-
Angewandte Chemie (International Ed. in... Jul 2021Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we...
Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with an IC of 67 μg mL (approx. 1.6 μm). This synthetic polysulfate exhibits more than 60-fold higher virus inhibitory activity than heparin (IC : 4084 μg mL ), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind more strongly to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interactions, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2.
Topics: A549 Cells; Animals; Antiviral Agents; Chlorocebus aethiops; Heparin; Humans; Molecular Dynamics Simulation; Pentosan Sulfuric Polyester; Polymers; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Static Electricity; Vero Cells; Virus Internalization
PubMed: 33860605
DOI: 10.1002/anie.202102717 -
International Urogynecology Journal Nov 2021Recent publications describe pigmentary changes in the retina associated with the use of pentosan polysulfate sodium, the only FDA-approved oral agent for relief of...
INTRODUCTION AND HYPOTHESIS
Recent publications describe pigmentary changes in the retina associated with the use of pentosan polysulfate sodium, the only FDA-approved oral agent for relief of bladder pain or discomfort associated with interstitial cystitis.
METHODS
To evaluate this association, we reviewed data from the FDA Adverse Event Reporting System and published case reports and observational studies.
RESULTS
The totality of clinical and epidemiology evidence does not resolve the question of causation between pentosan use and retinal pigmentary changes; however, several elements support a potential association.
CONCLUSION
Here, we provide our perspective on the available evidence the agency weighed when retinal pigmentary changes were added to pentosan labeling. It is important for urogynecologists prescribing pentosan to be aware of this potential association and be vigilant about assessing eye health in pentosan users.
Topics: Cystitis, Interstitial; Humans; Pelvic Pain; Pentosan Sulfuric Polyester; United States; United States Food and Drug Administration
PubMed: 34505923
DOI: 10.1007/s00192-021-04970-0 -
JAMA Ophthalmology Nov 2019A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for...
IMPORTANCE
A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.
OBJECTIVE
To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy.
DESIGN, SETTING, AND PARTICIPANTS
In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019.
MAIN OUTCOMES AND MEASURES
Drug exposure, visual acuity, and retinal imaging characteristics.
RESULTS
Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (-0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes [53%]) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes [23%]; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities.
CONCLUSIONS AND RELEVANCE
These findings suggest that PPS-associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium-photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.
PubMed: 31486843
DOI: 10.1001/jamaophthalmol.2019.3392 -
BMJ Open May 2024Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain...
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.
Topics: Humans; Osteoarthritis, Knee; Pentosan Sulfuric Polyester; Dyslipidemias; Quality of Life; Male; Treatment Outcome; Female; Middle Aged; Clinical Trials, Phase II as Topic; Australia; Pain Measurement; Adult
PubMed: 38777590
DOI: 10.1136/bmjopen-2023-083046 -
International Urogynecology Journal May 2021The objective was to compare the clinical efficacy and safety of pharmacological interventions for interstitial cystitis and bladder pain syndrome (IC/BPS) with direct... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION AND HYPOTHESIS
The objective was to compare the clinical efficacy and safety of pharmacological interventions for interstitial cystitis and bladder pain syndrome (IC/BPS) with direct and indirect evidence from randomized trials.
METHODS
We searched PubMed, the Cochrane library, and EMBASE for randomized controlled trials (RCTs) that assessed the pharmacological therapies for IC/BPS. Primary efficacy outcomes included ICSI (O'Leary Sant Interstitial Cystitis Symptom Index), ICPI (O'Leary Sant Interstitial Cystitis Problem Index), 24-h micturition frequency, visual analog scale (VAS), and Likert score for pain. Safety outcomes are total adverse events (AEs, intravesical instillation, and others), gastrointestinal symptoms, headache, pain, and urinary symptoms. A systematic review and Bayesian network meta-analysis were performed.
RESULTS
A total of 23 RCTs with 1,871 participants were identified. The ICSI was significantly reduced in the amitriptyline group (MD = -4.9, 95% CI: -9.0 to -0.76), the cyclosporine A group (MD = -7.9, 95% CI: -13.0 to -3.0) and the certolizumab pegol group (MD = -3.6, 95% CI:-6.5 to -0.63) compared with placebo group. Moreover, for ICPI, cyclosporine A showed superior benefit compared to placebo (MD = -7.6, 95% CI: -13 to -2.3). VAS score improved significantly in cyclosporine A group than pentosan polysulfate sodium (MD = 3.09, 95% CI: 0.13 to 6.07). None of the agents revealed a significant alleviation of 24-h micturition frequency. In terms of safety outcomes, the incidence rate on urinary symptoms for botulinum toxin A was the only variate higher than chondroitin sulfate (MD = -2.02, 95% CI: -4.99 to 0.66) and placebo (MD = -1.60, 95% CI:-3.83 to 0.17). No significant difference was found among the other treatments.
CONCLUSIONS
Cyclosporine A might be superior to other pharmacological treatments in efficacy. Amitriptyline and certolizumab pegol were capable of lowering the ICSI as well.
Topics: Administration, Intravesical; Botulinum Toxins, Type A; Cystitis, Interstitial; Humans; Network Meta-Analysis; Pain Measurement; Treatment Outcome
PubMed: 33638677
DOI: 10.1007/s00192-020-04659-w -
PloS One 2021Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis....
Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis. Interestingly, clinical presentation of CHIKV arthritides have many overlapping features with rheumatoid arthritis including cellular and cytokine pathways that lead to disease development and progression. Currently, there are no specific treatments or vaccines available to treat CHIKV infections therefore advocating the need for the development of novel therapeutic strategies to treat CHIKV rheumatic disease. Herein, we provide an in-depth analysis of an efficacious new treatment for CHIKV arthritis with a semi-synthetic sulphated polysaccharide, Pentosan Polysulfate Sodium (PPS). Mice treated with PPS showed significant functional improvement as measured by grip strength and a reduction in hind limb foot swelling. Histological analysis of the affected joint showed local inflammation was reduced as seen by a decreased number of infiltrating immune cells. Additionally, joint cartilage was protected as demonstrated by increased proteoglycan staining. Using a multiplex-immunoassay system, we also showed that at peak disease, PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5) which may be associated with the reduction in cellular infiltrates. Further characterisation of the local effect of PPS in its action to reduce joint and muscle inflammation was performed using NanoString™ technology. Results showed that PPS altered the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation. Overall, this study shows that PPS is a promising treatment for alphaviral arthritis by reducing inflammation and protecting joint integrity.
Topics: Animals; Anticoagulants; Arthritis, Rheumatoid; Chikungunya Fever; Chikungunya virus; Cytokines; Disease Models, Animal; Female; Inflammation; Intercellular Signaling Peptides and Proteins; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Pentosan Sulfuric Polyester
PubMed: 34492036
DOI: 10.1371/journal.pone.0255125 -
Retinal Cases & Brief Reports Jun 2023Pentosan polysulfate (PPS), a drug used for interstitial cystitis, has recently been detected to cause maculopathy in a dose-dependent manner. Outer retinal atrophy is...
PURPOSE
Pentosan polysulfate (PPS), a drug used for interstitial cystitis, has recently been detected to cause maculopathy in a dose-dependent manner. Outer retinal atrophy is the hallmark of this condition.
METHODS
History, examination and multimodal imaging were used to guide diagnosis and management.
RESULTS
We report a case of PPS-related maculopathy in a 77-year-old lady, who presented with florid retinal atrophy at the posterior pole in both eyes, and a concurrent macular hole in the left eye. She had been diagnosed with interstitial cystitis several years prior for which she was prescribed PPS (Elmiron). She had noticed a drop in vision 5 years following initiation of PPS and self-discontinued the drug after 24 years of use. A diagnosis of PPS-related maculopathy with a macular hole was made. She was counselled regarding the prognosis and was advised to avoid PPS. Surgery for macular hole was deferred in view of the severe retinal atrophy.
CONCLUSIONS
PPS-related maculopathy can lead to severe retinal atrophy and a subsequent degenerative macular hole. A high index of suspicion is required for early detection and cessation of drug to prevent this irreversible vision loss.
PubMed: 37321232
DOI: 10.1097/ICB.0000000000001444 -
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 Aug 2020Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).
IMPORTANCE
Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).
OBJECTIVE
To evaluate the disease course in PPS-associated maculopathy after drug cessation.
DESIGN, SETTING, AND PARTICIPANTS
In this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019.
MAIN OUTCOMES AND MEASURES
Change in visual acuity and retinal imaging characteristics over time.
RESULTS
Of the 11 included patients, all were female, and the median (interquartile range [IQR]) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year.
CONCLUSIONS AND RELEVANCE
These retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.
Topics: Adult; Anticoagulants; Female; Follow-Up Studies; Humans; Middle Aged; Optical Imaging; Pentosan Sulfuric Polyester; Retinal Diseases; Retinal Pigment Epithelium; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity; Withholding Treatment
PubMed: 32644147
DOI: 10.1001/jamaophthalmol.2020.2349 -
Retinal Cases & Brief Reports Nov 2022To describe a potential case of pentosan polysulfate maculopathy that seemed to manifest nearly 3 years after drug cessation.
PURPOSE
To describe a potential case of pentosan polysulfate maculopathy that seemed to manifest nearly 3 years after drug cessation.
METHODS
Complete ophthalmic examination, including multimodal fundus imaging, electroretinography, automated perimetry, and molecular testing, was performed.
RESULTS
A 44-year-old woman with a 435 g cumulative exposure to pentosan polysulfate sodium presented 38 months after drug cessation with 6 months of worsening metamorphopsia and prolonged dark adaptation. Fundus examination and multimodal fundus imaging demonstrated characteristic features of pentosan polysulfate maculopathy, and molecular testing was unremarkable. By contrast, color fundus photographs of the same patient acquired at an outside facility 25 months before did not display features consistent with pentosan polysulfate sodium maculopathy.
CONCLUSION
This case suggests that new-onset clinically detectable pentosan polysulfate maculopathy may develop years after drug cessation. If corroborated, this finding has important ramifications for pentosan polysulfate sodium dosing and surveillance guidelines.
Topics: Female; Humans; Adult; Pentosan Sulfuric Polyester; Macular Degeneration; Retinal Diseases; Electroretinography; Vision Disorders
PubMed: 33229920
DOI: 10.1097/ICB.0000000000001090