Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets.
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-alpha responses at doses up to 10 microg/kg in piglets. LPS-induced hematological changes were antagonized, and the tumor necrosis factor-alpha 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.
Beumer
Chantal
C
Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands.
Wulferink
Marty
M
Raaben
Willem
W
Fiechter
Daniëlle
D
Brands
Ruud
R
Seinen
Willem
W
D000469:Alkaline Phosphatase / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism; D002417:Cattle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058851:GPI-Linked Proteins; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C063088:ALPI protein, human; D000469:Alkaline Phosphatase