Pentosan Polysulfate Research Articles

Characteristics of Pentosan Polysulfate Sodium-Associated Maculopathy and Similarities With Other Maculopathies Commonly Managed in a Retina Practice.

This work describes characteristics of pentosan polysulfate sodium (PPS)-associated maculopathy and its similarities with common maculopathies in a retina practice cohort. Thirty-two patients were identified through electronic medical record query who were exposed to PPS. One patient was excluded for lack of retinal imaging. Thirty-one patients (62 eyes) were included. A retrospective review was used to obtain patient characteristics, examination findings, and retinal imaging of the study patients. Classification into "likely," "unlikely," or "possible" to have PPS-associated maculopathy groups was based on the fundus photography and retinal imaging. Main outcome measures were best-corrected visual acuity, age, sex, diagnosis of reason for referral, allocation into designated maculopathy group, and presence of choroidal neovascularization. Of 31 patients (62 eyes), the median age was 70 years (range, 24-104 years) and the majority were women (87%). Mean best-corrected visual acuity was 0.3 ± 0.4 logMAR at presentation. The most common reason for referral was age-related macular degeneration (29%). Maculopathy grades were "likely" (29%, 9 total patients), "possible" (26%, 8 total patients), or "unlikely" (45%, 14 total patients). Choroidal neovascularization was noted in 9.7% of all eyes and 11% of eyes in the "likely" group. The "possible" and "likely" groups had older ages of presentation (P < .05) compared with the "unlikely" group. A high percentage (55%) of patients with a history of chronic PPS exposure showed features of "likely" or "possible" maculopathy. Similarities with common maculopathies such as age-related macular degeneration and the importance of screening and recognizing at-risk patients are highlighted.

Macular Findings of Patients on Pentosan Polysulfate Sodium.

In 2018, a unique maculopathy associated with chronic pentosan polysulfate sodium (PPS) use for the treatment of interstitial cystitis (IC) was described, where the authors detailed macular retinal pigment epithelial abnormalities in six patients. In this paper, a retrospective study of a larger patient pool at one large tertiary retina practice was undertaken to evaluate patients taking PPS and their macular findings. A retrospective chart review was performed on all patients presenting to a single large retina practice between 2011 and 2019. Patient's macular diagnosis, findings, optical coherence tomography scans, and macular auto-fluorescent scans were assessed. This project was Institutional Review Board (IRB) approved by the St Luke's Hospital IRB board (St Louis, MO, USA). Fifty-five patients were identified as taking PPS for IC. Fifty-three patients were found to have a diagnosis consistent with changes attributable to known macular diseases to include macular degeneration and pattern dystrophies. Two (4%) of fifty-five patients had macular findings suggestive of PPS toxicity. The first was a 58-year-old female with subtle retinal pigment epithelium (RPE) deposits on optical coherence tomography that exhibited hyper-autofluorescence. The second was a 72-year-old female with 14 years of PPS use who exhibited RPE excrescences and parafoveal areas of atrophy. Pentosan polysulfate sodium may be the cause of macular findings in a small percentage of patients referred to a tertiary retina practice. Although causation of macular changes with PPS use has yet to be elucidated, clinicians should be aware of this possibility when assessing patients with atypical macular findings. Future longitudinal studies are necessary to evaluate a definitive relationship. This paper should remind all clinicians of the importance of a throughout review of the patient's medication list as novel toxicities may become apparent years after initial FDA trials. The strength of this study is the larger patient population compared to earlier studies, and the main weaknesses include the retrospective nature of the study, lack of family and genetic testing, and lack of multimodal imaging for all patients.

Expanded Clinical Spectrum of Pentosan Polysulfate Maculopathy: A Macula Society Collaborative Study

Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings. Multi-institutional retrospective study. Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4,2020. Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics. Pentosan polysulfate exposure characteristics and fundus imaging features. There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2-18.9), with a median cumulative exposure of 1.5 kg (0.9-2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients. Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.

