erular dysfunction results; and in the eye, where characteristic corneal copper deposits are known as kayser-fleischer rings. 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. diagnosis, suspected on the basis of family or individual history, physical examination, or a low serum concentration of ceruloplasmin*, is confirmed by the demonstration of kayser-fleischer rings or, particularly in the asymptomatic patient, by the quantitative demonstration in a liver biopsy specimen of a concentration of copper in excess of 250 mcg/g dry weight. treatment has two objectives: (1) to minimize dietary intake and absorption of copper. (2) to promote excretion of copper deposited in tissues. 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 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 penicillamine tablets. despite this, the drug should not be discontinued permanently. although temporary interruption may result in clinical improvement of the neurological symptoms, it carries an increased risk of developing a sensitivity reaction upon resumption of therapy (see warnings ). *for 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 to 195. 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 penicillamine tablets 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, penicillamine tablets may be used as additional therapy. when patients refuse to adhere to conventional treatment, penicillamine tablets 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= cystine cs'= deprotonated cysteine pssp=penicillamine ps'=deprotonated penicillamine sulfhydryl cssp= penicillamine-cysteine mixed disulphide 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 penicillamine tablets, 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 penicillamine tablets (see precautions ). image 03

osinophils. a confirmed reduction in wbc below 3500 per cubic ml mandates discontinuance of penicillamine therapy. thrombocytopenia may be on an idiosyncratic basis with decreased or absent megakaryocytes in the marrow, when it is part of an aplastic anemia. in other cases the thrombocytopenia is presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be normal or sometimes increased. the development of a platelet count below 100,000 per cubic ml, even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. a progressive fall in either platelet count or wbc in three successive determinations, even though values are still within the normal range, likewise requires at least temporary cessation. proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome. close observation of these patients is essential. in some patients the proteinuria disappears with continued therapy; in others penicillamine must be discontinued. when a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine. rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on penicillamine therapy, provided that quantitative 24-hour urinary protein determinations are obtained at intervals of one to two weeks. penicillamine dosage should not be increased under these circumstances. proteinuria which exceeds 1 g/24 hours, or proteinuria which is progressively increasing requires either discontinuance of the drug or a reduction in the dosage. in some patients, proteinuria has been reported to clear following reduction in dosage. in rheumatoid arthritis patients, penicillamine should be discontinued if unexplained gross hematuria or persistent microscopic hematuria develops. in patients with wilson's disease or cystinuria the risks of continued penicillamine therapy in patients manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits. when penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. cystine stones form rapidly, sometimes in six months. up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has been discontinued. because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy. goodpasture's syndrome has occurred rarely. the development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on x-ray requires immediate cessation of penicillamine. obliterative bronchiolitis has been reported rarely. the patient should be cautioned to report immediately pulmonary symptoms such as exertional dyspnea, unexplained cough, or wheezing. pulmonary function studies should be considered at that time. myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. ptosis and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. in the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine. most of the various forms of pemphigus have occurred during treatment with penicillamine. pemphigus vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. the seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. when pemphigus is suspected, penicillamine tablets should be discontinued. treatment has consisted of high doses of corticosteroids alone or, in some cases, concomitantly with an immunosuppressant. treatment may be required for only a few weeks or months, but may need to be continued for more than a year. once instituted for wilson's disease or cystinuria, treatment with penicillamine should, as a rule, be continued on a daily basis. interruptions for even a few days have been followed by sensitivity reactions after reinstitution of therapy. use in pregnancy penicillamine has been shown to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human use (based on a standard weight of 50 kg). skeletal defects, cleft palates, and fetal toxicity (resorptions) have been reported. there are no controlled studies on the use of penicillamine in pregnant women. although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. penicillamine should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. women on therapy with penicillamine who are of childbearing potential should be apprised of this risk, advised to report promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy. wilson’s disease reported experience* shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the wilson's disease, and that discontinuation of penicillamine has deleterious effects on the mother. if penicillamine is administered during pregnancy to patients with wilson's disease, it is recommended that the daily dosage be limited to 1 g. if cesarean section is planned, the daily dosage should be limited to 250 mg during the last six weeks of pregnancy and post-operatively until wound healing is complete. cystinuria if possible, penicillamine should not be given during pregnancy to women with cystinuria (see contraindications ). there are reports of women with cystinuria on therapy with penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery. if stones continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the fetus. rheumatoid arthritis penicillamine should not be administered to rheumatoid arthritis patients who are pregnant (see contraindications ) and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. there is a report that a woman with rheumatoid arthritis treated with less than one gram a day of penicillamine during pregnancy gave birth (cesarean delivery) to an infant with growth retardation, flattened face with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin.

