title: Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Michael
authors: M
authors: Frohbergh
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Yi
authors: Y
authors: Ge
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Fanli
authors: F
authors: Meng
authors: Department of Pediatrics, University of Mainz, Mainz, Germany.
authors: Nesrin
authors: N
authors: Karabul
authors: Department of Pediatrics, University of Mainz, Mainz, Germany; Department of Pediatrics, University of Pécs, Pécs, Hungary.
authors: Alexander
authors: A
authors: Solyom
authors: Orthopedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Alon
authors: A
authors: Lai
authors: Orthopedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: James
authors: J
authors: Iatridis
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Edward H
authors: EH
authors: Schuchman
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Calogera M
authors: CM
authors: Simonaro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001696:Biomechanical Phenomena; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D007279:Injections, Subcutaneous; D008297:Male; D009068:Movement / Q000187:drug effects; D009087:Mucopolysaccharidosis VI / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010426:Pentosan Sulfuric Polyester / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D006025:Glycosaminoglycans; D010426:Pentosan Sulfuric Polyester