Penicillamine for Wilson’s disease

Gilman PA, Holtzman NA. Acute lymphoblastic leukemia in a patient receiving penicillamine for Wilson s disease. JAMA 1982 248(4) 467-8. 

When patients are treated with n-pcnicilluminc for schleroderma, cystinuria. rheumatoid arthritis, and idiopathic pulmonary fibrosis. 32% show decreased taste acuity (hypo-geusia). In contrast, only 4% of the patients being treated with D-penicillamine for Wilson s disease exhibit hypogeusia. Discuss a possible mechanism. How might the hypogeusia be treated 192... 

Scheinborg and Stemlieb reviewed a total of 29 pregnancies occurring in 18 women, treated with penicillamine for Wilson s disease. A further 2 women used penicillamine during only a part of the pregnancy in these cases the withdrawal of the penicillamine resulted in severe exacerbation of the disease. All 31 infants were normal. 

Figure 7.30 (A) D-Penicillamine used for Wilson s disease treatment. (B) Copper-histidine...

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. 

Veen, C., van den Hamer, C.JA., de Leeuw, P.W. Zinc sulphate therapy for Wilson s disease after acute deterioration during treatment with low-dose D-penicillamine. J. Intern. Med. 1991 229 549—552... 

A 12-year-old boy with a history of a generalized pruritic rash after penicillin took penicillamine up to 500 mg/day for Wilson s disease. He had a rash after using penicillamine for 1 week. The penicillamine was stopped for 3 days. He developed nephrotic syndrome 2 weeks after restarting penicillamine. On electron microscopy, there was the typical picture of minimal change disease with extensive foot process effacement. 

When penicillamine is administered for a long time and in high doses (for example for Wilson s disease) it can cause a characteristic delayed skin eruption, with increased friability, hemorrhagic bullous lesions, and miliary papules (66,260-266). The lesions develop predominantly in those parts of the skin that are often exposed to trauma. This disorder is a manifestation of the effects of penicillamine on collagen and elastin. Occasionally, these eruptions imitate other rare... 

Although rare, Wilson s disease may itself be associated with a polyarthritis resembhng rheumatoid arthritis and when it develops during the use of penicillamine it can be mistaken for an adverse reaction to the drug (331). Demineralization osteopathy has been reported in a study on the use of o-penicillamine in Wilson s disease (SED-8, 536). 

A 6-year-old Taiwanese girl, who had taken penicillamine (dosage not specified) for Wilson s disease for 17... 

A baby with a bilateral cleft lip with total cleft palate was born at 41 weeks to a 22-year-old mother who had taken penicillamine (dosage not specified) throughout an uncomplicated pregnancy for Wilson s disease (386). The child did not have a lax skin. 

Miyagawa S, Yoshioka A, Hatoko M, Okuchi T, Sakamoto K. Systemic sclerosis-like lesions during longterm penicillamine therapy for Wilson s disease. Br J Dermatol 1987 116(1) 95-100. 

Treatment of active, symptomatic Wilson s disease is aimed at increasing urine copper excretion to eliminate excess copper from tissue. The primary therapy for Wilson s disease involves chelating agents such as o-penicillamine and trientine, which is now more widely used because of its lower rate of side effects. In patients with minimal symptoms or in asymptomatic family members, zinc is used to competitively inhibit copper absorption from the intestinal tract. Lifelong therapy with one of these types of treatment is required and is usually successful in limiting further damage. 

The medical value of a drug may be independent of the efficacy and rarity of the disease. For example, for Wilson s disease there are several products on the market that are effective and yet additional ones are still being developed. Penicillamine is often effective, but often causes serious adverse reactions. Zinc acetate and trientine are newer products and molybdenum is being evaluated for the same indication. 

Penicillamine is the drug of choice for treatment for Wilson s disease. However, the dmg produces undesirable effects, and some patients become intolerant. For these individuals, trientine (triethylenetetramine dehydrochloride, Cuprid) is an acceptable alternative. Trientine is an effective cupriuretic agent in patients with Wilson s disease, although it may be less potent than penicillamine. The drug is effective orally. Maximal daily doses of 2 g for adults or 1.5 g for children are taken in two to four divided portions on an empty stomach. Trientine may cause iron dehciency this can be overcome with short courses of iron therapy, but iron and trientine should not be ingested within 2 hours of each other. 

An early form of therapy involves eliminating the substrate either by excluding the substrate from the diet, as in phenylketonuria, or by administering drugs—such as penicillamine in Wilson s disease or allopurinol in gout. Orotic aciduria can be corrected by the administration of uridine, which provides the substrate for the biosynthesis of the nucleosides used in RNA and DNA synthesis and is also a substrate for the biosynthesis of inhibitors of the carbamyl aspartate synthetase, the first enzyme in the formation of orotic acid. By this feedback inhibition, the levels of orotic acid in the urine are reduced by the administration of uridine. 

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],... 

Treatment. Since the 1950s, the treatment of Wilson s disease has relied on chelating agents [25]. Early attempts to use BAL or EDTA for this purpose were unsuccessful, but penicillamine, triethylene tetramine dihydrochloride (trientine), and tetrathiomolybdate, all in combination with a low-copper diet, have proved to be effective, and result in the urinary excretion of large amounts of copper. The use of penicillamine is complicated by the fact that it may induce a transient worsening of neurologic function due to rapid mobilization of copper, and also has other side-effects, such as the development of nephrosis. Tetrathiomolybdate is an effective alternative with fewer side-effects [26]. In cases in which the dose was rapidly escalated, however, bone marrow suppression or liver function abnormalities have been described. 

Although chelation is not helpful for Alzheimer s disease patients, it is the key to treating patients with dementia due to Wilson s disease. Wilson s disease is a genetically inherited disorder that usually strikes before age 30. The disease causes toxic levels of copper to accumulate in the liver, brain, eyes, and kidney. Untreated, Wilson s disease leads to tremors, cirrhosis, depression, psychosis, dementia, and ultimately death. Chelation with penicillamine (Cuprimine) can stop and even reverse the accumulation of copper. 

Wilson s disease - Penicillamine is a chelating agent that removes excess copper in patients with Wilson s disease. Noticeable improvement may not occur for 1 to 3 months. 

Dietary suppiementation Because of their dietary restriction, give patients with Wilson s disease, cystinuria, and rheumatoid arthritis whose nutrition is impaired 25 mg/day of pyridoxine during therapy, because penicillamine increases the requirement for this vitamin. 

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use in outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has generally replaced penicillamine for these purposes. 

The use of chelating or complexing agents to treat metabolic dysfunction. The classical example is the use of D-penicillamine to treat Wilson s disease, which is caused by an inability of the body to metabolize copper in the normal way. Another example is the use of desferrioxamine for iron overload in Cooley s anemia, which is caused by a fault in hemoglobin synthesis. 

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