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Treatment of cystinuria with D-penicille, introduced by Crawhall, Scowen, and Watts (1963), has dramatically reduced morbidity due to cystine urolithiasis in selected patients, both by preventing new stone formation (Crawhall, Scowen, and Watts, 1964; Bartter, Lotz, Thier, Rosenberg, and Potts, 1965;MacDonald and Fellers, 1966) and by dissolving stones lodged in the renal pelvis (Lotz and Bartter, 1965;McDonald and Henneman, 1965). These effects were apparently based on formation of the more soluble mixed disulphide, penicillaminecysteine, in place of cystine. However, the administration of D-penicillamine involves a definite risk of complications, such as reactions resembling serum sickness, skin rash, nephrotic syndrome, agranulocytosis, impairment of taste sensation, and iron depletion. In addition, D-penicillamilne inactivates pyridoxal-5-phosphate and gives rise to biochemical changes typical of pyridoxine deficiency in experimental animals (Asatoor, 1964) and in man (Jaffe, Altman, and Merryman, 1964). It also affects collagen metabolism, producing inhibition of wound-healing in normal rats (Nimni and Bavetta, 1965) and in patients after long-term treatment for Wilson's disease or cystinuria (Scheinberg, 1964;Harris and Sjoerdsma, 1966).All three of the reactive sites of the D-penicillamine molecule -the a-amino group, the sulphydryl group, and the terminal carboxyl group-are required for maximal metal-chelating activity (Aposhian, 1961); interference with pyridoxal phosphate involves at least two, the a-amino and the sulphydryl (du Vigneaud, Kuchinskas, and Horvath, 1957 Henry, Sobel, and Chiamori (1958), respectively. In six patients urinary excretion of kynurenine during 24 hours after a 2-g. oral load of L-tryptophan was determined by the method of Tompsett (1959). N-acetyl-penicillamine, 2 to 4 g./day by mouth in equally divided six-hourly doses, was administered for a period of five days to five weeks. Haematological, liverfunction, and tryptophan-loading tests were repeated at weekly intervals; serum copper, ceruloplasmin, and inulin and P.A.H.clearances were determined on one or more occasions; and the 24-hour urinary output of free cystine, N-acetylpenicillamine-cysteine mixed disulphide and cysteine-homocysteine mixed disulphide was measured daily or at intervals. Similar studies were also carried out in eight patients during a course of D-penicillamine 2 to 4 g./day.The procedures for collecting 24-hour urine specimens, for determining renal clearances, and for measuring cystine and mixed disulphides in urine and plasma were as described elsewhere (Stokes, Potts, Lotz, and Bartter, 1966a, 1968), except for a modification of the automatic amino-acid analyser system necessary for the determination of homocysteine-cysteine; elution at 550 C. with 0.2 M sodium citrate pH 3.5 buffer (68 ml./hour) was followed after 30 minutes by 0.2 M citrate pH 4.1 buffer containing 2.3% benzyl alcohol and 5% propanol. ResultsCharacteristics of N-acetyl-D-penicillamine and N-acetyl-D-penicillamine-cysteine N-ace...

A man aged 49 was admitted to hospital on 15 October 1964 with a two-day history of increasingly severe abdominal pain, vomiting, and diarrhoea. He had been admitted to hospital five years, six months, and two months previously on account of abdominal pain,

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Many in v'ivo studies have been carried out on purine metabolism in man because of the presence of a readily available end product, uric acid. In the absence of a comparable unique end product, no previous over-all measurements of pyrimidine metabolism in the intact organism have been reported. Studies have been limited to the excretion of /8-aminoisobutyric acid, as a metabolite of thymine (1), the incorporation of pyrimidine precursors into circulating leukocytes (2), the induced urinary excretion of orotic acid and orotidine (3), and the spontaneous urinary excretion of certain trace pyrimidines (4). In this report a method is described for evaluating pyrimidine nucleotide synthesis in the intact organism, based on the release of carbon dioxide-C14 from carboxyl-labeled pyrimidine precursors. The usefulness of this procedure in defining the onset, degree, and duration of action of certain antimetabolites is illustrated by studies in rats, and in patients with leukemia. MATERIALS AND METHODSIntravenous injections of labeled compounds were given through indwelling jugular vein catheters to male albino rats, weighing 125 to 150 g. For collection of expired C1402, air was flushed through a closed metabolic chamber and the carbon dioxide trapped in 3 N NaOH. Acidification of aliquots of this solution allowed trapping of the carbon dioxide in Hyamine base and counting in a Packard Tri-Carb liquid scintillation spectrometer at an efficiency of approximately 45 per cent. Indwelling cystostomy catheters were operatively placed in rats for urinary studies. Sedation with perphenazine (Trilafon, Schering), and hydration with normal or hypotonic saline *

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