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1.
J Inherit Metab Dis ; 47(2): 355-365, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38467596

RESUMO

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.


Assuntos
Mucopolissacaridose I , Humanos , Mucopolissacaridose I/tratamento farmacológico , Poliéster Sulfúrico de Pentosana/uso terapêutico , Poliéster Sulfúrico de Pentosana/farmacologia , Cartilagem/metabolismo , Biomarcadores , Dor/tratamento farmacológico , Dor/etiologia , Terapia de Reposição de Enzimas
2.
Zhonghua Wai Ke Za Zhi ; 62(2): 122-127, 2024 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-38310379

RESUMO

In 2022, American Urological Association updated the guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). A significant change has been made in treatment recommendations. The updated guideline no longer divided treatments into first-line through sixth-line tiers. Instead, treatment is categorized into behavioral/non-pharmacologic, oral medicines, bladder instillations, procedures, and major surgery. This change emphasizes the heterogeneity of IC/BPS patients and the importance of individualized treatment, overturns traditional unreasonable ideas about hierarchical and progressive treatment, and encourages patients and physicians to make treatment decisions together. At the same time, the panel emphasized the importance of early implementation of cystoscopy in patients suspected of Hunner lesions and warned against the possibility of pentosan polysulfate causing a unique retinal pigmentary maculopathy. Urinary reconstruction surgery was considered to only be used as a last resort for the treatment of IC/BPS, and there is uncertainty about the overall balance between benefits and risks/burdens. The updated guideline provides a new understanding and decision-making basis for the diagnosis and treatment of IC/BPS. However, it should be noted that the clinical characteristics of Chinese patients should be considered in practice and the application of the guideline should be localized.


Assuntos
Cistite Intersticial , Humanos , Cistite Intersticial/diagnóstico , Cistite Intersticial/terapia , Cistite Intersticial/patologia , Cistoscopia/efeitos adversos , Poliéster Sulfúrico de Pentosana
3.
Invest Ophthalmol Vis Sci ; 65(2): 28, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38381414

RESUMO

Purpose: There are numerous reports of a distinctive maculopathy in adults exposed to pentosan polysulfate sodium (PPS), a drug prescribed to treat bladder discomfort associated with interstitial cystitis. We tested whether PPS treatment of mice injures RPE or retina to provide insight into the etiology of the human condition. Methods: Mice were fed PPS-supplemented chow over 14 months. RPE and retinal function was assessed by electroretinography (ERG) regularly. Following euthanasia, one eye was used for sagittal sectioning and histology, the contralateral for RPE flatmounting. ZO-1 positive RPE cell borders were imaged using confocal microscopy and cell morphology was analyzed using CellProfiler. Results: After 10 months of PPS treatment, we observed diminution of mean scotopic c-wave amplitudes. By 11 months, we additionally observed diminutions of mean scotopic a- and b-wave amplitudes. Analysis of flatmounts revealed altered RPE cell morphology and morphometrics in PPS-treated mice, including increased mean en face cell area and geometric eccentricity, decreased RPE cell solidity and extent, and cytosolic translocation of alpha-catenin, all markers of RPE cell stress. Sex and regional differences were seen in RPE flatmount measures. Shortened photoreceptor outer segments were also observed. Conclusions: PPS treatment reduced RPE and later retina function as measured by ERG, consistent with a primary RPE injury. Post-mortem analysis revealed extensive RPE pleomorphism and polymegathism and modest photoreceptor changes. We conclude that PPS treatment of mice causes slowly progressing RPE and photoreceptor damage and thus may provide a useful model for some retinal pathologies.


Assuntos
Poliéster Sulfúrico de Pentosana , Doenças Retinianas , Adulto , Humanos , Animais , Camundongos , Retina , Eletrorretinografia , Causalidade
4.
Can J Urol ; 30(6): 11732-11739, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38104330

RESUMO

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.


