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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 -
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 -
Central European Journal of Urology 2021Bladder pain syndrome/interstitial cystitis (BPS/IC) is a condition that is characterized by urgency, frequency and/or pelvic pain. The disease occurs mainly in women....
Safety and efficacy of pentosan polysulfate in patients with bladder pain syndrome/interstitial cystitis: a multicenter, double-blind, placebo-controlled, randomized study.
INTRODUCTION
Bladder pain syndrome/interstitial cystitis (BPS/IC) is a condition that is characterized by urgency, frequency and/or pelvic pain. The disease occurs mainly in women. BPS/IC can be severe enough to have a significant impact on patients' quality of life, but it can also be associated with moderate symptoms that are equally debilitating.The aim of this article was to evaluate the possibility of the use of pentosan polysulfate sodium in patients in the complex treatment of BPS/IC.
MATERIAL AND METHODS
A multicenter, double-blind, placebo-controlled, randomized study was conducted in parallel groups in 7 Russian medical centers.
RESULTS
Efficacy and safety have been established as the main criteria. A total of 93 patients were screened. Statistical analysis was performed. It has been shown that pentosan therapy is more effective than in the placebo. Average change in the number of points on the scale O'Leary-Santa Interstitial Cystitis Symptom Index compared to baseline data in the pentosan group 4.93 ±3, 03, in the placebo group 1.66 ±3.19 (p = 0.014), and the adverse events and safety of pentosan are comparable to the placebo group.
CONCLUSIONS
Oral glycosaminoglycan (pentosan polusulfate sodium) is an effective and safe drug and should be included in the complex treatment of patients with bladder pain syndrome/interstitial cystitis.
PubMed: 34336239
DOI: 10.5173/ceju.2021.0340.R1 -
JFMS Open Reports 2021A 14-year-old male castrated Cornish Rex cat was referred for lethargy progressing rapidly to collapse in the hours following a subcutaneous injection of a product...
CASE SUMMARY
A 14-year-old male castrated Cornish Rex cat was referred for lethargy progressing rapidly to collapse in the hours following a subcutaneous injection of a product containing 100 mg/ml pentosan polysulfate sodium and 168 mg/ml glucosamine. Physical examination revealed the cat to be in hypotensive shock with swelling and interstitial oedema around the cranial thorax and caudal cervical regions without cutaneous haemorrhage. Initial diagnostics revealed a severe anaemia (packed cell volume 11%) which later deteriorated further, necessitating a blood transfusion and aggressive fluid therapy. Post-transfusion, the patient remained dyspnoeic and subsequent diagnostics found evidence of pre-existing cardiomyopathy and congestive heart failure. The cat was euthanased 24 h following presentation due to increasing dyspnoea. Post-mortem findings were of severe subcutaneous and intermuscular haemorrhage over the neck and thorax, among other changes. There were no detectable levels of coumarin anticoagulants in the liver.
RELEVANCE AND NOVEL INFORMATION
This is the first reported case of acute subcutaneous and intermuscular haemorrhage of this severity suspected to be related to the off-label use of an injectable product containing pentosan polysulfate in a cat. Given the popularity of its use for feline arthritis, there is a need for large-scale clinical trials to evaluate the safety and efficacy of products containing pentosan polysulfate for cats, and any side effects to be reported.
PubMed: 34777848
DOI: 10.1177/20551169211058650 -
Research and Reports in Urology 2023Hemorrhagic cystitis (HC) can be one of the most challenging clinical scenarios for urologists to manage. It most commonly occurs as a toxicity of pelvic radiation... (Review)
Review
Hemorrhagic cystitis (HC) can be one of the most challenging clinical scenarios for urologists to manage. It most commonly occurs as a toxicity of pelvic radiation therapy or in patients treated with the oxazaphosphorine class of chemotherapy. Successful management of HC necessitates a stepwise approach with a thorough understanding of the various treatment options. Once ensuring hemodynamic stability, conservative management includes establishing bladder drainage, manual clot evacuation, and continuous bladder irrigation through a large-bore urethral catheter. If gross hematuria persists, operative cystoscopy with bladder clot evacuation is often required. There are multiple intravesical options for treating HC, including alum, aminocaproic acid, prostaglandins, silver nitrate, and formalin. Formalin is an intravesical option that has caustic effects on the bladder mucosa and is most often reserved as a last-line intravesical treatment. Non-intravesical management tools include hyperbaric oxygen therapy and oral pentosan polysulfate. If needed, nephrostomy tube placement or superselective angioembolization of the anterior division of the internal iliac artery can be performed. Finally, cystectomy with urinary diversion is a definitive, albeit invasive, treatment option for refractory HC. While there is no standardized algorithm, treatment modalities typically progress from less to more invasive. Clinical judgement and shared decision-making with the patient are required when choosing therapies for managing HC, as success rates are variable and some treatments may have significant or irreversible effects.
