Adverse reactions to D-penicillamine after gold toxicity.

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

D-penicillamine and enzymatic activities.

The influence of incubation with D-penicillamine on pure enzyme preparations and on enzymatic activities of serum and skin homogenates was investigated. Three of the nine enzymatic activities studied underwent significant changes. Such effects of D-penicillamine must be taken into consideration if therapeutic or unwanted actions of this drug are to be fully understood; they are elicited by concentrations reached under conditions used for human therapy.     

The efficacy of 2,3-dimercaptopropanol and D-penicillamine on methyl mercury induced neurological signs and weight loss

In order to test the effectiveness of complexing therapy on methyl mercury induced neurotoxicity, female rats were treated for five days with either 2,3-dimercaptopropanol (BAL) or D-penicillamine (DPA) beginning 1 or 12 days after the final dose of methyl mercury hydroxide (MMOH). MMOH was administered orally at a dose of 13.3 mg/kg once each day for 3 successive days. BAL, dissolved in peanut oil, was administered sc in a dose of 30 mg/kg twice each treatment day. DPA was dissolved in water and administered sc in a dose of 1200 mg/kg once each treatment day. Therapy begun 1 day after the last MMOH administration was prior to the appearance of toxic signs but therapy begun 12 days later was after signs had developed. The ability of BAL or DPA therapy to alter the distribution of radio-labelled (²⁰³Hg) MMOH was determined. Both DPA and BAL significantly reduced tissue concentrations of mercury when administered beginning 1 day after MMOH, but only DPA was effective in removing mercury from tissues when treatment was begun 12 days after the last dose of MMOH. In a separate experiment when either BAL or DPA therapy was initiated as above 1 day after the last dose of MMOH, the appearance of neurological signs of toxicity was prevented and weight loss was reversed. When therapy was initiated the twelfh day after the last MMOH dose, neither BAL nor DPA was effective in reversing either neurotoxic signs or weight loss. Therefore, therapy is ineffective in reversing neurological signs if it is delayed too long after MMOH administration, even though it is effective in reducing tissue mercury levels.     

Phenylketonuria in a patient with cystinuria.

During routine screening procedures for amino-acid disorders by thin-layer chromatography, a 16-year-old boy was found to have phenylketonuria and cystinuria. A phenylalanine and a cystine loading were carried out. The patient was found to be homozygous for phenylketonuria and heterozygous for cystinuria type II. His father was heterozygous for phenylketonuria and cystinuria, while his mother proved to be heterozygous only for phenylketonuria.     

A practical classification of untoward drug effects.

All drug effects can be explained as results of complex interactions between the drug, the patient and his condition, and additional extrinsic factors. On the basis of these three "determinants", a practical classification of untoward drug effects (UDE) is suggested. UDE lists using this classification would fulfill the physician''s informational needs better than the material with which he is presently provided.     

The molecular bases of cystinuria and lysinuric protein intolerance

Cystinuria and lysinuric protein intolerance are inherited aminoacidurias caused by defective amino-acid transport activities linked to a family of heteromeric amino-acid transporters (HATs). HATs comprise two subunits: co-expression of subunits 4F2hc and y(+)LAT-1 induces the efflux of dibasic amino acids from cells, whereas co-expression of subunits rBAT and b(o,+)AT induces the renal reabsorption and intestinal absorption of cystine and dibasic amino acids at the brush border of epithelial cells. Recently, the role of b(o,+)AT (SLC7A9) in cystinuria (non Type I) and the role of y(+)LAT-1 (SLC7A7) in lysinuric protein intolerance have been demonstrated.     

The effect of D-penicillamine on human myeloperoxidase, a mechanism for the efficacy of the drug in rheumatoid arthritis

We investigated the effect of D-penicillamine on the ability of myeloperoxidase, purified from human leukocytes, to catalyse the oxidation of chloride ions to hypochlorite (HOCl) in the presence of H2O2. It is shown that, due to the interaction of D-penicillamine with both myeloperoxidase itself and HOCl, the chlorinating activity of myeloperoxidase in the presence of H2O2 and chloride ions is prevented. A concentration of 100 microM D-penicillamine inhibits the chlorinating activity of myeloperoxidase completely, which Is due to the stabilization of Compound II, an inactive form of the enzyme. In addition, HOCl reacts directly with D-penicillamine. Analysis of the reaction products of D-penicillamine and HOCl showed that D-penicillamine was oxidized to penicillamine disulphide and penicillamine sulphinic acid, and eventually deaminated (indicated by the release of ammonia). Lower concentrations of D-penicillamine (10 microM) inhibited myeloperoxidase less, but still acted as effective scavengers of HOCl. In very low concentrations (1 microM), D-penicillamine did not scavenge HOCl effectively, but rather stimulated the chlorinating activity of myeloperoxidase. However, when instead of D-penicillamine a comparable amount of ascorbate was added, a similar but even larger stimulation was observed. Since the concentration of free D-penicillamine in serum from rheumatoid patients treated with this drug is about 20 microM (Saetre, R. and Rabenstein, D.L. (1978) Anal. Chem. 50, 276-280), the therapeutic effect of D-penicillamine may be due to the protection of tissues against the reactive HOCl released by activated granulocytes at inflammation sites.     

Tissue stabilisation during histochemical reactions: The use of collagen polypeptides

Summary The incorporation of polyvinyl alcohol into the incubation medium prevents the loss of material from unfixed tissue sections during incubation. Polypeptides, derived from the partial degradation of collagen, are equally effective in retaining this material; at the same time they offer certain advantages over polyvinyl alcohol as tissue stabilisers.I wish to thank Mr. G. Frost for providing the polypeptides and Dr. J. Chayen for his interest and advice. I am grateful to the Medical Research Council for a grant and the Arthritis and Rheumatism Council for Research for general support.     

The amino acid transport system bo,+ and cystinuria

Amino acid transport in mammalian plasma membranes is mediated by a multiplicity of amino acid transport systems. Some of them (systems L, y⁺L, x_c^- and b^o,+) are the result of the activity of heteromeric amino acid transporters (HAT) (i.e. transport activity is elicited by the coexpression of a heavy and a light subunit). The two heavy subunits known today (HSHAT: rBAT and 4F2hc) were identified in 1992, and light subunits (LSHAT: LAT-1, LAT-2, asc-1, y⁺LAT-1, y⁺LAT-2, xCT and b^o,+AT) have been cloned in the last 2 years. Defects in two genes of this family (SLC3A1, encoding rBAT and SLC7A9, encoding b^o,+AT) are responsible for cystinuria, an inherited aminoaciduria of cystine and dibasic amino acids. This finding and functional studies of rBAT and b^o,+AT suggested that these two proteins encompassed the high-affinity renal reabsorption system of cystine. In contrast to this view, immunofluorescence studies showed that rBAT is most abundant in the proximal straight tubule, and b^o,+AT is most abundant in the proximal convoluted tubule of the nephron. The need for a newlight subunit for rBAT and a heavy subunit for b^o,+AT is discussed.