Assuntos
Cistite Intersticial , Degeneração Macular , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Degeneração Macular/induzido quimicamente , Degeneração Macular/complicações , Cistite Intersticial/induzido quimicamente , Cistite Intersticial/complicações , Dor , Inflamação
5.
Can J Urol ; 30(6): 11740, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38104331

RESUMO

How should a conscientious physician advise patients with Interstitial Cystitis /Bladder Pain Syndrome (IC/BPS) when they want to know if taking Pentosan Polysulfate Sodium (PPS) will lead to loss of vision? Ever since the initial report from Pearce et al in 2018 suggesting that PPS usage can lead to the development of pigmented maculopathy (PM), my patients have been inundated with solicitations from attorneys looking to sign up clients for class action lawsuits.1 While there have been additional reports suggesting a relationship between PPS exposure and the development of PM, Ludwig et al found that there was no difference in the rate of macular disease between patients with documented IC/BPS who had taken PPS and those with IC/BPS with no history of PPS use.2 The large size of Ludwig's study certainly suggests that PPS may not cause PM to develop, and if the rate of PM in the IC population is higher than in controls, it may be due to the disease itself and not from the medication. In this manuscript, Proctor clearly describes the immune inflammatory response that is responsible for the development of the bladder damage seen with IC/BPS. Also, he describes how inflammatory mediators can enter the blood stream and might be a potential cause for the development of PM.3 This is a thought-provoking hypothesis that demands further evaluation. I have prescribed PPS since its approval and have many patients who feel it is an essential part of their IC treatment regimen. There is no other prescription medication that functions in the same fashion. I require them to follow the FDA recommendations for annual eye exams to look for PM development. I also advise patients that as they improve, we will discuss dose reduction and even discontinuation if their IC symptoms have abated. By following these suggestions, one should be able to continue to prescribe PPS for appropriate patients while carefully monitoring them for PM. I found this article extremely informative and will refer to it when counseling patients about IC/BPS and PPS.


Assuntos
Cistite Intersticial , Degeneração Macular , Masculino , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Cistite Intersticial/tratamento farmacológico , Degeneração Macular/tratamento farmacológico
6.
Brain Pathol ; 33(5): e13197, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37525413

RESUMO

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.


Assuntos
Síndrome de Creutzfeldt-Jakob , Príons , Humanos , Síndrome de Creutzfeldt-Jakob/tratamento farmacológico , Síndrome de Creutzfeldt-Jakob/genética , Príons/genética , Proteínas Priônicas/genética , Poliéster Sulfúrico de Pentosana/farmacologia , Poliéster Sulfúrico de Pentosana/uso terapêutico , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/uso terapêutico , Mutação/genética
7.
J Pharm Biomed Anal ; 235: 115672, 2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37619291

RESUMO

Several publications have recently proposed NMR spectroscopy to evaluate the critical quality attributes (CQA) of pentosan polysulfate sodium (PPS), the active ingredient of Elmiron™ approved to treat interstitial cystitis. PPS is a polymer of sulfated ß(1-4)-d-xylopyranose residues randomly substituted by 4-O-methyl-glucopyranosyluronic acid, containing, beyond the main xylose-2,3-O-disulfate repetitive unit, some minor residues that can be marker of both the starting material and preparation process. In the present study we assigned some previously unknown cross-peaks in 1H-13C HSQC NMR of PPS related to its minor sequences adding additional details to its CQA. Four anomeric cross-peaks related to glucuronate-branched xylose and different sulfation pattern as well as the preceding xyloses were identified. Two minor process-related signals of monosulfated xyloses (unsubstituted in position 2 or 3) were also assigned. The isolation of a disaccharide fraction allowed the assignment of the reducing end xylose-α/ß as well as the preceding xylose residues to be corrected. Additionally, the oversulfation of PPS allowed detection of the reducing end xylose-tri-1,2,3-O-sulfate. The newly identified cross-peaks were integrated into an updated quantitative NMR method. Finally, we demonstrated that an in-depth PPS analysis can be obtained using NMR instruments at medium magnetic fields (500 MHz/600 MHz), commonly available in pharmaceutical industries.


