PT  - JOURNAL ARTICLE
AU  - Beumer, Chantal
AU  - Wulferink, Marty
AU  - Raaben, Willem
AU  - Fiechter, Daniëlle
AU  - Brands, Ruud
AU  - Seinen, Willem
TI  - Calf Intestinal Alkaline Phosphatase, a Novel Therapeutic Drug for Lipopolysaccharide (LPS)-Mediated Diseases, Attenuates LPS Toxicity in Mice and Piglets
AID  - 10.1124/jpet.103.056606
DP  - 2003 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 737--744
VI  - 307
IP  - 2
4099  - http://jpet.aspetjournals.org/content/307/2/737.short
4100  - http://jpet.aspetjournals.org/content/307/2/737.full
SO  - J Pharmacol Exp Ther2003 Nov 01; 307
AB  - 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 t1/2 of 3 to 5 min and a second phase t1/2 of 2 to 3 h. Although CIAP is cleared much faster than HPLAP, it attenuates LPS-mediated effects on hematology and tumor necrosis factor-α responses at doses up to 10 μg/kg in piglets. LPS-induced hematological changes were antagonized, and the tumor necrosis factor-α 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. The American Society for Pharmacology and Experimental Therapeutics