title: Safety pharmacology, toxicology and pharmacokinetic assessment of human Gc globulin (vitamin D binding protein).
abstract: Gc globulin is an important protein of the plasma actin-scavenger system. As such, it has been shown to bind free actin and prevent hypercoagulation and shock in patients with massive actin release resulting from severe tissue injuries. Treatment of such patients with Gc globulin could therefore potentially be life-saving. This article presents pre-clinical toxicology experiments conducted on purified plasma-derived human Gc globulin. The Gc globulin formulation was shown to be stable for at least 4 years with full retention of actin-binding capacity. In vitro studies did not reveal activation of the kallikrein system or the complement system and cellular studies showed no toxic effects on a variety of human cell lines. In vivo studies showed no acute toxic effects in mice, rats or guinea pigs upon intravenous infusion. A 14-day local tolerance study in rabbits showed no adverse effects, and 14-day toxicity studies in rats and horses did not show any unwanted reactions. In a 14-day toxicology study in beagle dogs, formation of antibodies was seen and in the end of the study period, three out of four dogs showed clinical immunological reactions, which could be ascribed to the formation of antibodies. The half-life, T, for human Gc globulin was 12 hr in rats, 16 hr in horses and 30 hr in dogs. The safety profile of plasma-derived Gc globulin is concluded to be consistent to that required for use in man.
authors.affiliation: Medicine and Surgery, Department of Large Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tina Holberg
authors.initials: TH
authors.lastname: Pihl
authors.forename: Charlotte Svaerke
authors.initials: CS
authors.lastname: Jørgensen
authors.forename: Eric
authors.initials: E
authors.lastname: Santoni-Rugiu
authors.forename: Páll Skúli
authors.initials: PS
authors.lastname: Leifsson
authors.forename: Erik Wind
authors.initials: EW
authors.lastname: Hansen
authors.forename: Inga
authors.initials: I
authors.lastname: Laursen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houen
mesh_terms: D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006168:Guinea Pigs; D018922:HL-60 Cells; D006736:Horses / Q000097:blood; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009928:Organ Specificity; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic; D014809:Vitamin D-Binding Protein / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D014809:Vitamin D-Binding Protein