three months, by which time the most reliable method of monitoring maintenance treatment is the determination of free copper in the serum. this equals the difference between quantitatively determined total copper and ceruloplasmin-copper. adequately treated patients will usually have less than 10 mcg free copper/dl of serum. it is seldom necessary to exceed a dosage of 2 g/day. if the patient is intolerant to therapy with penicillamine tablets alternative treatment is trientine hydrochloride. in patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions. cystinuria it is recommended that penicillamine tablets be used along with conventional therapy. by reducing urinary cystine, it decreases crystalluria and stone formation. in some instances, it has been reported to decrease the size of, and even to dissolve, stones already formed. the usual dosage of penicillamine tablets in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. for pediatric patients, dosage can be based on 30 mg/kg/day. the total daily amount should be divided into four doses. if four equal doses are not feasible, give the larger portion at bedtime. if adverse reactions necessitate a reduction in dosage, it is important to retain the bedtime dose. initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions. in addition to taking penicillamine tablets, patients should drink copiously. it is especially important to drink about a pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid than during the day. the greater the fluid intake, the lower the required dosage of penicillamine tablets. dosage must be individualized to an amount that limits cystine excretion to 100 to 200 mg/day in those with no history of stones, and below 100 mg/day in those who have had stone formation and/or pain. thus, in determining dosage, the inherent tubular defect, the patient's size, age, and rate of growth, and his diet and water intake all must be taken into consideration. the standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose*: * lotz, m., potts, j.t. and bartter, f.c.: britmed j 2 : 521, august 28, 1965 (in medical memoranda). add 2 ml of freshly prepared 5 percent sodium cyanide to 5 ml of a 24-hour aliquot of protein-free urine and let stand ten minutes. add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. cystine will turn the mixture magenta. if the result is negative, it can be assumed that cystine excretion is less than 100 mg/g creatinine. although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta. if there is any question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt: add 3 percent ferric chloride dropwise to the urine. penicillamine will turn the urine an immediate and quickly fading blue. cystine will not produce any change in appearance. rheumatoid arthritis the principal rule of treatment with penicillamine tablets in rheumatoid arthritis is patience. the onset of therapeutic response is typically delayed. two or three months may be required before the first evidence of a clinical response is noted (see clinical pharmacology ). when treatment with penicillamine tablets has been interrupted because of adverse reactions or other reasons, the drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly. initial therapy the currently recommended dosage regimen in rheumatoid arthritis begins with a single daily dose of 125 mg or 250 mg which is thereafter increased at one to three month intervals, by 125 mg or 250 mg/day, as patient response and tolerance indicate. if a satisfactory remission of symptoms is achieved, the dose associated with the remission should be continued (see maintenance therapy). if there is no improvement and there are no signs of potentially serious toxicity after two to three months of treatment with doses of 500 to 750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory remission occurs (see maintenance therapy) or signs of toxicity develop (see warnings and precautions ). if there is no discernible improvement after three to four months of treatment with 1000 to 1500 mg of penicillamine/day, it may be assumed the patient will not respond and penicillamine tablets should be discontinued. maintenance therapy the maintenance dosage of penicillamine tablets must be individualized, and may require adjustment during the course of treatment. many patients respond satisfactorily to a dosage within the 500 to 750 mg/day range. some need less. changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation rate for two to three months after each dosage adjustment. some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease suppression. in those patients who do respond, but who evidence incomplete suppression of their disease after the first six to nine months of treatment, the daily dosage of penicillamine tablets may be increased by 125 mg or 250 mg/day at three-month intervals. it is unusual in current practice to employ a dosage in excess of 1 g/day, but up to 1.5 g/day has sometimes been required. management of exacerbations during the course of treatment some patients may experience an exacerbation of disease activity following an initial good response. these may be self-limited and can subside within twelve weeks. they are usually controlled by the addition of nonsteroidal anti-inflammatory drugs, and only if the patient has demonstrated a true "escape" phenomenon (as evidenced by failure