D-Penicillamine:
A white or almost white, finely crystalline powder with a
slight characteristic odour. Freely soluble in water: slightly
soluble in alcohol; practically insoluble in chloroform and in
ether. A I % solution in water has a pH of 4.5 to 5.5. Store in
airtight containers.
Adverse Effects and Treatment
Side-effects of penicillamine are frequent. Gastro-
intestinal disturbances including anorexia, nausea
and vomiting may occur; oral ulceration and stoma-
titis have been reported and impaired taste sensitivity
is common.
Skin rashes occurring early in treatment are com-
monly allergic and may be associated with pruritus.
lirticaria. and fever: they are usually transient but
temporary drug withdrawal and treatment with cor-
ticosteroids or antihistamines may be required. Lu-
pus erythematosus and pemphigus have been
reported. A Stevens-Johnson-like syndrome has
been observed during penicillamine treatment. Pro-
longed use of high doses may affect skin collagen
and elastin. resulting in increased skin friability,
eruptions resembling elastosis perforans serpigino-
sa, and a late rash or acquired epidermolysis bullosa
(penicillamine dermatopathy) that may necessitate
dosage reduction or discontinuation.
Haematological side-effects have included throm-
bocytopenia and less frequently leucopenia: these
are usually reversible but agranulocytosis and aplas-
tic anaemia have occurred and fatalities have been
reported. Haemolytic anaemia has also occurred.
Proteinuria occurs frequently and in some patients
may progress to glomerulonephritis or nephrotic
syndrome. Penicillamine-induced haematuria is rare
but normally requires immediate discontinuation.
Other side-effects associated with penicillamine in-
clude Goodpasture's syndrome, bronchiolitis and
pneumonitis. myasthenia gravis. polymyositis (rare-
ly with cardiac involvement), intrahepatic cholesta-
sis, and pancreatitis.
Effects on the blood. Of the 18 deaths ascribed to peni-
cillamine reported to the UK Committee on Safety of Medi-
cines between January 1964 and December 1977, fourteen
were apparently due to blood disorders, at least 7 of them be-
ing marrow aplasias. The myelotoxicity of penicillamine was
reviewed in 10 patients with confirmed or suspected marrow
depression during penicillamine treatment for rheumatoid ar-
thritis or scleroderma: 6 of these 10 patients died.
Thomas et al reported an incidence of 12 to 27% of peni-
cillamine-induced thrombocytopenia in patients with rheu-
matoid arthritis. Thrombocytopenia appeared to be due to
bone-marrow suppression and a reduced platelet-production
rate.
There have been isolated reports of thrombotic thrombocy-
topenic purpura attributed to the use of penicillamine with
some fatalities.
Effects on the breast. Breast enlargement has been report-
ed both in women and in men taking penicillamine and
may be a rare complication of penicillamine therapy. In some
patients breast enlargement was prolonged with poor resolu-
tion and others required surgery. Danazol has been used suc-
cessfully to treat penicillamine-induced breast gigantism.
Effects on the gastro-intestinal tract. There have been
isolated reports of acute colitis in patients taking penicilia-
mine. Heal ulceration and stenosis in a patient with Wil-
son's disease was considered to be related to elastosis
probably resulting from long-term penicillamine therapy.'
Effects on the heart. For reports of heart block, Stokes-
Adams syndrome, and fatal myocarditis in patients taking
penicillamine. see under Effects on the Muscles and the Neu-
romuscular System, Polymyositis, below.
Effects on the kidneys. Proteinuria associated with peni-
cillamine has usually occurred within 4 to 18 months of start-
ing therapy though onset can be later. A greater incidence has
been found in patients with rheumatoid arthritis and cystinu-
ria than in those with Wilson's disease. The severity of pro-
teinuria varies: proteinuria of nephrotic proportions usually
develops rapidly but resolves on drug cessation. Minimal
change, mesangioproliferative, and membranous nephropa-
thy have all been associated with penicillamine treatment and
progressive glomertilonephritis has been observed in a few
patients who had developed features of Goodpasture's syn-
drome.'
Although there is some evidence of a relationship between
nephropathy and penicillamine dose and its rate of increased
Hall and colleagues' in a study of 33 rheumatoid arthritis pa-
tients with penicillamine-induced nephropathy, found no cor-
relation with the dose or duration of treatment. Appreciable
proteinuria could still be detected 12 months after stopping
penicillamine in 40% of their patients, but subsequently re-
solved in those whose proteinuria was solely related to peni-
cillamine.
Penicillamine was successfully reintroduced and adminis-
tered for at least 13 months in 5 patients with rheumatoid ar-
thritis who had developed proteinuria during the first course
of therapy. Proteinuria did not recur.
Corticosteroids have been used in patients developing rapidly
progressive glomerulonephritis but may be unnecessary and
potentially hazardous in patients who develop the nephrotic
syndrome.
For reports of Goodpasture's syndrome in patients taking
penicillamine, see also under Effects on the Respiratory Sys-
tem, below.