PENTOSAN POLYSULFATE AND VISION: Findings from an International Survey of Exposed Individuals.

To investigate patient-reported visual function among individuals taking pentosan polysulfate (PPS) for interstitial cystitis. A 27-item online survey was distributed to an international mailing list of individuals with interstitial cystitis in November 2018. Demographic characteristics, PPS exposure history, subjective visual function, and previous macular diagnoses were queried. The impact of PPS use, grouped by tertile of cumulative exposure, on visual function and macular diagnoses was assessed with multivariate logistic regression. The survey was completed by 912 respondents. Eight hundred and sixty-one (96.4%) were women, and the median age was 55 [interquartile range (IQR), 45-64 years]. Among PPS users, the median exposure was 547.5 g (IQR, 219-1,314 g). Respondents in the highest PPS exposure tertile were more likely to report difficulty with reading small print [adjusted odds ratio 2.29, 95% confidence interval (CI) 1.15-4.57] and to have a diagnosis of macular degeneration and/or pigmentary maculopathy (adjusted odds ratio 2.41, 95% CI 1.44-4.03) than unexposed respondents. In this large sample of individuals with interstitial cystitis, those in the highest PPS exposure category were more likely to have difficulties reading small print and to report a previous diagnosis of macular disease. Further study of objective measures of visual function in PPS users is warranted.

P0004 - Pentosan polysulfate in patients with bladder pain syndrome/interstitial cystitis: Multicenter randomized controlled double-blind trial

P0004 - Pentosan polysulfate in patients with bladder pain syndrome/interstitial cystitis: Multicenter randomized controlled double-blind trial

A Rapid and Mild Sulfation Strategy Reveals Conformational Preferences in Therapeutically Relevant Sulfated Xylooligosaccharides.

Although sulfated xylooligosaccharides are promising therapeutic leads for a multitude of afflictions, the structural complexity and heterogeneity of commercially deployed forms (e. g. Pentosan polysulfate 1) complicates their path to further clinical development. We describe herein the synthesis of the largest homogeneous persulfated xylooligomers prepared to date, comprising up to eight xylose residues, as standards for biological studies. Near quantitative sulfation was accomplished using a remarkably mild and operationally simple protocol which avoids the need for high temperatures and a large excess of the sulfating reagent. Moreover, the sulfated xylooligomer standards so obtained enabled definitive identification of a pyridinium contaminant in a sample of a commercially prepared Pentosan drug and provided significant insights into the conformational preferences of the constituent persulfated monosaccharide residues. As the spatial distribution of sulfates is a key determinant of the binding of sulfated oligosaccharides to endogenous targets, these findings have broad implications for the advancement of Pentosan-based treatments.

Maculopathy caused by pentosan polysulfate.

Interstitial cystitis is a chronic bladder disorder causing pelvic pain and urinary frequency or urgency, with an estimated prevalence of 2.7%–6.5% among adult women.[1][1] Pentosan polysulfate may buffer the bladder epithelium against irritants and is the only oral medication approved by Health

