Sheep Model

In the following paragraphs, the medical procedures utilised are described in much detail. There are many similar studies available in the literature that were designed to test and optimise in vivo the biomedical performance of bioactive coating systems. To avoid being overly repetitive, only a very few of these studies will be dealt with in this section. 

Hydroxyapatite Coatings Cylindrical Ti6Al4V rods of 130 mm in length and diameters between 11 and 13 mm were grit blasted with alumina (grain size 

The implanting operations were performed on skeletally mature sheep (42-84kg body weight) under general (55 mg Dormicum i.v. 700 mg Ketamin 

A solid metal cylinder (11-13 mm x 130 mm) was inserted into the femoral canal after reaming and the osteochondral block was replaced into its bed. Finally the wound was closed in layers and the sheep received a single shot antibiosis as well as pain medication. 

All animals were able fully weight bearing (FWB) until the end of their observation period of 6 months. It should be emphasised that the selected model of an intramedullary cylindrical rod resembles closely the situation of an endopros-thetic stem replacement operation. The cylindrical prosthesis stem was positioned in the medulla with a rather wide distance from the cortical bone wall. Since the establishment of a solid bony bridge between corticalis and implant requires an extended period of time, a thin hydroxyapatite coating with a short resorption time would not have been sufficient to guarantee a bony integration. Hence a coating thickness of about 150 pm was selected. 

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This was further reduced with NaBFLt in MeOH at 0 °C to give 53. Compound 53 displayed excellent activity in our jird and sheep models. Indeed, in our hands, this compound was two to four times more potent in sheep than the parent compound (PHA) against the important... 

Fleser PS, Nuthakki VK, Malinzak LE, et al. Nitric oxidereleasing biopolymers inhibit thrombus formation in a sheep model of arteriovenous bridge grafts. J Vase Surg 2004 40(4) 803-81 I. 

The monofunctional tryptase inhibitor APC-366 (Axys Pharmaceuticals) reduces the acute airway response and histamine release to allergen in a pig model of allergen-induced asthma [19]. APC-366 is also effective in a sheep model of allergen-induced asthma but was only poorly effective in asthma patients (proof-of-principle) [8], The compound was in clinical development phase II for asthma (inhalative). Although highly selective for tryptase over plasmin and plasma kal-likrein, APC-366 was not selective against thrombin and trypsin [13], Another monofunctional tryptase inhibitor is bis(5-amidino-2-benzimidazol-yl)methane (BABIM) which has been shown to be effective in the sheep. Further development of the compound was, however, discontinued, maybe because of the lack of selectivity over trypsin [13, 16, 17] (Figure 3.2.2). 

Owunwanne et al. (1988) evaluated technetium-99 m mercaptoacetylglycine for the detection and localization of gastrointestinal bleeding in a sheep model for the detection and localization of the site of gastrointestinal bleeding. 

Since the concentrations of insulin to be administered in the sheep model would have been large, the insulin-loaded chitosan nanoparticles were not investigated in that model. However, the pharmacodynamics and pharmacokinetics of various insulin-chitosan preparations were compared with postloaded insulin-chitosan nanoparticles. It was found that chitosan solution and chitosan powder formulations were far better, with the chitosan powder formulation showing a bioavailability of 17% as against 1.3 and 3.6% for the chitosan nanoparticles and chitosan solution [72], The effects of the concentration and osmolarity of chitosan and the presence of absorption enhancers in the chitosan solution on the permeation of insulin across the rabbit nasal mucosa in vitro and in vivo were investigated, and the same... 

The nasal absorption of insulin after administration in chitosan powder was the most effective formulation for nasal delivery of insulin in sheep compared to chitosan nanoparticles and chitosan solution [11], Similarly, chitosan powder formulations have been shown to enable an efficient nasal absorption of goserelin in a sheep model where bioavailabilities of 20-40% were obtained depending on the nature of the formulation [9],... 

Begin R, Masse S, Rola-Pleszczynski M, et al. 1987b. Asbestos exposure dose-bronchoalveolar milieu response in asbestos workers and the sheep model Evidences of a threshold for chrysotile-induced fibrosis. Drug Chem Toxicol 10 87-107. 

Lee TC, Gold LI, Reibman J, et al. 1997. Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-I in asbestosis in the sheep model. Int Arch Occup Environ Health 69 157-164. 

Kasaian MT, Donaldson DD, Tchistiakova L, Marquette K, Tan XY, Ahmed A, Jacobson BA, Widom A, Cook TA, Xu X, Barry AB, Goldman SJ, Abraham WM.. Efficacy of IL-13 neutralization in a sheep model of experimental asthma. Am. J. Respir. Cell. Mol. Biol. 2007 36 368-376. 

AlAT) has been used in injectable form for the treatment of hereditary AlAT deficiency that markedly increases the risk of development of emphysema. Absorption of aerosolized human plasma and recombinant AlAT into the lymph and blood was studied in sheep and humans. Human plasma AlAT was found in the sheep blood and interstitial lymph at concentrations 1/1000 of that in the alveolar epithelial lining fluid (ELF). The recombinant human AlAT is non-glycosylated and has a terminal methionine residue. In the sheep model, this molecule disappears from the alveolar fluid faster than the human plasma AlAT, with the lymph levels around 10% of ELF and blood levels about 10% of the lymph. The recombinant form... 

Charman S A, McLennan D N, Edwards G A, et al. (2001). Lymphatic absorption is a significant contributor to the subcutaneous bioavailability of insulin in a sheep model. Pharm. Res. 18 1620-1626. 

E. Kon, G. Filardo, M. Tschon, M. Fini, G. Giavaresi, L. Marchesini Reggiani, C. Chiari, S. Nehrer, I. Martin, D.M. Salter, L. Ambrosio, M. Marcacci, Tissue engineering for total meniscal substitution animal study in sheep model—results at 12 months. Tissue Eng. A... 

Simpson, D. M., Beynon, R. J., Robertson, D. H. L., Loughran, M., and Haywood, S., 2004, Copper associated liver disease a proteomics study of copper challenge in a sheep model, Proteomtcs 4 (in press). 

Penel G, Leroy N, Van Landuyt P, Flautre B, Hardouin P, Lemaitre J, et al. Raman microspectrometry studies of brushite cement in vivo evolution in a sheep model. Bone. 1999 Aug 25(2 Suppl) 81S S. 

In this paper our work on the marmoset and the sheep models is reviewed. 

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