D-Penicillamine Therapy in Cystinuria

Lotz, Myron; Potts, John T.; Holland, James M.; Kiser, William S.; Bartter, Frederic C.

doi:10.1016/s0022-5347(17)63443-8

Cited by 55 publications

(16 citation statements)

References 15 publications

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“…In a majority of the patients treated with tiopronin the excre tion of the mixed disulfide increased with increasing sodi um excretion. The concept of total urinay cystine, defined as the sum of free cystine and the amount of cystine corre sponding to the cysteine content in the mixed disulfide, was introduced by Lotz et al [27], We found that the posi tive correlation between urinary total cystine and sodium ( fig. 5) was stronger than the correlation between the excretion of free cystine and sodium ( fig.…”

Section: Discussionmentioning

confidence: 88%

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

Lindell¹,

Denneberg²,

Edholm³

et al. 1995

Nephron

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As with many other amino acids the transport of cystine across the tubular epithelium is coupled to a parallel transport of sodium. We have studied the effect of a sodium-restricted diet on the urinary excretion of cystine in 13 patients with cystinuria, 7 of whom were treated with the SH compound tiopronin (2-mercaptopropionylglycine). Five of the patients with tiopronin and 5 without were also given sodium bicarbonate. The patients were instructed to follow a sodium-restricted diet during three periods of 2 weeks each. Four levels of sodium intake were obtained including the preexperimental unrestricted diet. The average 24-hour excretion of free cystine increased by 3.1 μmol (0.75 mg) for each millimole increase in urinary sodium (p < 0.001). There was a greater sodium-related increase in excretion of cystine among patients without tiopronin treatment compared with the group with tiopronin (p < 0.01). Withdrawal of sodium bicarbonate resulted in a decrease in the 24-hour cystine excretion (p < 0.05). In the patients treated with tiopronin the excretion of the mixed disulfide increased with increasing urinary sodium (p < 0.05) suggesting a sodium-dependent active tubular reabsorption of this compound as well. We conclude that in spite of a defective proximal tubular reabsorption of cystine in cystinuria the reabsorption can be increased by restricting the intake of sodium. This effect of sodium may have clinical consequences for some cystinuric patients.

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Section: Discussionmentioning

confidence: 88%

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

Lindell¹,

Denneberg²,

Edholm³

et al. 1995

Nephron

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“…Because of the assumed mechanism of action of sulfhydryl compounds, namely a simple urinary disulfide exchange of reaction [2,26], one expects an unchanged amount of excreted total cystine during treat ment. In the investigations of Lotz et al [25] and Harbar et al [27] administration of D-penicillamine and tiopro nin, respectively, to noncystinuric control patients re sulted in a considerable urinary excretion of cystine-con taining mixed disulfides. These findings also suggest that an unchanged or even an increased excretion of urinary total cystine would result from administration of tiopron in or D-penicillamine to cystinurics.…”

Section: Total Urinary Excretion O F Cystine As Free Cystine and Mixementioning

confidence: 96%

“…10). Lotz et al [25], who introduced the con cept of 'total cystine', also found a reduced excretion of total cystine during administration of 1,000 mg (6.7 mmol) to 6,000 mg (40 mmol) of D-penicillamine/ day. In our patients, however, it seemed as if administra tion of smaller amounts of tiopronin caused an increase in total cystine ( fig.…”

Section: Total Urinary Excretion O F Cystine As Free Cystine and Mixementioning

confidence: 97%

Urinary Excretion of Free Cystine and the Tiopronin-Cysteine-Mixed Disulfide during Long-Term Tiopronin Treatment of Cystinuria