POS-170 LEISHMANIASIS COMPLICATE SYSTEMIC LUPUS ERYTHEMATOSUS: ABOUT 7 CASES

The association between leishmania (Lsc) and systemic lupus erthematosus (SLE) is rare. It is particularly serious in cases of visceral leishmania (VL). It is a parasitic infection whose hallmarks may mimic SLE symptoms especially when the two pathologies appear concomitantly. The prognosis of SLE depends on the one hand on the rapidity of diagnosis and on the other hand on the quality of treatment. The aim of this study was to analyze the characteristics of infection in leishmania in patients affected by SLE. It was a retrospective study including 07 patients hospitalized for leishmania and systemic lupus erthematosus (SLE) in the Internal Medicine Department of the Charles Nicolle hospital during the period between January 1976 and November 2020. All patients fulfilled four or more criteria defined by the American College of Rheumatology1982, revised in 1997. The diagnosis of cutaneous leishmaniasis (CL) was confirmed by a biopsy specimen. The diagnosis of VL was confirmed by the association of clinical and biology sings associated with positive bone marrow smear and/or positive serologic tests for Leishmania antibodies. Seven patients were enrolled in the study. Their mean age was 27, 85 years [14-41].There were six women and one man. The diagnosis of and SLE was concomitant in three patients, while in four cases the diagnosis of leishmania was after the diagnosis of LES. The time interval between the date of discovery of leishmaniasis and the date of confirmation of the diagnosis of SLE was 36 months[2-24]. For the diagnosis of LES, malar rash, photosensitivity, nephritis, arthralgia and positive antinuclear antibody were observed in six cases. Anti-double stranded DNA antibody was positive in two cases. For the diagnosis of CL, it was based on clinical manifestation in one case and was based in cutaneous biopsy in two cases. Five patients had nephrotic syndrom and one patient had proteinuria. Patients who had renal biopsy had active lupus nephritis class III in one case and lupus nephritis class IV in three cases. Two patients had not renal biopsy because one of them had severe hypertension and the other had severe sepsis. The diagnosis of CL was clinical in one case and histological in two cases. Clinical manifestations of VL were dominated by fever, pale mucous membranes and splenomegaly. There was pancytopenia in all patients with VL. The diagnosis of VL was confirmed by serology(n=3) andbone marrow smear (n=4). Meglumine antimonite was prescribed in the three cases of CL, in the other cases pentosan polysulfate was prescribed in a single patient while in the other two cases, they required the addition of liposomal amphotericin B. One patient was died by tamponade before treatment. Two patients were died by septic shock and only one was cured. Patients with CL had scar in two cases. The last patient died of it. The distinction between the diagnosis of SLE or its exacerbation and VL may be a clinical dilemmaresponsible for diagnostic delay. All the cases diagnosed so far have been by conventional techniques, which may underestimate the incidence of this association. The results of this study highlight a high mortality rate in cases of VL with SLE accordingly with several studies in literature.

Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, randomized, double-blind, placebo-controlled study

BackgroundAlphaviruses, such as Ross River (RRV) and chikungunya virus (CHIKV), cause significant global morbidity, with outbreaks of crippling joint inflammation and pain, leaving patients incapacitated for months to years. With no available vaccine or specific therapeutic for any alphaviral disease, and a growing economic and public health burden, there is a serious need for the development of specific therapies.MethodsThis study evaluated the safety and efficacy of pentosan polysulfate sodium (PPS) in subjects with RRV-induced arthralgia in a double-blind, placebo-controlled trial. Twenty subjects were randomized 2:1 to subcutaneous PPS (2 mg/kg) or placebo (sodium chloride 0.9%) twice weekly for 6 weeks. Safety evaluation included physical examination, concomitant medications, and laboratory findings. Efficacy assessments included change from baseline in joint function (hand grip strength and RAPID3) and quality of life (SF-36) at Days 15, 29, 39 and 81 after treatment initiation. Inflammatory and cartilage degradation biomarkers were exploratory endpoints.ResultsPPS was well tolerated, with a similar proportion of subjects reporting at least one treatment-emergent adverse event (TEAE) in the treatment and placebo groups. Injection site reactions were the most common TEAE and occurred more frequently in the PPS group. Dominant hand grip strength and SF-36 scores improved with PPS at all time points assessed, with hand grip strength improvement of 6.99 kg (p = 0.0189) higher than placebo at Day 15. PPS showed significant improvements versus placebo in adjusted mean relative change from baseline for RAPID3 Pain (p = 0.0197) and Total (p = 0.0101) scores at Day 15. At the conclusion of the study overall joint symptoms, assessed by RAPID3, showed near remission in 61.5% of PPS subjects versus 14.3% of placebo subjects. Additionally, PPS treatment improved COMP, CTX-II, CCL1, CXCL12, CXCL16 and CCL17 biomarker levels versus placebo.ConclusionsOverall, the improvements in strength and joint symptoms warrant further evaluation of PPS as a specific treatment for RRV-induced and other forms of arthritis.Trial registrationThis trial is registered at the Australian New Zealand Clinical Trials Registry #ACTRN12617000893303.

