title: Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats.
abstract: OBJECTIVE
  Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model.
  
  
  METHODS
  LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration.
  
  
  RESULTS
  PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with <14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S.
  
  
  CONCLUSIONS
  Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, HSC T17-080, Stony Brook, New York 11794-8173, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Nengtai
authors.initials: N
authors.lastname: Ouyang
authors.forename: Ka Wing
authors.initials: KW
authors.lastname: Cheng
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001169:Arthritis, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001862:Bone Resorption / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D013467:Sulindac / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D016328:NF-kappa B; C553002:OXT-328; D009943:Organophosphorus Compounds; D016753:Interleukin-10; D013467:Sulindac; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat