Cystinuria, treatment

Fig. 2.1.2a-c A Urine amino acids in a patient with cystinuria assayed by an amino acid analyzer (AAA). The indicated peaks are 1 glycine, 2 cystine, 3 ammonia, 4 ornithine, 5 lysine, 6 arginine, i.s. internal standard (S-amino thyl-cysteine). Cystinuria treatment is best followed-up by analyzing an early morning urine specimen, which usually shows the highest amino acid concentrations. b-c see next page... 

Penicillamine has also been used in cystinuria and for the treatment of rheumatoid arthritis. Discovery of its chelating properties led to its use in patients with Wilson s disease (hepatolenticular degeneration) and heavy-metal intoxications. Penicillamine is administered by mouth and should be taken on an empty stomach [4],... 

Lupus erythematosus Certain patients will develop a positive antinuclear antibody (ANA) test and some may show a lupus erythematosus-like syndrome similar to other drug-induced lupus, but it is not associated with hypocomplementemia and may be present without nephropathy. A positive ANA test does not mandate drug discontinuance however, a lupus erythematosus-like syndrome may develop later. Sensitivity reactions Once instituted for Wilson s disease or cystinuria, continue treatment with penicillamine on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after reinstitution of therapy. 

In the area of rheumatology, the importance of using optically pure drugs is well illustrated by penicillamine o-penicillamine has been used for many years in treatment of Wilson s disease and cystinuria and is now widely used in rheumatoid arthritis. It is well established now that this drug, which is chiral, should only be given in the pure d (or S) form, because the toxicity of the l (or R), or the dl (RS) racemic forms, is much greater. This fact was found by trial and error, with some earlier patients on DL-penicillamine experiencing severe adverse side reactions such as optic neuritis. Now only the pure d form is available for prescription (see also 62.2.3.4).61... 

Stephens AD. Cystinuria and its treatment 25 years experience at St. Bartholomew s Hospital. J Inherit Metab Dis 1989 12(2) 197-209. 

Ludolph AC, Masur H, Oberwittler C, Koch HG, Ullrich K. Sensory neuropathy and vitamin B6 treatment in homo-cystinuria. Eur J Pediatr 1993 152(3) 271. 

In 66 patients with cystinuria, adverse reactions to tiopronin (mean dose 1193 mg/day) were common, and occurred in 76% of the patients with a history of D-penicillamine treatment and 65% of those without a history of D-penicillamine treatment, compared with 84% who had adverse effects with D-penicillamine (3). Serious adverse reactions requiring drug withdrawal were less common with tiopronin. Among the patients who took both drugs 31% had to stop taking tiopronin, whereas 69% could not tolerate D-penicillamine. 

In a comparison of tiopronin and penicillamine in the treatment of cystinuria in 15 children, nephrotic syndrome developed in one of the patients taking tiopronin no further details were given (16). 

Cystinuria la. Type I (kidney 4- gut) lb. Type II (kidney -f gut) lc. Type III (kidney 4" gut) (reoesBive ) Cystine 4 dibasic amino acids Cystine + dibasic amino acids Cystine 4- dibasic anuno adds Cystine and dibasic amino acids 1 Dibasic amino acids / Normal absorption 1 Renal calculi usually containing cystine (treatment with high water intake or penicillamine administration) Chromato phy, cystine crystals in urine urinary nitro-prusside test is podtive (B6, E5, H17, H18, K12, M8. P12, H6, R8, T3a)... 

D-Penicillamine, which is structurally related to the amino acids valine and cysteine, is used as an anti-inflammatory drug in the treatment of rheumatoid arthritis, cystinuria, and Wilson disease. Because of a high incidence of adverse events and the strong association with several autoimmune-like phenomena, including myasthenia, pemphigus, and Goodpasture disease, the clinical use is limited. Patients with HLA-DR3 haplotype as well as those with inherited impaired sulfoxidation status are at increased risk (Emery Panayi, 1989). 

D-penicillamine is so named because it was first isolated as an amine, from the degradation products of penicillin by Abraham et al [87]. Later studies showed the characteristic chemical behavior of D-penicillamine which involve three types of reactions, formation of disulphide links, formation of thiazolidine rings, and formation of metal complexes and chelates [67]. It was first used in 1956 in the treatment of Wilson s disease [88]. D-penicillamine has since been used in the treatment of many diseases, such as cystinuria [89], rheumatoid arthritis [90-92], systemic sclerosis [93], primary bdiary cirrhosis [94], heavy metal poisoning due to lead [95], cadmium [%], and mercury [97], and hyperviscosity syndrome [99]. In rheumatoid arthritis, D-peni-cdlamine has been widely accepted as an effective second line treatment. Despite of its effectiveness, it causes many adverse effects, such as skin rashes [99,100], taste abnormalities [100,101], hepatic dysfunction [102-104], gastrointestinal toxiciiy [99,105], proteinuria [100,106], hematuria [107, 108], thrombocytopenia [92, 109], aplastic anemia [110], lupus-like syndrome [111, 112], Goodpasture s-tike pulmonary renal syndrome [113-115], vasculitis [116,117], myasthenia gravis [118-122], polymyositis [123, 124], and dermatomyositis [125]. 

D-penicillamine (D-3-mercaptovaline, Cuprimine), a breakdown product of penicillin, was, after the discovery of its chelating properties of copper ion (Fig. 2-6), introduced as an antidote to copper poisoning. It was also found useful in the treatment of Wilson s disease, where excess copper accumulation causes liver cell damage. Heavy metal poisoning treatment is not limited to copper. Mercury and lead poisoning are also successfully reversed. Formation of cysteine calculi (cystinuria) can also be reversed with penicillamine by forming a soluble disulfide compound. 

A chelating agent used in the treatment of a variety of conditions. These include lead poisoning and Wilson s disease where it helps remove lead and copper respectively. It is also used in the treatment of cystinuria. 

Thiola (Of-mercaptopropionyl glycine) is a new drug developed to replace D-penicill-amine in the treatment of cystinuria. The drug was used in 9 patients for treatment and post-operative prophylaxis. Dosage was 200—1,000 mg daily for 3-42 months with an average of 13 months. Seven out of 9 patients reacted favourably to the treatment, but the number is too small to allow definitive conclusions. 

Remien, A., Kallistratos, G. and Burck-hatdt, P. (1975) Treatment of cystinuria with Thiola (a-mercaptopropionyl glycine). Europ. Urol, 1, 227. 

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