PubMed: 37404838
DOI: 10.2147/RRU.S320684 -
Asia-Pacific Journal of Ophthalmology...Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder... (Review)
Review
Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder pain syndrome. A symptomatic pigmentary maculopathy associated with PPS was reported in 2018. Since then, recognition of this unique drug toxicity has increased rapidly. This potentially sight-threatening side effect prompted the FDA in June 2020 to update the label for PPS to warn about "retinal pigmentary changes." A challenging feature of pentosan maculopathy is its ability to mimic many other retinal conditions, including inherited retinal dystrophies such as pattern dystrophy, mitochondrially inherited diabetes and deafness, and Stargardt disease, and age-related macular degeneration. In this review, we discuss the history of PPS maculopathy and its implications for thousands of at-risk interstitial cystitis patients. We use published literature and an illustrative case from our institution to highlight the importance of diagnosing PPS maculopathy. We also compare PPS maculopathy to age-related macular degeneration, explain why differentiating between the 2 is clinically important, and highlight avenues for further research. Finally, we highlight the paucity of data on patients of color and why this lack of understanding may impact patient care.
Topics: Anticoagulants; Cystitis, Interstitial; Female; Humans; Macular Degeneration; Male; Pentosan Sulfuric Polyester; Retinal Dystrophies
PubMed: 35533330
DOI: 10.1097/APO.0000000000000504 -
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 -
Pharmaceuticals (Basel, Switzerland) Sep 2022This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal... (Review)
Review
This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by pathogenic organisms obviating the need for dietary antibiotic supplementation, a practice which has been used to maintain animal productivity but which has led to the emergence of antibiotic resistant bacteria that are passed up the food chain to humans. Seaweed xylan-based animal foodstuffs have been developed to eliminate ruminant green-house gas emissions by gut methanogens in ruminant animals, contributing to atmospheric pollution. Biotransformation of pentosan polysulfate by the gut microbiome converts this semi-synthetic sulfated disease-modifying anti-osteoarthritic heparinoid drug to a prebiotic metabolite that promotes gut health, further extending the therapeutic profile and utility of this therapeutic molecule. Xylans are prominent dietary cereal components of the human diet which travel through the gastrointestinal tract as non-digested dietary fibre since the human genome does not contain xylanolytic enzymes. The gut microbiota however digest xylans as a food source. Xylo-oligosaccharides generated in this digestive process have prebiotic health-promoting properties. Engineered commensal probiotic bacteria also have been developed which have been engineered to produce growth factors and other bioactive factors. A xylan protein induction system controls the secretion of these compounds by the commensal bacteria which can promote gut health or, if these prebiotic compounds are transported by the vagal nervous system, may also regulate the health of linked organ systems via the gut-brain, gut-lung and gut-stomach axes. Dietary xylans are thus emerging therapeutic compounds warranting further study in novel disease prevention protocols.
PubMed: 36145372
DOI: 10.3390/ph15091151 -
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 -
Clinical Ophthalmology (Auckland, N.Z.) 2021To investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).
AIM
To investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).
METHODS
Patients exposed to PPS and seen in the ophthalmology clinic at Northwestern University during 1/1/2002 to 1/1/2019 were identified from electronic health records (EHR) by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit, ocular conditions, and duration of exposure to PPS were noted. Chart review was performed for fundus exam findings and ophthalmologic imaging, specifically fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When OCT or fundus photography was available, studies were evaluated by two independent graders.
RESULTS
A total of 131 patients who were exposed to PPS and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for PPS maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of PPS use was 4.2 years (range 0.3-11.6 years, interquartile range 5.5 years) and the average cumulative dose was 380g (range 29-1092g, interquartile range 132g).
CONCLUSION
A novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.
PubMed: 33603329
DOI: 10.2147/OPTH.S285013