), a small semi-synthetic highly sulfated heparan sulfate (HS)-like molecule, shares many of the interactive properties of HS. The aim of this... (Review)
Review
Pentosan polysulfate (PPS), a small semi-synthetic highly sulfated heparan sulfate (HS)-like molecule, shares many of the interactive properties of HS. The aim of this review was to outline the potential of PPS as an interventional therapeutic protective agent in physiological processes affecting pathological tissues. PPS is a multifunctional molecule with diverse therapeutic actions against many disease processes. PPS has been used for decades in the treatment of interstitial cystitis and painful bowel disease, it has tissue-protective properties as a protease inhibitor in cartilage, tendon and IVD, and it has been used as a cell-directive component in bioscaffolds in tissue engineering applications. PPS regulates complement activation, coagulation, fibrinolysis and thrombocytopenia, and it promotes the synthesis of hyaluronan. Nerve growth factor production in osteocytes is inhibited by PPS, reducing bone pain in osteoarthritis and rheumatoid arthritis (OA/RA). PPS also removes fatty compounds from lipid-engorged subchondral blood vessels in OA/RA cartilage, reducing joint pain. PPS regulates cytokine and inflammatory mediator production and is also an anti-tumor agent that promotes the proliferation and differentiation of mesenchymal stem cells and the development of progenitor cell lineages that have proven to be useful in strategies designed to effect repair of the degenerate intervertebral disc (IVD) and OA cartilage. PPS stimulates proteoglycan synthesis by chondrocytes in the presence or absence of interleukin (IL)-1, and stimulates hyaluronan production by synoviocytes. PPS is thus a multifunctional tissue-protective molecule of potential therapeutic application for a diverse range of disease processes.
PubMed: 36986536
DOI: 10.3390/ph16030437 -
Asia-Pacific Journal of Ophthalmology...This study will provide a thorough review of systemic (and select intravitreal) medications, along with illicit drugs that are capable of causing various patterns of...
This study will provide a thorough review of systemic (and select intravitreal) medications, along with illicit drugs that are capable of causing various patterns of retinal toxicity. The diagnosis is established by taking a thorough medication and drug history, and then by pattern recognition of the clinical retinal changes and multimodal imaging features. Examples of all of these types of toxicity will be thoroughly reviewed, including agents that cause retinal pigment epithelial disruption (hydroxychloroquine, thioridazine, pentosan polysulfate sodium, dideoxyinosine), retinal vascular occlusion (quinine, oral contraceptives), cystoid macular edema/retinal edema (nicotinic acid, sulfa-containing medications, taxels, glitazones), crystalline deposition (tamoxifen, canthaxanthin, methoxyflurane), uveitis, miscellaneous, and subjective visual symptoms (digoxin, sildenafil). The impact of newer chemotherapeutics and immunotherapeutics (tyrosine kinase inhibitor, mitogen-activated protein kinase kinase, checkpoint, anaplastic lymphoma kinase, extracellular signal-regulated kinase inhibitors, and others), will also be thoroughly reviewed. The mechanism of action will be explored in detail when known. When applicable, preventive measures will be discussed, and treatment will be reviewed. Illicit drugs (cannabinoids, cocaine, heroin, methamphetamine, alkyl nitrite), will also be reviewed in terms of the potential impact on retinal function.
Topics: Humans; Retina; Retinal Diseases; Macular Edema; Uveitis; Illicit Drugs; Retinal Vein Occlusion; Intravitreal Injections; Tomography, Optical Coherence
PubMed: 36971705
DOI: 10.1097/APO.0000000000000605 -
Osteoarthritis and Cartilage Open Jun 2023To evaluate the efficacy and safety of pentosan polysulfate sodium (PPS, Elmiron®) for dyslipidaemia and knee osteoarthritis (OA) related symptoms. (Clinical Trial)
Clinical Trial
OBJECTIVE
To evaluate the efficacy and safety of pentosan polysulfate sodium (PPS, Elmiron®) for dyslipidaemia and knee osteoarthritis (OA) related symptoms.
METHOD
This was a single-arm, open-label, prospective, non-randomised pilot study. People with painful knee OA and a history of primary hypercholesterolemia were included. PPS was taken orally in a dosage of 10 mg/kg once every 4 days for 5 weeks for two cycles. There was 5 weeks of no medication between the cycles. The main outcomes included the change in lipidemia levels, the change in knee OA-related symptoms assessed by pain numerical rating scale (NRS) and Knee Osteoarthritis Outcome Score (KOOS), and knee MRI semi-quantitative score. The changes were analysed using paired t-tests.