Pentosan polysulfate maculopathy versus age-related macular degeneration: comparative assessment with multimodal imaging

ObjectiveTo evaluate whether pentosan polysulfate maculopathy manifests distinctive imaging features that can be differentiated from those found in age-related macular degeneration (AMD). MethodsLocal databases were queried to identify patients with a diagnosis of interstitial cystitis who were seen at the Emory Eye Center between May 2014 and January 2019 and who had fundus imaging available for review. Ninety patients met the eligibility criteria. Masked graders categorized patients based on imaging characteristics as follows: category 1: pentosan polysulfate maculopathy; category 2: AMD or drusen; category 3: neither; and category 4: unsure. Pentosan polysulfate exposure characteristics were compared among groups. ResultsOf the 90 subjects evaluated, 79 (88%) were female and the median age was 61.5 years (range, 30–89). Seventeen patients were placed in category 1; 25 in category 2; 47 in category 3, and; 1 in category 4. Among categories 1 to 4, respectively, 17 (100%), 15 (60%), 28 (60%), and 0 patients had exposure to pentosan polysulfate (p = 0.007). Mean cumulative exposure to pentosan polysulfate across the four categories was 2.1, 0.36, 0.34, and 0 kg, respectively (p < 0.00001). Eyes with pentosan polysulfate maculopathy did not have typical drusen in the macula. ConclusionAlthough pentosan polysulfate maculopathy resembles some aspects of AMD, the two conditions can be differentiated with the use of multimodal fundus imaging.

Update on maculopathy secondary to pentosan polysulfate toxicity.

The aim of the present review is to provide a comprehensive summary of available knowledge regarding toxic maculopathy secondary to pentosan polysulfate sodium (PPS). PPS toxicity was described in 2018, and additional studies characterize it as dysfunction of the retinal pigment epithelium centered on the posterior pole, which can progress despite drug cessation. Requisite exposure can be as little as 0.325 kg and 2.25 years but averages closer to 1-2 kg and 10-15 years. Multimodal imaging should include near-infrared reflectance, optical coherence tomography, and fundus autofluorescence. Cross-sectional studies demonstrate evidence correlating cumulative dosing and the likelihood/severity of maculopathy. Early estimates of prevalence range from 12.7 to 41.7% depending on dosing, with overall rates around 20%. Reasonable evidence associates maculopathy with extended exposure to PPS, with an average reported incidence of around 20% in patients with long-term exposures. Patients with unexplained retinal pigment epithelium changes and difficulty with dark adaptation should be questioned regarding PPS exposure, and patients with known exposure to PPS should be examined. Further research is needed to refine screening protocols. Currently, providers should consider baseline examination and examination at 5 years and/or 500 g of exposure followed by yearly screening.

Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the availability of human cell-based models of prion disease. Recently, an induced pluripotent stem cell derived human cerebral organoid model was shown to take up and propagate human CJD prions. This model offers new opportunities to screen drug candidates for the treatment of human prion diseases in an entirely human genetic background. Here we provide the first evidence that human cerebral organoids can be a viable model for CJD drug screening by using an established anti-prion compound, pentosan polysulfate (PPS). PPS delayed prion propagation in a prophylactic-like treatment paradigm and also alleviated propagation when applied following establishment of infection in a therapeutic-like treatment paradigm. This study demonstrates the utility of cerebral organoids as the first human 3D cell culture system for screening therapeutic drug candidates for human prion diseases.