Assuntos
Monossacarídeos , Poliéster Sulfúrico de Pentosana , Xilose , Imageamento por Ressonância Magnética , Sulfatos , Espectroscopia de Ressonância Magnética
9.
Retin Cases Brief Rep ; 17(5): 507-510, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37643033

RESUMO

PURPOSE: The purpose of this study was to describe a case of development of pentosan polysulfate sodium (PPS)-related maculopathy that exhibited potential improvement in imaging findings after drug cessation. METHODS: This study is a case report. RESULTS: A 66-year-old woman presented with progressive pigmentary maculopathy associated with long-term PPS usage, including development of a choroidal neovascular membrane in her right eye. After discontinuation of PPS, her clinical course was notable for partial subjective and objective improvement in visual acuity, as well as partial improvement in outer retinal architecture on ocular coherence tomography, but persistence of retinal pigment epithelium atrophy and autofluorescence changes. CONCLUSION: The course of retinopathy after discontinuation of PPS has yet to be fully determined and has so far been suggested to be progressive. Anatomical improvements seen in our case suggest that further investigations are warranted to determine whether there is potential for partial reversal of some changes in PPS maculopathy.


Assuntos
Neovascularização de Coroide , Degeneração Macular , Doenças Retinianas , Feminino , Humanos , Idoso , Poliéster Sulfúrico de Pentosana/efeitos adversos , Degeneração Macular/induzido quimicamente , Degeneração Macular/diagnóstico , Degeneração Macular/tratamento farmacológico , Retina
10.
Am J Ophthalmol ; 255: 57-67, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37327961

RESUMO

PURPOSE: To describe the progression of pentosan polysulfate sodium (PPS) maculopathy after drug discontinuation qualitatively and quantitatively using multimodal imaging assessmen. DESIGN: Prospective case series. METHODS: Patients with PPS maculopathy were evaluated after discontinuation of PPS. Near-infrared reflectance (NIR), fundus autofluorescence (FAF), and optical coherence tomography (OCT) were evaluated in all patients at baseline and at the final follow-up visit at least 12 months later. A qualitative and quantitative analysis of the retinal imaging findings was performed. Patterns of disease progression were evaluated. Area of disease involvement on FAF, retinal pigment epithelium (RPE) atrophy on FAF and NIR, and retinal layer thicknesses on OCT were measured at baseline and at the follow-up visit. RESULTS: A total of 26 eyes were included, with a follow-up period ranging from 13 to 30 months. The diseased area measured on FAF showed significant expansion in all eyes from baseline to follow-up despite drug cessation (P = .03) with a median linearized rate of change of 0.42 mm/y. There was significant reduction in the central macular thickness (P = .04), inner nuclear layer thickness (P = .003), outer nuclear layer thickness (P = .02), and subfoveal choroidal thickness (P = .003) at follow-up vs baseline. New areas of RPE atrophy on FAF in the macula developed in 4 eyes while preexisting atrophic lesions increased in size in 5 eyes. CONCLUSION: Eyes with baseline PPS maculopathy all exhibited remarkable progression with qualitative and quantitative multimodal imaging analysis despite drug discontinuation. Disease progression may be attributed to underlying inner choroidal ischemia or RPE impairment.


Assuntos
Degeneração Macular , Doenças Retinianas , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Angiofluoresceinografia/métodos , Degeneração Macular/patologia , Doenças Retinianas/patologia , Tomografia de Coerência Óptica/métodos , Progressão da Doença , Atrofia , Epitélio Pigmentado da Retina/patologia
11.
Ophthalmic Surg Lasers Imaging Retina ; 54(7): 388-394, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37310751