Lindell

Denneberg

Jeppsson

1995

Nephron

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We report the results of a biochemical evaluation of long-term treatment of cystinuria with the SH compound tiopronin (2-mercaptopropionylglycine). The effects of tiopronin were studied by monitoring the urinary excretion of free cystine and the mixed disulfide between tiopronin and cysteine. Thirty-one patients with homozygous cystinuria were treated with tiopronin for 0.4-12 years (mean 7.8 years). The urinary concentration of free cystine was used to adjust the tiopronin dose. In 28 of the 31 patients a mean urinary cystine concentration of less than 1,200 μmol/1 (288 mg/l) was achieved with the final dose. The final daily doses of tiopronin ranged from 250 mg (1.5 mmol) to 3,000 mg (18.4 mmol; mean 1,540 mg; 9.4 mmol). In a majority of the patients the treatment reduced the 24-hour urinary free cystine excretion effectively, on average by 0.61 μmol (0.15 mg)/mg of tiopronin administered. No changes in the efficacy of tiopronin over time were observed, and the frequency of adverse effects was acceptable. To evaluate the effects of tiopronin on the metabolism of cystine we calculated the total urinary excretion of cystine as the sum of free cystine and the amount of cystine corresponding to the cysteine content of the tiopronin-cysteine disulfide. At low doses of tiopronin there was an increase in urinary excretion of the mixed disulfide as well as of total cystine, whereas higher doses were followed by an unexpected decrease in the urinary excretion of these compounds. We conclude that long-term treatment with tiopronin in cystinuria effectively reduces the urinary excretion of free cystine. Monitoring urinary cystine concentration is necessary to achieve adequate individualized doses of tiopronin. Assessment of the mixed tiopronin-cysteine disulfide and the urinary excretion of total cystine shows that tiopronin may interfere with cystine metabolism in a more complex way than through a simple disulfide exchange reaction with urinary cystine.

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“…Die Cystinurie-Therapie mit D-Penicillamin wurde von Crawhall et al [88] 1963 eingeführt. Bei einer üblichen Dosierung von 1-2 g pro Tag wurden mehrere günstige Therapieverläufe erzielt [89][90][91]. Dass durch die Anwendung von ZLPenicillamin bei rheumatischen Er krankungen störende Nebenerscheinungen auftreten können, wie penicillinallergie-ähn liche Reaktionen [92] oder ein nephrotisches Syndrom mit Proteinurie [93], warschon frü her bekannt.…”

Section: Bildung Von Asymmetrischem Disulfdunclassified

Cystinurietherapie mit Ascorbinsäure

Asper¹,

Schmucki²

1982

Urol Int

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At the beginning of the four chapters on phaenomena, analysis, pathophysiology and therapy of cystinuria the essentials of the published literature are summarized. The frequency of cystinuria is in the order of 1:10,000. Besides the cystine lithiasis occurring in nine tenths of all cystinuria patients neurological diseases may also be observed. All commonly applied methods to analyze cystine detect the sum of cystine and cysteine. Cystinuria is characterized by a higher cystine excretion, up to the 100-fold of the normal. Also the concentrations of lysine, arginine and ornithine in the urine of cystinuria patients are elevated, caused by intestinal and renal transport defects. Inevitable damage of renal parenchyma by multiple operations can drastically be reduced by the therapy with D-penicillamine or α-mercaptopro-pionylglycine. The disadvantages of that formation of soluble asymmetric disulfides are the side effects, such as nausea, gastric difficulties and dermatosis, occurring in up to 50% of the patients. Using the especially developed method with HPLC separation and electrochemical detector with a mercury electrode, cystine and cysteine are analyzed simultaneously. In the urine of healthy persons the molar concentration of cysteine is in the same order as cystine. But in cystinuria the cysteine concentration in urine is about a thousand times less than that of cystine. These results are evidence that a shifted redox-equilibrium of cystine-cysteine is also typical of cystinuria. The molar cysteine percentage of cysteine in healthy persons is increased from 30 to 50% by oral ascorbic acid administration. Therefore a vitamine C therapy for cystinuria is developed. 31 cystinuria patients who receive 5 g of vitamine C a day show a decrease in the cystine concentration of about 40%. Up to now, no side effects have been observed. The most obvious sign of the positive effect of the proposed vitamine C therapy for cystinuria is the missing cystine sediment in fresh urine.

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D-Penicillamine Therapy in Cystinuria

Cited by 55 publications

References 15 publications

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

The Effect of Sodium Intake on Cystinuria with and without Tiopronin Treatment

Urinary Excretion of Free Cystine and the Tiopronin-Cysteine-Mixed Disulfide during Long-Term Tiopronin Treatment of Cystinuria

Cystinurietherapie mit Ascorbinsäure

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