Pentosan Polysulfate Maculopathy: Prevalence, Spectrum of Disease, and Choroidal Imaging Analysis Based on Prospective Screening

Purpose: To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of choroidal vascularity index (CVI) analysis.Design: Prospective cohort studyMethods: Of 741 patients prescribed PPS within a large university database, 100 (13.4%) with any consumption agreed to participate in a prospective screening investigation. Multimodal retinal imaging including near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) was performed in all patients. Characteristic findings of affected patients were identified, and affected and unaffected cohorts were compared. CVI, defined as stromal choroidal area (SCA) divided by the total choroidal area, was analyzed.Results: The prevalence of PPS maculopathy was 16%. NIR illustrated punctate hyperreflective lesions with early presentation. FAF illustrated a speckled macular network of hypo- and hyperautofluorescence colocalized with multifocal hyperreflective retinal pigment epithelial lesions on SD-OCT. Advanced cases demonstrated varying degrees of atrophy. The affected cohort exhibited significantly greater mean PPS therapy duration, mean daily dosage, and mean cumulative dosage (19.5±5.5 years, 433.9±137.6 mg, 3,103.1±1,402.2 g) compared with the unaffected cohort (7.1±6.6 years, 291.6±177.6 mg, 768.4±754.8 g). SCA was significantly lower and CVI was significantly greater in the affected vs the unaffected group.Conclusions: This prospective cohort study identified a prevalence of PPS maculopathy of 15%-20% among PPS users who agreed to participate. A spectrum of findings may be observed with multimodal retinal imaging. Significant choroidal abnormalities associated with this characteristic maculopathy may provide surrogate markers of macular toxicity.

Efficacy and safety comparison of pharmacotherapies for interstitial cystitis and bladder pain syndrome: a systematic review and Bayesian network meta-analysis.

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. 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. 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. Cyclosporine A might be superior to other pharmacological treatments in efficacy. Amitriptyline and certolizumab pegol were capable of lowering the ICSI as well.

Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone

Prion and prion-like diseases involve the propagation of misfolded protein conformers. Small-molecule pharmacological chaperones can inhibit propagated misfolding, but how they interact with disease-related proteins to prevent misfolding is often unclear. We investigated how pentosan polysulfate (PPS), a polyanion with antiprion activity in vitro and in vivo, interacts with mammalian prion protein (PrP) to alter its folding. Calorimetry showed that PPS binds two sites on natively folded PrP, but one PPS molecule can bind multiple PrP molecules. Force spectroscopy measurements of single PrP molecules showed PPS stabilizes not only the native fold of PrP but also many different partially folded intermediates that are not observed in the absence of PPS. PPS also bound tightly to unfolded segments of PrP, delaying refolding. These observations imply that PPS can act through multiple possible modes, inhibiting misfolding not only by stabilizing the native fold or sequestering natively folded PrP into aggregates, as proposed previously, but also by binding to partially or fully unfolded states that play key roles in mediating misfolding. These results underline the likely importance of unfolded states as critical intermediates on the prion conversion pathway.

Maculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience.

AimTo investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).MethodsPatients 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.ResultsA 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).ConclusionA novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.

Treatment with pentosan polysulfate improves neuropathological measures in the canine model of MPS IIIB

Treatment with pentosan polysulfate improves neuropathological measures in the canine model of MPS IIIB

Quantitative determination of dextran sulfate and pentosan polysulfate and their binding with protamine using chronopotentiometry with polyion-selective electrodes