RESULTS
38 participants were included, with a mean age of 62.2 years. We found a statistically significant decrease in total cholesterol (from 6.23 ± 0.74 to 5.95 ± 0.77 mmol/L; = 0.01) and low-density lipoprotein (from 4.03 ± 0.61 to 3.82 ± 0.61 mmol/L; = 0.009) from baseline to week 16. Knee pain NRS was significantly reduced at weeks 6, 16 and 26 from 6.39 ± 1.33 to 4.18 ± 1.99, 3.63 ± 2.28 and 4.38 ± 2.55, respectively ( < 0.001). However, there was no significant difference in terms of the primary outcome of triglyceride levels before and after treatment. The most common AEs were positive faecal occult blood tests, followed by headache and diarrhoea.
CONCLUSION
The findings suggest that PPS has promising effects on improving dyslipidaemia and symptomatic pain relief in people with knee OA.
PubMed: 36879559
DOI: 10.1016/j.ocarto.2023.100343 -
Frontiers in Immunology 2023There is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The...
INTRODUCTION
There is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The semi-synthetic polysaccharide, Pentosan polysulfate sodium (PPS), an inhibitor of NF-kB activation, was investigated for its systemic and local anti-inflammatory effects in a mouse model of influenza virus A/PR8/1934 (PR8 strain) mediated infection.
METHODS
Immunocompetent C57BL/6J mice were infected intranasally with a sublethal dose of PR8 and treated subcutaneously with 3 or 6 mg/kg PPS or vehicle. Disease was monitored and tissues were collected at the acute (8 days post-infection; dpi) or post-acute (21 dpi) phase of disease to assess the effect of PPS on PR8-induced pathology.
RESULTS
In the acute phase of PR8 infection, PPS treatment was associated with a reduction in weight loss and improvement in oxygen saturation when compared to vehicle-treated mice. Associated with these clinical improvements, PPS treatment showed a significant retention in the numbers of protective SiglecF+ resident alveolar macrophages, despite uneventful changes in pulmonary leukocyte infiltrates assessed by flow cytometry. PPS treatment in PR8- infected mice showed significant reductions systemically but not locally of the inflammatory molecules, IL-6, IFN-g, TNF-a, IL-12p70 and CCL2. In the post-acute phase of infection, PPS demonstrated a reduction in the pulmonary fibrotic biomarkers, sICAM-1 and complement factor C5b9.
DISCUSSION
The systemic and local anti-inflammatory actions of PPS may regulate acute and post-acute pulmonary inflammation and tissue remodeling mediated by PR8 infection, which warrants further investigation.
Topics: Mice; Animals; Pentosan Sulfuric Polyester; Alphainfluenzavirus; Mice, Inbred C57BL; Pneumonia; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 36845136
DOI: 10.3389/fimmu.2023.1030879 -
JAMA Ophthalmology Mar 2023Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan...
IMPORTANCE
Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan polysulfate (PPS).
OBJECTIVE
To evaluate the 2-year evolution of maculopathy associated with PPS use after drug cessation.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study prospectively evaluated the natural history of patients with maculopathy associated with PPS use. Participants seen at the Emory Eye Center were enrolled between December 1, 2018, and December 1, 2019, and data were collected through November 30, 2021.
MAIN OUTCOMES AND MEASURES
The main outcomes were changes in visual function and structure. Visual function was assessed annually with refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), mesopic microperimetry, and dark adaptometry. Structural outcomes included presence and extent of complete retinal pigment epithelium and outer retinal atrophy (cRORA), macular central subfield thickness (CST), and subfoveal choroidal thickness (SFCT).
