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New Agent in the Treatment of Cystinuria: N-Acetyl-D-Penicillamine

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New Agent in the Treatment of Cystinuria: N-Acetyl-D-Penicillamine BrJRNA 284 3 February 1968 MEDCAL JOURNAL Br Med J: first published as 10.1136/bmj.1.5587.284 on 3 February 1968. Downloaded from New Agent in the Treatment of Cystinuria: N-acetyl-D-penicillamine G. S. STOKES,* M.D., B.S.; J. T. POTTS, jun.,t M.D.; M. LOTZ,4 M.D.; F. C. BARTTER,§ M.D. Brit. med. Y., 1968, 1, 284-288 Treatment of cystinuria with D-penicille, introduced by D-penicillamine 2 g./day. During a drug-free control period Crawhall, Scowen, and Watts (1963), has dramatically reduced of 6 to 12 days routine haematological, renal, and hepatic morbidity due to cystine urolithiasis in selected patients, both function tests were carried out, two or more 24-hour urine by preventing new stone formation (Crawhall, Scowen, and collections were analysed for cystine, and serum copper and Watts, 1964; Bartter, Lotz, Thier, Rosenberg, and Potts, 1965; ceruloplasmin were determined; in one patient urinary iron MacDonald and Fellers, 1966) and by dissolving stones lodged and copper excretion were estimated by the methods of Gubler, in the renal pelvis (Lotz and Bartter, 1965; McDonald and Lahey, Ashenbrucker, Cartwright, and Wintrobe (1952) and Henneman, 1965). These effects were apparently based on Henry, Sobel, and Chiamori (1958), respectively. In six formation of the more soluble mixed disulphide, penicillamine- patients urinary excretion of kynurenine during 24 hours after cysteine, in place of cystine. However, the administration of a 2-g. oral load of L-tryptophan was determined by the method D-penicillamine involves a definite risk of complications, such of Tompsett (1959). N-acetyl-penicillamine, 2 to 4 g./day by as reactions resembling serum sickness, skin rash, nephrotic mouth in equally divided six-hourly doses, was administered syndrome, agranulocytosis, impairment of taste sensation, and for a period of five days to five weeks. Haematological, liver- iron depletion. In addition, D-penicillamilne inactivates function, and tryptophan-loading tests were repeated at weekly pyridoxal-5-phosphate and gives rise to biochemical changes intervals; serum copper, ceruloplasmin, and inulin and P.A.H. typical of pyridoxine deficiency in experimental animals clearances were determined on one or more occasions; and (Asatoor, 1964) and in man (Jaffe, Altman, and Merryman, the 24-hour urinary output of free cystine, N-acetyl- 1964). It also affects collagen metabolism, producing inhibition penicillamine-cysteine mixed disulphide and cysteine-homo- of wound-healing in normal rats (Nimni and Bavetta, 1965) cysteine mixed disulphide was measured daily or at intervals. and in patients after long-term treatment for Wilson's disease Similar studies were also carried out in eight patients during or cystinuria (Scheinberg, 1964; Harris and Sjoerdsma, 1966). a course of D-penicillamine 2 to 4 g./day. All three of the reactive sites of the D-penicillamine molecule The procedures for collecting 24-hour urine specimens, for -the a-amino group, the sulphydryl group, and the terminal determining renal clearances, and for measuring cystine and carboxyl group-are required for maximal metal-chelating mixed disulphides in urine and plasma were as described else- activity (Aposhian, 1961); interference with pyridoxal phos- where (Stokes, Potts, Lotz, and Bartter, 1966a, 1968), except phate involves at least two, the a-amino and the sulphydryl for a modification of the automatic amino-acid analyser system (du Vigneaud, Kuchinskas, and Horvath, 1957). It is likely necessary for the determination of homocysteine-cysteine; that the other undesirable side-effects are related to molecular elution at 550 C. with 0.2 M sodium citrate pH 3.5 buffer (68 configuration involving the participation of two or more of ml./hour) was followed after 30 minutes by 0.2 M citrate pH http://www.bmj.com/ the reactive groups. The known actions of D-penicillamine in 4.1 buffer containing 2.3% benzyl alcohol and 5% propanol. decreasing free urinary cystine in cystinuria involve only the sulphydryl group necessary to form a mixed disulphide with cysteine (Eldjarn and Hambraeus, 1964; Bartter et al., 1965). Results Thus it was of interest to study in cystinuric patients the effects of N-acetyl-D-penicillamine, a thiol structurally similar Characteristics of N-acetyl-D-penicillamine and to D-penicillamine but lacking a free a-amino group. N-acetyl-D-penicillamine-cysteine It was shown that N-acetyl-D-penicillamine is an effective on 26 September 2021 by guest. Protected copyright. N-acetyl-D-penicillamine (Fig. 1) is a white crystalline cozh therapeutic agent in cystinuria, causing a decrease in urinary soluble in water and same as but pound (M.W.191.25) sparingly ninhydrin- free cystine by the mechanisms D-penicillamine, to the lack of a reactive a-amino