RESUMO

BACKGROUND AND OBJECTIVE: To compare the risk factors for the development and progression of pigmentary retinopathy in patients exposed to pentosan polysulfate sodium (PPS). MATERIALS AND METHODS: Retrospective cohort study of patients exposed to PPS with at least two follow-up visits with multimodal imaging. RESULTS: A total of 97 patients were included (33 with PPS-associated retinopathy and 64 without). The average follow-up was 29.4 months, overall cumulative dose was 1,220 ± 910 g (1,730 ± 870 vs 959 ± 910; P < 0.0001), and total PPS duration was 12.1 ± 7.1 years (16.0.2 ± 6.1 vs 10.1 ± 6.9; P < 0.0001). The best-corrected visual acuity remained stable during follow-up. At presentation, the average area of the retinopathy in the worse eye was 54.1 ± 50 mm2 in the PPS-retinopathy group, worsening at a rate of 6.10 ± 10 mm2/year. Patients who developed choroidal neovascular membranes (CNVMs) had faster rates of retinopathy progression (11.6 ± 12 vs 3.53 ± 7.6 mm2/year, P = 0.036). No patient had the exact same gene mutation. CONCLUSION: PPS-associated pigmentary retinopathy can continue to progress over time, even after discontinuing the medication. CNVM development may be associated with faster rates of retinopathy progression. [Ophthalmic Surg Lasers Imaging Retina 2023;54:388-394.].


Assuntos
Doenças Retinianas , Retinite Pigmentosa , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Seguimentos , Estudos Retrospectivos , Doenças Retinianas/tratamento farmacológico , Sódio
12.
J Vet Med Sci ; 85(6): 680-690, 2023 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-37150611

RESUMO

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.


Assuntos
Cartilagem Articular , Doenças do Cão , Osteoartrite , Animais , Cães , Condrócitos/metabolismo , Poliéster Sulfúrico de Pentosana/farmacologia , Peso Molecular , Colágeno Tipo II/metabolismo , Fenótipo , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Células Cultivadas , RNA Mensageiro/metabolismo , Diferenciação Celular , Fatores de Transcrição SOX9/metabolismo , Doenças do Cão/metabolismo
13.
AAPS J ; 25(3): 50, 2023 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-37147461

RESUMO

Pentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to yield a mixture of 4-6 kDa polysaccharides. The chain is mainly composed of sulfated xylose (Xyl) with branched 4-O-methyl-glucuronate (MGA). During generic drug development, the quality attributes (QAs) including monosaccharide composition, modification, and length need to be comparable to those found in the reference list drug (RLD). However, the range of QA variation of the RLD PPS has not been well characterized. Here, multiple PPS RLD lots were studied using quantitative NMR (qNMR) and diffusion ordered spectroscopy (DOSY) to quantitate the components in the mixture and to probe both inter- and intra-lot precision variability. The DOSY precision assessed using coefficient of variation (CV) was 6%, comparable to PPS inter-lot CV of 5%. The QAs obtained from 1D qNMR were highly precise with a precision CV < 1%. The inter-lot MGA content was 4.8 ± 0.1%, indicating a very consistent botanical raw material source. Other process-related chemical modification including aldehyde at 0.51 ± 0.04%, acetylation at 3.3 ± 0.2% and pyridine at 2.08 ± 0.06%, varied more than MGA content. The study demonstrated that 1D qNMR is a quick and precise method to reveal ranges of variation in multiple attributes of RLD PPS which can be used to assess equivalency with generic formulations. Interestingly, the synthetic process appeared to introduce more variations to the PPS product than the botanical source of the material.


Assuntos
Imageamento por Ressonância Magnética , Poliéster Sulfúrico de Pentosana , Espectroscopia de Ressonância Magnética
14.
Retina ; 43(9): 1472-1479, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37229759

RESUMO

PURPOSE: To refine the retinal phenotypes of suspected pentosan polysulfate sodium toxicity using ultra-widefield imaging. METHODS: Patients with complete dosing profiles who visited the ophthalmology department and with ultra-widefield and optical coherence tomography imaging records were identified using electronic health records at a large academic center. Retinal toxicity was initially identified using previously published imaging criteria, while grading was categorized using both previously reported and new classification systems. RESULTS: One hundred and four patients were included in this study. Twenty-six (25%) were identified as having toxicity from PPS. The mean duration of exposure and cumulative dose between the retinopathy group (162.7 months, 1,803.2 g) were longer and higher compared with the nonretinopathy group (69.7 months, 972.6 g) (both P < 0.001). There was variability of extramacular phenotype in the retinopathy group, with four eyes having only peripapillary involvement and six eyes having far peripheral extension. CONCLUSION: Retinal toxicity in the setting of prolonged exposure and increased cumulative dosing from PPS therapy produces phenotypic variability. Providers should be aware of the extramacular component of toxicity when screening patients. Understanding the different retinal phenotypes may prevent continued exposure and reduce the risk of vision-threatening foveal-involving disease.


