title: Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.
abstract: Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko) muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.
authors.affiliation: Phrixus Pharmaceuticals Inc., Ann Arbor, Michigan, United States of America.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Markham
authors.affiliation: Phrixus Pharmaceuticals Inc., Ann Arbor, Michigan, United States of America.
authors.forename: Stace
authors.initials: S
authors.lastname: Kernodle
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jean
authors.initials: J
authors.lastname: Nemzek
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Pathology and Comparative Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Sigler
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D003964:Diaphragm / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D006207:Half-Life; D006321:Heart / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000503:physiopathology; D010991:Plethysmography; D020442:Poloxamer / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011241:Prednisone / Q000494:pharmacology / Q000627:therapeutic use; D049411:Utrophin / Q000172:deficiency / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D049411:Utrophin; D020442:Poloxamer; D011241:Prednisone