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INFLAMMATION AND IMMUNOPHARMACOLOGY

Calf Intestinal Alkaline Phosphatase, a Novel Therapeutic Drug for Lipopolysaccharide (LPS)-Mediated Diseases, Attenuates LPS Toxicity in Mice and Piglets

Institute for Risk Assessment Sciences, University Utrecht, Utrecht, The Netherlands (C.B., M.W., W.R., D.F., R.B., W.S.); and AM-Pharma Holding BV, Bunnik, The Netherlands (M.W., W.R., R.B.)

It has been demonstrated that human placental alkaline phosphatase (HPLAP) attenuates the lipopolysaccharide (LPS)-mediated inflammatory response, likely through dephosphorylation of the lipid A moiety of LPS. In this study, it is demonstrated that also alkaline phosphatase derived from calf intestine (CIAP) is able to detoxify LPS. In mice administered CIAP, 80% of the animals survived a lethal Escherichia coli infection. In piglets, previous to LPS detoxification, the pharmacokinetic behavior of CIAP was studied. CIAP clearance was shown to be dose-independent and showed a biphasic pattern with an initial t_1/2 of 3 to 5 min and a second phase t_1/2 of 2 to 3 h. Although CIAP is cleared much faster than HPLAP, it attenuates LPS-mediated effects on hematology and tumor necrosis factor- responses at doses up to 10 µg/kg in piglets. LPS-induced hematological changes were antagonized, and the tumor necrosis factor- response was reduced up to 98%. Daily i.v. bolus administration of 4000 units CIAP, the highest dose used in the LPS intervention studies, in piglets for 28 days was tolerated without any sign of toxicity. Therefore, CIAP potentially encompasses a novel therapeutic agent in the treatment of LPS-mediated diseases. Based on the data mentioned above, human clinical trials have been initiated.

Address correspondence to: Prof. W. Seinen, Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, The Netherlands. E-mail: w.seinen{at}iras.uu.nl

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