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Title: LACK OF TOXICITY IN LAMBS RECEIVING REPEATED, HIGH DOSES OF RETINOYL B-GLUCURONIDE (RAG) INTRAVENOUSLY

Author
item ACKERMANN, MARK - IA STATE UNIV., AMES, IA
item MOHAMMADI, G - IA STATE UNIV., AMES, IA
item GRUBOR, B - IA STATE UNIV., AMES, IA
item GALLUP, J - IA STATE UNIV., AMES, IA
item Brogden, Kim
item BARUA, A - IA STATE UNIV., AMES, IA
item OLSON, J - IA STATE UNIV., AMES, IA

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 6/21/2001
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Retinoids can influence lung differentiation and repair; however, delivery of lipid-soluble retinoids to the lung by aerosol and intravenous injection are hindered by their lack of solubility in nebulizers and in the blood. In this study, we used an ovine model to determine if: 1) high doses of a water soluble retinoid (retinoyl b-glucuronide; RAG) could be formulated for repeated intravenous injections, 2) high, repeated does of RAG induce toxicity, and 3) the high, repeated doses of RAG are beneficial in repair of chronic lung injury caused by Mannheimia (Pasteurella) haemolytica. We determined that up to 419.7 mM RAG could be solubilized in 99.9% DMSO. Weaned lambs were inoculated intrabronchially with either 5 cc of saline or 109**9 CFU/ml of M. haemolytica in 5 cc saline. Intravenous injections of 2 mL of DMSO or RAG (115.97 mM)/DMSO were given 33, 38, 42, and 47 days post-intrabronchial inoculations and tissues were collected on day 50. RAG-treated lambs received a calculated initial average plasma concen- tration of 143.8 mM RAG/DMSO; the highest initial plasma concentration of RAG in any lamb was calculated to be 189.3 mM. Lambs had no evidence of clinical toxicity and lacked gross lesions in all organs as well as microscopic lesions in lung and liver. RAG did not have an influence on repair of lung lesions histologically. This work demonstrates that RAG can be given intravenously to sheep repeatedly at high doses without evidence of gross or microscopic toxicity.