Jan Aaseth

Argyria—tissue deposition of silver as selenide

Generalized argyria was precipitated in a patient by treating gingival erosions with a solution of silver nitrate for several months. High silver concentrations were measured in skin biopsies. treatment with penicillamine did not increase the urinary silver excretion, indicating that silver is deposited in tissues in a chemically stable and apparently inert form. Electron microscopy showed that in the kidney, silver was deposited mainly in the basal membranes as electron-dense particles. These particles were studied by using X-ray emission spectrometry and electron diffraction. the particles consisted of Ag2Se in the low temperature orthorhombic alfaform. The lattice parameters are: a = 0.433 nm, b = 0.693 nm and c = 0.784 nm. This selenide complex seems to be remarkably non-toxic, since the renal function of the patient was unaffected and only negligible reactive changes were observed in kidney biopsies.

Mercaptodextran, a metal-chelating and disulphide-reducing polythiol of high molecular weight

Abstract A high molecular weight polythiol, mercaptodextran has been synthesized by thiolating various dextrans with N -acetyl homocysteine thiolactone. The thiol groups are unusually stable towards autoxidation. They are highly reactive and readily reduce disulphide bonds. Because of these properties mercaptodextran may be used to keep autoxidizable thiols in the reduced form. Mercaptodextran has no radioprotective effect, since it does not penetrate the cellular membrane. Mercaptodextran has a very high affinity for heavy metal ions. Competitive binding experiments show that mercapto-dextran has much higher affinity for silver, mercuric, cupric and auric ions than most other thiols (glutathione, penicillamine, N -acetyl-DL-penicillamine, cysteamine, mercapto-propionyl glycine, cysteine and diethyl dithiocarbamate) and other chelating agents (EDTA). Only 2,3-dimercaptopropanol (BAL) shows comparable binding properties. The stability constants for the Hg-BAL and Hg-mercaptodextran complexes are both about 10 20 , and about 100-times higher than for the Hg-penicillamine complex. The high metal-binding ability combined with a low toxicity suggest a possible use of mercaptodextran in acute metal-intoxications.

Gold and Thiol Compounds in the Treatment of Rheumatoid Arthritis

Double isotope-labelled auro thiomalate (Au195-C14-thiomalate) has been administered to mice and rats, and the excretory fate and tissue distribution have been studied. The results show that the gold and the thiomalate separate in vivo resulting in protein-bound gold and release of free thiomalate. About half of this thiol is excreted in the urine during the first day and the remaining half is taken up by the tissues. Thiomalate penetrates cellular membranes poorly, but is able to interact slowly with proteins (mixed disulphide formation). Part of the thiomalate which remains in the body is membrane bound. In contrast to penicillamine little thiomalate remains in circulation a few hours after administration. Gas chromatography--mass spectrometry has been used to search for the presence of free thiomalate in rheumatoid arthritis patients on Myocrisin (auro thiomalate) therapy. Thiomalate was found in their urine, but not in serum and synovial fluid 20 hours after administration. As thiomalate is released in the body after administration of Myocrisin. the question arises whether this thiol, like penicillamine, may have a beneficial effect in the treatment of rheumatoid arthritis.

THE EFFECT OF PENICILLAMINE AND 2,3-DIMERCAPTOSUCCINIC ACID ON URINARY EXCRETION AND TISSUE DISTRIBUTION OF GOLD

In order to study interactions in vivo between Au+ and SH-containing agents, groups of mice were given 35 mumol/kg of radiolabelled [195Au] thiomalate (Myocrisin) intramuscularly. The administration of Myocrisin is known to result in protein-bound gold and free thiomalate (mercaptosuccinate). High doses of dimercaptosuccinate (1 mmol/kg daily) increased the urinary excretion of radiolabelled gold [195Au] for several days. Treatment for 7 days with 1 mmol/kg of penicillamine or dimercaptosuccinate reduced the blood and kidney levels of gold to 30--50% of the controls. The oral administration of penicillamine in high doses, 1--10 mmol/kg, increased significantly the urinary excretion of [195Au] the first day after the Myocrisin injection, but on the subsequent days the radio-metal excretion was unaffected by the treatment. A lower dose level of penicillamine (0.3 mmol/kg daily) gave rise to only a small and insignificant increase in the urinary excretion of gold. The present results indicate that penicillamine at low clinical doses is an inefficient chelator of gold, while high doses (presumably comparable to about 1 200 mg daily in humans) may mobilize certain amounts of the metal deposits.