group. The some toxic effects of the parent compound. Further, negative owing lacking blocking of the a-amino group was shown also to prevent it was shown that restriction of dietary methionine, a precursor inactivation of pyridoxal. Pyridoxal-5-phosphate in 0.1 M of cystine, can potentiate the effectiveness of N-acetyl-D- buffer has a green of the urine phosphate pH 7.4 (0.21 /Amole/ml.) pale penicillamine in cystinuria, and that alkalinization which fades on addition 0.63 is also effective as adjunctive treatment. colour rapidly of D-penicillamine, (1) Cystine (2) N-Acetyl-D-Penicillomine ,NH2 Materials and Methods CH3 HOOC-CH-CH2-S HS-C-CH-COOH Ten patients with homozygous cystinuria were studied, seven CH3 NH of whom had been previously treated for 3 to 36 months with HOOC- H-CH2- S NH2 C=O * Overseas Research Fellow of the National Heart Foundation of CH3 Australia, Clinical Endocrinology Branch, National Heart Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. Present (3) N-Acetyl-D-Penicillaminef-Cysteine address: Medical Research Department, Kanematsu Memorial Insti- tute, Sydney Hospital, Sydney, Australia. NH2 CH3 t Chief, Section on Polypeptides, Laboratory of Metabolism, National HOOC - CH - CH2- S-S-C-CH-COOH Heart Institute, National Institutes of Health, Bethesda, Maryland, CH3 NH U.S.A. t Clinical Endocrinology Branch, National Heart Institute, National Insti- C=O tutes of Health, Bethesda, Maryland, U.S.A. Present address: Assistant Professor of Medicine, Georgetown Medical School, Wash- CH3 ington, D.C., U.S.A. 1.-Structural formulae of cystine, of S Chief, Clinical Endocrinology Branch, National Heart Institute, National FIG. N-acetyl-D-penicill- Institutes of Health, Bethesda, Maryland, U.S.A. amine, and of the mixed disulphide formed by their interaction. BRmSH 285 3 February 1968 Cystinuria-Stokes et al. MEDICAL JOURNAL 285 ,umole/ml., as a new compound is formed, apparently a thiazo- 30-g. protein, low methionine diet, and no other treatment her lidine involving the sulphydryl and a-amino groups of D-peni- urinary cystine excretion averaged 488 mg./day (Fig. 3). After Br Med J: first published as 10.1136/bmj.1.5587.284 on 3 February 1968. Downloaded from cillamine (du Vigneaud et al., 1957). The absorption spectrum treatment with N-acetyl-penicillamine 2 g./day for four days and of this new compound is in the ultraviolet range. In contrast, 4 g./day for three days her urinary free cystine had decreased to the addition of an equimolar amount of N-acetyl-penicillamine less than 100 mg./day. to the pyridoxal-5-phosphate solution caused no loss of colour N-acetyl-penicillamine thus reduced urinary cystine to lower or shift in absorption spectrum. values in Case 1 than in Case 7. The possibility that this N-acetyl-D-penicillamine-cysteine formed by disulphide difference could derive from the adjunctive effect of the low- interchange between N-acetyl-D-penicillamine and cystine methionine intake in Case I was investigated in Case 3. in vitro and in vivo is ninhydrin-positive by virtue of the a- Case 3.-This patient was a 47-year-old businessman (Fig. 4). amino group of cysteine. Like cysteine and cystine, it reacts After equilibration on a diet containing 70 g. of protein and 1.9 g. with ninhydrin to produce a colour with lower absorbance at of methionine per day his urinary cystine averaged 695 mg./day. 570 m/A than most other amino-acids and relatively high absorbance at 440 Its solubility in water is about 500 mFL. Dietary protein =70J9d. times that of cystine and 10 times that of D-penicillamine- Methioniae = 1.5 gid. cysteine. N-acetyl-penicillamine, like D-penicillamine, gives a Cystine =1-2qJd N-Acetyt- ° positive reaction with the standard nitroprusside cyanide test Penicillamine 2 (Lewis, 1932), while N-acetyl-penicillamine disulphide and N- 9 I d. 4 acetyl-penicillamine-cysteine both give negative results. This 1000 observation suggested that the nitroprusside cyanide.test could 800] be used to assess decreases in urinary free cystine during treat- ment with N-acetyl-penicillamine, as has been reported in the Urinary free 600] case of D-penicillamine therapy (Lotz, Potts, and Bartter, Cystine mq./d. 4001 1 965b). In two patients with similar daily cystine outputs cystine in urine samples collected before and during treatment 200 with N-acetyl-penicillamine was estimated both by Spinco 0 1/2 Cystine in4 001 El_ analysis and by a quantitative cyanide-nitroprusside test urinary (Coxon and Kolb, 1954). The results are shown in Table I. N-Acetyl- 200 - They indicate that N-acetyl-D-penicillamine is effective in Penicilllamine - Cysteine O 00 00 00 LBP-FI p~ I " ~ -s 0 reducing urinary cystine and that the nitroprusside cyanide test 3 5 7 19 11 13 I5 17 19 21 24 provides a rough measure of the therapeutic effectiveness of N- Days acetyl-penicillamine, though it tends to overestimate cystine Fig. 3 concentration. Dietary protein = 30q /d. Methsonine = 05q./d.
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