No abstract

Therapy of Wilson's disease continues to evolve. In 1997, zinc acetate was added to the list of drugs approved by the Food and Drug Administration, which includes penicillamine and trientine. The mechanism of zinc's anticopper action is unique. It induces intestinal cell metallothionein, which binds copper and prevents its transfer into blood. As intestinal cells die and slough, the contained copper is eliminated in the stool. Thus, zinc prevents the intestinal absorption of copper. It is universally agreed that pregnant Wilson's disease patients should remain on anticopper therapy during pregnancy. There are numerous reports of such patients stopping penicillamine therapy to protect their fetus from teratogenicity, only to undergo serious deterioration and even death from renewed copper toxicity. Penicillamine and trientine have teratogenic effects in animals, and penicillamine has known teratogenic effects in humans. In this report we discuss the results of 26 pregnancies in 19 women who were on zinc therapy throughout their pregnancy. The evidence is good that zinc protects the health of the mother during pregnancy. Fetal outcomes were generally quite good, although one baby had a surgically correctable heart defect and one had microcephaly. (HEPATOLOGY 2000;31:364-370.)

No abstract

Monoclonal antibodies linked to toxic proteins (immunotoxins) can selectively kill some tumor cells in vitro and in vivo. However, reagents that combine the full potency of the native toxins with the high degree of cell type selectivity of monoclonal antibodies have not previously been designed. Two heretofore inseparable activities on one polypeptide chain of diphtheria toxin and ricin account for the failure to construct optimal reagents. The B chains (i) facilitate entry of the A chain to the cytosol, which allows immunotoxins to efficiently kill target cells, and (ii) bind to receptors present on most cells, which imparts to immunotoxins a large degree of non-target cell toxicity. This report identifies point mutations in the B polypeptide chain of diphtheria toxin that block binding but allow cytosol entry. Three mutants of diphtheria toxin have 1/1,000 to 1/10,000 the toxicity and 1/100 to 1/8,000 the binding activity of diphtheria toxin. Linking of either of two of the inactivated mutant toxins (CRM103, Phe508; CRM107, Phe390, Phe525) to a monoclonal antibody specific for human T cells reconstitutes full target-cell toxicity--indistinguishable from that of the native toxin linked to the same antibody--without restoring non-target cell toxicity. This separation of the entry function from the binding function generates a uniquely potent and cell type-specific immunotoxin that retains full diphtheria toxin toxicity, yet is four to five orders of magnitude less toxic than the native toxin is to nontarget cells.