Wilson s disease penicillamine

Wilson s disease. Penicillamine is a chelating agent that removes excess copper in patients with Wilson s disease. From in vitro studies that indicate that one atom of copper combines with two molecules of penicillamine, it would appear that 1 g of... 

In patients with Wilson s disease, penicillamine is rapidly attached to copper and, although higher doses are used, taste disturbances develop in a lower frequency, about 4% (SED-8, 536). It has been suggested that dysgeusia is related to deficiency of copper or zinc, but a strong connection between taste impairment and urinary copper excretion has not been demonstrated (118). Serum copper concentrations remained within normal limits and copper supplements were not effective in prevention (119). 

Several case reports have demonstrated that penicillamine can cause hver damage (SEDA-13, 199) (184), mainly cholestatic hepatitis, often associated with other signs of hypersensitivity such as fever, rash (185), and pulmonary (159,186) or hematological reactions (162). In two children with Wilson s disease, penicillamine was thought to have caused persistence of a pre-existing increase in aminotransferase activity (187). 

Penicillamine forms stable, soluble complexes with copper, iron, mercury, lead, and other heavy metals that are excreted in urine it is particularly useful in chelating copper in patients with Wilson s disease. Penicillamine also combines with cystine alone, reducing free cystine below the level of urinary stone formation. 

Though in SED VIII it was stated that in patients suffering from conditions other than Wilson s disease penicillamine does not interfere with the serum copper level, it has recently been observed that the increased serum copper levels which are seen in patients with rheumatoid arthritis fall during penicillamine therapy (la ). 

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. 

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

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. 

D-penidllamine can promote the elimination of copper (e.g., in Wilson s disease) and of lead ions. It can be given orally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal regimen (p. 320). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. 

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. 

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 (Cuprimine) can be used to treat acute, severe rheumatoid arthritis, producing reductions in joint pain, edema, and stiffness. The response to penicillamine is usually delayed (4-12 weeks), and remissions can last several months after withdrawal of treatment. Radiographic evidence of this drug s efficacy is limited thus, penicillamine is seldom used to treat rheumatoid arthritis. The mechanism of action of penicillamine is unknown, but some evidence suggests that it may involve the inhibition of angiogenesis, synovial fibroblast proliferation, or transcriptional activation. Because penicillamine can chelate copper and promote its excretion, it is used to treat Wilson s disease (hepatolenticular degeneration) and has also been used in mercury and lead intoxication. 

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. 

Both trien745 and 2,3,2-tet856 have been used to treat Wilson s disease in patients sensitive to D-penicillamine. Wilson s disease results from an inherited metabolic disorder which leads to the... 

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. 

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... 

A woman with Wilson s disease treated with penicillamine developed severe hirsutism (257). After treatment with oral contraceptives, her breasts enlarged rapidly, and she had cyclic mastodynia. Around the same time she also developed gingival hyperplasia. 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

Figure 2.8 Clonidine 23 was designed as a nasal decongestant but it turned out to be a potent antihypertensive drug. Clinical tests revealed the antidepressant activity of iproniazid 24, an isopropyl analog of the antituberculosis drug isoniazid 25. D-Penicillamine 26 was originally used to treat Wilson s disease, to eliminate an excess of copper ions later it was recognized to have beneficial effects in rheumatoid arthritis.

D-Penicillamine 26 (Figure 2.8) has for long time been used for the treatment of Wilson s disease, a metabolic disorder in which absorbed copper is deposited mainly in the liver and in the brain. Long-term application of this compound leads to suppression of rheumatoid arthritis, which now is its main therapeutic use [3],... 

Copper toxicity has been observed, althongh it is not a function of dietary overload. Abnormally low levels of ceruloplasmin associated with the genetic disorder, Wilson s disease, lead to excessive deposition of copper in the central nervous system, ocular tissue, liver, and other organs. Severe psychotic symptoms are observed. Urinary excretion of the copper can be achieved with specific chelating agents such as British anti-lewisite (BAL, 2,3-dimercaptopropanol) or penicillamine, orally administered. Symptoms of the disease are reversed as the copper levels return to normal. Reduction of dietary copper nptake by competition with relatively high levels of oral zinc is also effective. ... 

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