of the flare to subside within this time period) should an increase in the maintenance dose ordinarily be considered. in the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate from an exacerbation of the rheumatoid arthritis. discontinuance or a substantial reduction in the dosage of penicillamine tablets for up to several weeks will usually determine which of these processes is responsible for the arthralgia. duration of therapy the optimum duration of penicillamine tablets therapy in rheumatoid arthritis has not been determined. if the patient has been in remission for six months or more, a gradual, stepwise dosage reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted. concomitant drug therapy penicillamine tablets should not be used in patients who are receiving gold therapy, anti-malarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see precautions ). other measures, such as salicylates, other nonsteroidal anti-inflammatory drugs or systemic corticosteroids may be continued when penicillamine tablets is initiated. after improvement commences, analgesic and anti-inflammatory drugs may be slowly discontinued as symptoms permit. steroid withdrawal must be done gradually, and many months of penicillamine tablets treatment may be required before steroids can be completely eliminated. dosage frequency based on clinical experience, dosages up to 500 mg/day can be given as a single daily dose. dosages in excess of 500 mg/day should be administered in divided doses.

l agents (see precautions ). urticaria and exfoliative dermatitis have occurred. thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported. these reactions are extremely rare. some patients may develop a migratory polyarthralgia, often with objective synovitis (see dosage and administration ). gastrointestinal anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%). isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction and pancreatitis. intrahepatic cholestasis and toxic hepatitis have been reported rarely. there have been a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation and thymol turbidity tests. some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral ulcerations. although rare, cheilosis, glossitis, and gingivo-stomatitis have been reported (see precautions ). gastrointestinal side effects are usually reversible following cessation of therapy. hematological penicillamine can cause bone marrow depression (see warnings ). leukopenia (2%) and thrombocytopenia (4%) have occurred. fatalities have been reported as a result of thrombocytopenia, agranulocytosis, aplastic anemia, and sideroblastic anemia. thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis have also been reported. renal patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some, may progress to the development of the nephrotic syndrome as a result of an immune complex membranous glomerulopathy (see warnings ). central nervous system tinnitus, optic neuritis, and peripheral sensory and motor neuropathies (including polyradiculoneuropathy, i.e., guillain-barre syndrome) have been reported. muscular weakness may or may not occur with the peripheral neuropathies. neuromuscular myasthenia gravis (see warnings ). other adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see precautions ); falling hair or alopecia; lichen planus; polymyositis; dermatomyositis; mammary hyperplasia; elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and goodpasture's syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar hemorrhage (see warnings ). fatal renal vasculitis has also been reported. allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis, and pulmonary fibrosis have been reported in patients with severe rheumatoid arthritis, some of whom were receiving penicillamine. bronchial asthma also has been reported. increased skin friability, excessive wrinkling of skin, and development of small, white papules at venipuncture and surgical sites have been reported (see precautions ). the chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury, and lead. there have been reports associating penicillamine with leukemia. however, circumstances involved in these reports are such that a cause and effect relationship to the drug has not been established.

suppressants, penicillamine markedly lowers igm rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. also unlike cytotoxic immunosuppressants, which act on both, penicillamine in vitro depresses t-cell activity but not b-cell activity. in vitro , penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known. in rheumatoid arthritis, the onset of therapeutic response to penicillamine tablets may not be seen for two or three months. in those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling usually is generally apparent within three months. the optimum duration of therapy has not been determined. if remissions occur, they may last from months to years but usually require continued treatment (see dosage and administration ). in all patients receiving penicillamine, it is important that penicillamine tablets be given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food or milk. this permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract. methodology for determining the bioavailability of penicillamine is not available; however, penicillamine is known to be a very soluble substance.