Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy.
CUPRIMINE is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that CUPRIMINE is not of value in ankylosing spondylitis.
Wilson's disease (hepatolenticular degeneration) occurs in individuals who have inherited an autosomal recessive defect that leads to an accumulation of copper far in excess of metabolic requirements. The excess copper is deposited in several organs and tissues, and eventually produces pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain, where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are either asymptomatic or manifest only hepatic symptomatology.
Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic in whom it can be assumed the disease will develop in the future if the patient is not treated.
The diagnosis, if suspected on the basis of family or individual history or physical examination, can be confirmed if the plasma copper-protein ceruloplasminFor quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I.; Scheinberg, I.H.: Measurement of the concentration of ceruloplasmin in serum by determination of its oxidase activity, in "Laboratory Diagnosis of Liver Disease", F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St. Louis, Warren H. Green, Inc., 1968, pp. 193-195. is <20 mg/dL and either a quantitative determination in a liver biopsy specimen shows an abnormally high concentration of copper (>250 mcg/g dry weight) or Kayser-Fleischer rings are present.
Treatment has two objectives:
(1)to minimize dietary intake of copper;
(2)to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.
The first objective is attained by a daily diet that contains no more than one or two milligrams of copper. Such a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water contains more than 0.1 mg of copper per liter.
For the second objective, a copper chelating agent is used.
In symptomatic patients this treatment usually produces marked neurologic improvement, fading of Kayser-Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.
Clinical experience to date suggests that life is prolonged with the above regimen.
Noticeable improvement may not occur for one to three months. Occasionally, neurologic symptoms become worse during initiation of therapy with CUPRIMINE. Despite this, the drug should not be withdrawn. Temporary interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it may result in clinical improvement of neurological symptoms (see WARNINGS). If the neurological symptoms and signs continue to worsen for a month after the initiation of CUPRIMINE therapy, several short courses of treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE may be considered.
Treatment of asymptomatic patients has been carried out for over thirty years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with CUPRIMINE is continued.
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, CUPRIMINE may be used as additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE 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:
CSSC + PS'
CS' + CSSP
PSSP + CS'
PS' + CSSP
CSSC + PSSP'
CSSC = cystine
CS' = deprotonated cysteine
PSSP = penicillamine disulfide
PS' = deprotonated penicillamine sulfhydryl
CSSP = penicillamine-cysteine mixed disulfide
In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing about the disulfide interchange.
Because CUPRIMINE 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 CUPRIMINE (see PRECAUTIONS).
Published Studies Related to Cuprimine (Penicillamine)
Oral D-penicillamine for the prevention of retinopathy of prematurity in very low birth weight infants: a randomized, placebo-controlled trial. [2010.09]
PURPOSE: To compare prophylactic enteral D-penicillamine (DPA) with placebo for prevention of 'retinopathy of prematurity (ROP) or death' among very low birth weight (VLBW) infants... CONCLUSION: Prophylactic enterally administered DPA suspension in a dose 100 mg/kg/dose 8 h for 3 days, followed by 50 mg/kg once per day for next 11 days, does not prevent 'any stage ROP or death' or 'ROP requiring treatment' in VLBW infants. DPA is well tolerated and does not have any major short-term adverse effects. (c) 2010 The Author(s)/Journal Compilation (c) 2010 Foundation Acta Paediatrica.
Oral D-penicillamine for the prevention of retinopathy of prematurity in very low birth weight infants: a randomized, placebo-controlled trial. [2010.04.16]
Abstract Purpose: To compare prophylactic enteral D-penicillamine (DPA) with placebo for prevention of 'retinopathy of prematurity (ROP) or death' among very low birth weight (VLBW) infants. Methods: This was a double-blind, single-centre, randomized, placebo-controlled trial with stratification (for birth weight <1250 and >/=1250 g) and blocking...
High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned. [2004.02]
OBJECTIVES: To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine... CONCLUSIONS: Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.
The Disability Index of the Health Assessment Questionnaire is a predictor and correlate of outcome in the high-dose versus low-dose penicillamine in systemic sclerosis trial. [2001.03]
OBJECTIVE: To explore the clinical implications of a score of > or =1.0 on the Disability Index of the Health Assessment Questionnaire (HAQ DI) at the first patient visit, and to examine the implications of improvement in HAQ DI score over 2 years in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma... CONCLUSION: A baseline HAQ DI score of > or =1.0 predicted mortality over 4 years. Improvement in the HAQ DI score in these patients with diffuse scleroderma was associated with improvement in skin thickening, hand function, oral aperture, lung function, signs of arthritis, serum creatinine level, and the investigator's global assessment of improvement. The HAQ DI is a self-administered questionnaire that SSc patients can complete easily and rapidly and that gives the practicing physician important information about prognosis, patient status, and changes in disease course over time.
D-penicillamine is not an effective treatment in systemic sclerosis. 
Based on open studies. D-penicillamine (DPA) has been used for the treatment of systemic sclerosis (SSc) but we believe the controlled trial of this drug in SSc does not support its use to treat this disease.
Clinical Trials Related to Cuprimine (Penicillamine)
Post Marketing Surveillance Study of Cuprimine [No longer available]
Cuprimine (penicillamine) was made available in the Philippines by the Sponsor under a
Compassionate Special Permit issued by the Bureau of Food and Drugs. Physicians were able
to request the drug for their patients from the Sponsor. A Clinical Study Report form was
completed for each purchase of Cuprimine.
Penicillamine, Low Copper Diet, and Radiation Therapy in Treating Patients With Glioblastoma [Completed]
RATIONALE: Penicillamine may stop the growth of glioblastomas by stopping blood flow to the
tumor. A diet low in copper may interfere with the growth of brain tumor cells. Radiation
therapy uses high-energy x-rays to damage tumor cells. Combining these therapies may be
effective in treating glioblastoma.
PURPOSE: Phase II trial to study the effectiveness of penicillamine, a low copper diet, and
radiation therapy in treating patients who have newly diagnosed glioblastoma.
Study to Assess Long-Term Outcomes of Trientine in Wilson Disease Patients Withdrawn From Therapy With d-Penicillamine [Not yet recruiting]
A study to review Wilson disease patients who have previously been prescribed d-
Penicillamine but were changed to trientine as treatment for their disease, and to follow
them for a further 12 months.
Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine Capacity in Patients With Cystinuria [Recruiting]
The purpose of this study is to evaluate the effect of escalating doses of cystine biding
thiol drugs, including tiopronin and d-penicillamine, on the urinary cystine capacity, which
is a measure of the amount of cystine in the urine, in patients with cystinuria. The overall
goal will be to help guide therapy and ultimately minimize unnecessary side effects caused
by larger doses.
Cystine Capacity Clinical Study (CysCap) [Recruiting]
The purpose of this study is to determine whether urinary cystine capacity, an assay used to
measure the amount of cystine in the urine, can be used to predict stone recurrence in
patients with cystinuria.