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Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs. | LitMetric

AI Article Synopsis

  • - The study explored the long-term safety and effectiveness of pentosan polysulfate (PPS) in treating MPS I in dogs, showing promising therapeutic benefits similar to prior research in MPS VI rats.
  • - MPS I dogs received daily or biweekly PPS, and significant reductions in inflammatory markers, glycosaminoglycan (GAG) levels, and arterial inflammation were observed, with no adverse effects recorded.
  • - Both treatment methods improved vascular health by enhancing lumen size and decreasing arterial thickening, with subcutaneous administration proving more effective in reducing cytokines in cerebrospinal fluid.

Article Abstract

Background: We previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model.

Methodology/principal Findings: MPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed.

Conclusions: PPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827827PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153136PLOS

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