We report for the first time a chronopotentiometric measurement of polyanions based on localized ion depletion at the sample/membrane interface at a characteristic transition time τ, using polymer membrane polyanion-selective electrodes. Chronopotentiometric transduction of polyions based on the measurement of transition time has analytically more attractive applications compared to the controlled-current reversible pulsed chronopotentiometric transduction based on electromotive force (emf) measurement. This is because traditional polyion-selective electrodes based on emf measurement intrinsically give nonlinear (sigmoidal) calibration curves. While these can be used for indirect determination of polyions via polyanion-polycation titrations, they are not convenient for direct quantitation. However, under chronopotentiometric measurement based on the measurement of transition time, the square root of the transition time τ is linearly related to the concentration of the polyion according to the Sand equation and can be used for a direct calibration-free rapid determination. In this work, we have measured the concentrations of dextran sulfate (DS) and pentosan polysulfate (PPS) using polyanion selective electrodes under chronopotentiometric method where the transition time was measured and controlled-current pulsed chronopotentiometric transductions, where the phase boundary potential (emf) was measured. In addition, the protamine–DS and the protamine–PPS binding ratios have been determined using both transductions. The protamine–PPS binding ratio was determined to be 1.51:1 by the titration method and 1.54:1 by chronopotentiometry. The protamine–DS binding ratio was determined to be 1.37:1 by the titration method and 1.41:1 by chronopotentiometry, showing excellent agreement between the two methods. These simple measurement methods of binding ratios between polysaccharides and polypeptides may become important tools for screening safer and more reliable antidotes for the newer and safer anticoagulants such as Low Molecular Weight Heparins(LMWHs) and also to determine the dosages of antidotes needed to neutralize the anticoagulant activity.

Accuracy of the dimethylmethylene blue spectrophotometric assay in measuring the amount of encapsulated pentosan polysulfate into nanoparticles

Dimethylmethylene blue (DMMB) spectrophotometric assay was used to estimate the amount of pentosan polysulfate (PPS), a heparin-like glycosaminoglycan (GAG), encapsulated in chitosan-based nanoparticles (NPs) as an alternative method for capillary zone electrophoresis (CZE) that has been shown to lack sensitivity. The analytical performance of the DMMB method was evaluated, which revealed the response of PPS is linear in the investigated concentration range (R2 = 0.9996). The detection and quantification limits were < 0.22 µg/ml and < 0.75 µg/ml, respectively. The average recovery of the PPS was roughly 97.5%, with %DFA and %RSD < 5%. Based on indirect and direct estimation of the entrapment efficiency of the NPs, PPS encapsulated in NPs was 82.9 ± 0.084% and 84.1 ± 0.10%, respectively, with a %RSD of less than 1%. Comparison between the DMMB and CZE performances revealed that all the uncertainties related to results produced by the DMMB assay were at least 30-fold smaller than those produced by the CZE, revealing the higher precision and accuracy of the DMMB assay. The sensitivity of the DMMB was several times higher than the CZE. The DMMB also was found to have high stability and binding specificity for PPS. Overall, the DMMB was demonstrated to be more convenient than CZE in analytical terms and also in terms of practicality as a routine assay. Thus, the DMMB assay offers an alternative tool for the quantification of PPS, perhaps even in biological samples.

Multimodal analgesia in a Southern White Rhinoceros (Ceratotherium simum) with pentosan polysulfate, gabapentin, amantadine and phenylbutazone to manage chronic pain

A 38-year-old white rhinoceros bull (Ceratotherium simum) was treated with phenylbutazone over a period of four years for chronic osteoarthritic and neuropathic pain of the thoracic limbs. Initially the lameness was sporadic and responded well to phenylbutazone (4 mg/kg PO SID). The lameness increased in severity during the winter months. Four years after treatment was initiated, there was an increase in the severity and incidence of the lameness. Analgesia was augmented by the addition of non-conventional analgesic drugs. Pentosan polysulfate was administered IM at 3 mg/kg once a week for two treatments and thereafter monthly when possible. Gabapentin was used at 8 mg/kg but produced ataxia and anorexia. The dose was reduced to 4-5 mg/kg PO SID. Amantadine (3 mg/kg PO BID) was added to the multimodal analgesia and produced a significant improvement in the clinical lameness. Chronic inflammation was monitored using both automated and manual fibrinogen methods. Eventually the rhinoceros was euthanized on humane grounds when treatment was unable to produce suitable clinical relief.