Journal Article

Dose Responsive Effects of Subcutaneous Pentosan Polysulfate Injection in Mucopolysaccharidosis Type VI Rats and Comparison to Oral Treatment

Solyom, Alexander, Meng, Fanli, Karabul, Nesrin, Schuchman, Edward H., Simonaro, Calogera M., Ge, Yi, Frohbergh, Michael, Lai, Alon, Iatridis, James

2014

Overview

We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (s.c.) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. One-month-old MPS VI rats were given once weekly s.c. injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly s.c. PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of s.c. treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, s.c.. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of s.c. PPS administration. Once weekly s.c. administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from s.c. PPS administration were observed over the 6-month study period.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abnormalities / Administration, Oral / Animal tissues / Animals / Antigens / Arthritis / Bioavailability / Biocompatibility / Biological Availability / Biology and Life Sciences / Biomechanical Phenomena / Biomedical materials / Cartilage / Cartilage (articular) / Cartilage diseases / Cartilage, Articular - drug effects / Cartilage, Articular - pathology / Coagulation / Cost analysis / Deformation effects / Dentition / Dose-Response Relationship, Drug / Drug Administration Schedule / Drug dosages / Enzymes / Female / Femur - diagnostic imaging / Femur - drug effects / Genetic disorders / Glycosaminoglycans / Glycosaminoglycans - metabolism / Growth Plate - drug effects / Growth Plate - pathology / Inflammation / Injection / Injections, Subcutaneous / Liver / Male / Markers / Medicine / Medicine and Health Sciences / Metabolic disorders / Movement - drug effects / Mucopolysaccharides / Mucopolysaccharidoses / Mucopolysaccharidosis / Mucopolysaccharidosis VI - drug therapy / Mucopolysaccharidosis VI - metabolism / Mucopolysaccharidosis VI - pathology / Mucopolysaccharidosis VI - physiopathology / Oral administration / Orthopedics / Osteoarthritis / Pediatrics / Pentosan polysulfate / Pentosan Sulfuric Polyester - administration & dosage / Pentosan Sulfuric Polyester - pharmacokinetics / Pentosan Sulfuric Polyester - pharmacology / Pentosan Sulfuric Polyester - therapeutic use / Rats / Reduction / Research and Analysis Methods / Rodents / Side effects / Spine - diagnostic imaging / Spine - drug effects / Teeth / Tomography, X-Ray Computed / Tumor necrosis factor-TNF / Urine