Assuntos
Poliéster Sulfúrico de Pentosana , Doenças Retinianas , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Angiofluoresceinografia/métodos , Retina , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica/métodos , Fenótipo
15.
Retina ; 43(7): 1174-1181, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36996461

RESUMO

PURPOSE: To assess genetic associations for pentosan polysufate sodium maculopathy. METHODS: Genetic testing for inherited retinal dystrophy genes using exome testing and for 14 age-related macular degeneration-associated single nucleotide polymorphisms (SNPs) using panel testing were performed. In addition, full-field electroretinograms (ffERG) were obtained to identify any cone-rod dystrophy. RESULTS: Eleven of 15 patients were women, with a mean age of 69 (range 46-85). Inherited retinal dystrophy exome testing in five patients revealed six pathogenic variants, but failed to confirm inherited retinal dystrophy in any patient genetically. FfERG performed in 12 patients demonstrated only nonspecific a- and b-wave abnormalities in 11 cases and was normal in one case. For age-related macular degeneration single nucleotide polymorphisms, CFH rs3766405 ( P = 0.003) and CETP ( P = 0.027) were found to be statistically significantly associated with pentosan polysulfate maculopathy phenotype compared with the control population. CONCLUSION: Pentosan polysulfate maculopathy is not associated with Mendelian inherited retinal dystrophy genes. However, several age-related macular degeneration risk alleles were identified to be associated with maculopathy compared with their frequency in the normal population. This suggests a role for genes in disease pathology, particularly the alternative complement pathway. These findings would benefit from further investigation to understand the risk of developing maculopathy in taking pentosan polysulfate.


Assuntos
Distrofias de Cones e Bastonetes , Cistite Intersticial , Degeneração Macular , Distrofias Retinianas , Feminino , Masculino , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Degeneração Macular/induzido quimicamente , Degeneração Macular/diagnóstico , Degeneração Macular/genética
17.
JAMA Ophthalmol ; 141(3): 260-266, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36729449

RESUMO

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.


Assuntos
Retinopatia Diabética , Degeneração Macular , Degeneração Retiniana , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Poliéster Sulfúrico de Pentosana/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Tomografia de Coerência Óptica , Degeneração Macular/fisiopatologia , Retinopatia Diabética/complicações , Atrofia/complicações
19.
Front Immunol ; 14: 1030879, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36845136

RESUMO

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.


Assuntos
Pneumonia , Camundongos , Animais , Poliéster Sulfúrico de Pentosana/farmacologia , Poliéster Sulfúrico de Pentosana/uso terapêutico , Camundongos Endogâmicos C57BL , Pneumonia/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças
20.
Am J Gastroenterol ; 118(5): 905-908, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36689730

RESUMO

INTRODUCTION: This study evaluates the potential association of pentosan polysulfate (PPS) with inflammatory bowel disease (IBD) or dysplasia. METHODS: We searched electronic medical records to identify patients with IBD using PPS. RESULTS: Ten of 30 identified patients (33.3%) had colonic dysplasia. Six of them (60%) underwent colectomy for endoscopically unresectable dysplasia. Three (10%) discontinued PPS, each with an apparent benefit. DISCUSSION: Patients with IBD at 2 institutions who had taken PPS had high rates of colonic dysplasia leading to surgery. Patients who stopped PPS showed improvement in their colitis. PPS may play a causal role in the development of colitis and dysplasia.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico
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