Treatment of asymptomatic patients has been carried out for over ten years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with Depen can be continued.

Cystinuria - Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine, lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular dysfunction.

Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent pathology connected with their excretion in excessive quantities.

Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria. Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed 1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is indicated.

Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation, keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy because of its low protein content (see PRECAUTIONS).

When these measures are inadequate to control recurrent stone formation, Depen may be used as additional therapy. When patients refuse to adhere to conventional treatment, Depen may be a useful substitute. It is capable of keeping cystine excretion to near
 normal values, thereby hindering stone formation and the serious consequences of pyelonephritis and impaired renal function that develop in some patients.

Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-cysteine mixed disulfide as:

In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing about the disulfide interchange.

Rheumatoid Arthritis - Because Depen can cause severe adverse reactions, its use in rheumatoid arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy. Even then, benefit-to-risk ratio should be carefully considered. Other measures, such as rest, physiotherapy, salicylates, and corticosteroids should be used, when indicated, in conjunction with Depen (see PRECAUTIONS).

CONTRAINDICATIONS - Except for treatment of Wilson’s disease or certain cases of cyst