RESULTS
Of the 12 participants (23 eyes), 11 (91.7%) were female (1 [8.3%] male), 11 (91.7%) were White (1 [8.3%] Black), and median (IQR) age at enrollment was 58 (47-64) years. Median (IQR) time from PPS discontinuation to initial visit was 0.6 (0.4-1.9) years. Median baseline ETDRS BCVA letter score was 83 (Snellen equivalent, 20/20) (IQR, 80-86.5 [20/25-20/20]), with a median 2-year change of -3 (IQR, -6 to -0.5; P = .08). Four eyes (17.4%) had a letter score decline of 15 or more, all associated with progressive cRORA. Median change in microperimetry average threshold was -3.5 dB (IQR, -4.1 to -2.5 dB; P = .001), and percent reduced threshold was 32.5% (IQR, 20.3%-52.8%; P = .004). Nine eyes (39%) had macular cRORA at baseline, with a median linearized growth rate of 0.23 mm/y (IQR, 0.22-0.25 mm/y). Two eyes (8.7%) without atrophy at baseline developed new-onset cRORA. Median baseline CST was 284 μm (IQR, 253-291 μm), with a median 2-year change of -5 μm (IQR, -13 to 0.5 μm; P = .0497). Median 2-year change in SFCT was 1 μm (IQR, -18 to 16 μm; P = .91).
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest that functional and structural deficits continue to progress in PPS-associated maculopathy even after drug cessation. Additional study is needed to determine whether these findings can be generalized to other patients with PPS-associated maculopathy and whether longer follow-up could determine subsequent disease course.
Topics: Humans; Male; Female; Middle Aged; Pentosan Sulfuric Polyester; Cohort Studies; Retrospective Studies; Tomography, Optical Coherence; Macular Degeneration; Diabetic Retinopathy; Retinal Degeneration; Atrophy
PubMed: 36729449
DOI: 10.1001/jamaophthalmol.2022.6093 -
American Journal of Ophthalmology Case... Mar 2023To report the development of type 3 macular neovascularization (MNV) in a patient with pentosan polysulfate sodium (PPS) maculopathy one year after PPS cessation.
PURPOSE
To report the development of type 3 macular neovascularization (MNV) in a patient with pentosan polysulfate sodium (PPS) maculopathy one year after PPS cessation.
OBSERVATION
A 72-year-old woman presented for decreased visual acuity in the left eye. Medical history was significant for interstitial cystitis treated with PPS for 11 years (cumulative dose of 1205 g) and PPS maculopathy. PPS was discontinued 1 year prior to presentation. Blue-light fundus autofluorescence and spectral domain optical coherence tomography confirmed the diagnosis of bilateral PPS maculopathy. OCT-angiography illustrated the development of type 3 MNV with intraretinal fluid in the left eye. Intravitreal injections of aflibercept were initiated with a good visual and anatomical response.
CONCLUSION AND IMPORTANCE
This report describes the development of type 3 MNV in a patient with PPS macular toxicity one year after PPS cessation. This complication emphasizes the need for regular retinal surveillance even after discontinuation of the inciting drug.
PubMed: 36561881
DOI: 10.1016/j.ajoc.2022.101771 -
Viruses Dec 2022The now prevalent Omicron variant and its subvariants/sub-lineages have led to a significant increase in COVID-19 cases and raised serious concerns about increased risk...
The now prevalent Omicron variant and its subvariants/sub-lineages have led to a significant increase in COVID-19 cases and raised serious concerns about increased risk of infectivity, immune evasion, and reinfection. Heparan sulfate (HS), located on the surface of host cells, plays an important role as a co-receptor for virus-host cell interaction. The ability of heparin and HS to compete for binding of the SARS-CoV-2 spike (S) protein to cell surface HS illustrates the therapeutic potential of agents targeting protein-glycan interactions. In the current study, phylogenetic tree of variants and mutations in S protein receptor-binding domain (RBD) of Omicron BA.2.12.1, BA.4 and BA.5 were described. The binding affinity of Omicron S protein RBD to heparin was further investigated by surface plasmon resonance (SPR). Solution competition studies on the inhibitory activity of heparin oligosaccharides and desulfated heparins at different sites on S protein RBD-heparin interactions revealed that different sub-lineages tend to bind heparin with different chain lengths and sulfation patterns. Furthermore, blind docking experiments showed the contribution of basic amino acid residues in RBD and sulfo groups and carboxyl groups on heparin to the interaction. Finally, pentosan polysulfate and mucopolysaccharide polysulfate were evaluated for inhibition on the interaction of heparin and S protein RBD of Omicron BA.2.12.1, BA.4/BA.5, and both showed much stronger inhibition than heparin.
Topics: Humans; Spike Glycoprotein, Coronavirus; Phylogeny; COVID-19; SARS-CoV-2; Heparin; Heparitin Sulfate; Cell Communication; Protein Binding
PubMed: 36560700
DOI: 10.3390/v14122696