Effects on the liver. Seibold el al. reported a patient with
penicillamine-associated hepatotoxicity and reviewed other
reports Of the 9 patients considered all had liver function
profiles consistent with intrahepatic cholestasis: one patient
died of acute renal failure but the others improved rapidly af-
ter drug withdrawal, In a later report a 72-year-old man
with rheumatoid arthritis developed jaundice approximately 4
weeks after starting penicillamine therapy. Liver biopsy indi-
cated a slight degree of cholangitis with eosinophils in the
portal tracti and severe predominantly intrahepatocellular
cholestasis. Jaundice cleared within 3 weeks of slopping pen-
icillamine and liver enzyme values approached normal after 6
weeks. Monitoring of liver function and eosinophil counts in
the early weeks of penicillamine therapy was recommended.
Effects on the muscles and the neuromuscular system.
Neuromyotonia and profound sensory and motor neu-
ropathy have been reported in patients taking penicillamine.
Symptoms improved rapidly after the initiation of pyridoxine
supplementation. Low back pain in conjunction with fever
and rash developed in a patient during penicillamine treat-
ment. Fever and back pain recurred on rechallenge with pen-
icillamine. It was suggested that an allergic mechanism was
involved.
MYASTHENIA Myasthenia gravis is a well recognised, though
uncommon, complication of long-term penicillamine thera-
py. Symptoms are similar lo those seen with spontaneous
myasthenia gravis and include ptosis and diplopia. and gener-
alised weakness, occasionally affecting the respiratory mus-
cles.l-3 The onset ot symptoms usually occurs within 6 to 7
months but may be delayed for a number of years' Myasthen-
ic symptoms usually resolve spontaneously once penicilla-
mine is withdrawn, but some patients require
anticholinesterase therapy. Acetylcholine receptor antibod-
ies are found in about 75% of affected patients. Patients
with HLA antigens DRI and Bw35 may have a genetic predis-
position to developing myasthenia. Patients with auto-im-
mune diseases may well display an increased susceptibility to
drug-induced myasthenia.
POLYMYOSITIS. Penicillamine therapy has been associated rare-
ly with polymyositis and dermatomyositis, usually reversi-
ble but in some cases fatal. At least two deaths have resulted
from myocarditis.2 and Christensen and Sarensen* reported
complete heart block and severe Stokes-Adams attacks in pa-
tients with polymyositis. It is possible that some patients may
have a genetically determined susceptibility to this complica-
tion.
Effects on the respiratory system. Reports of pulmonary
haemorrhage associated with progressive renal failure in indi-
vidual patients treated with penicillamine have commonly
been classified as Goodpasture's syndrome, although an
immune complex syndrome has been suggested.) There have
been rare reports of Obliterative bronchiolitis in patients with
rheumatoid arthritis treated with penicillamine.
RHINITIS. Nasal blockage due to grossly oedematous nasal lin-
ings and severe disabling watery nasal discharge associated
with penicillamine administration was reported in a 76-year-
old patient. The patient also had pemphigus foliaceus. The
rhinitii resolved promptly when penicillamine was discontin-
ued. as did concurrent bilateral blepharitis.
Effuts on the skin. Penicillamine-induced skin lesions
have been reviewed. The cutaneous manifestations observed
during penicillamine therapy include those resulting from in-
terference with collagen and elastin such as penicillamine
dermatopathy, elastosis perforans serpiginosa. and cutis laxa:
those associated with auto-immune mechanisms such as pem-
phigus. pemphigoid, lupus erythematosus, and dermatomy-
ositis; and those classified as acute sensitivity reactions
including macular or papular eruptions and urticaria. The ef-
fects on collagen and elastin (see below) tend to occur only
after prolonged treatment with high doses of penicillamine, as
in patients with Wilson's disease or cystinuria, whereas pa-
tients with diseases characterised by altered immune systems,
such as rheumatoid arthritis, are more prone to develop the
antibody-related adverse skin reactions. Acute hypersensitiv-
ity reactions tend to occur early in penicillamine treatment.
usually within the first 7 to IO days, and appear not to be dose
related. Lichenoid reactions, stomatitis, nail changes, and ad-
verse effects on hair have also been reported.
EPIDERMAL NECROLYSIS. A 56-year-old woman developed
agranulocytosis and toxic epidermal necrolysis 7 weeks after
starling therapy with penicillamine 250 mg daily for primary
biliary cirrhosis.
INTERFERENCE WITH COLLAGEN AND ELASTIN. Long-term, high-
dose treatment with penicillamine can interfere with elastin
and collagen production giving rise to increased skin friabili-
ty, haemorrhagic lesions, miliary papules, and excessive
wrinkling and laxity of the skin' Penicillamine dermatopa-
thy. characterised by wrinkling and purpura over bony prom'
inences. was first reported by Stemheb and Scheinberg.' In
addition, lesions resembling pseudoxanthoma elasticum have
been reported. Abnormal elastic tissue has also been report-
ed in patients taking low doses of penicillamine (less than I g
daily), not only in the skin but also in joint capsules.' and
elastosis perforans serpiginosa has been reported in a child
receiving a low cumulative dose over a short period. In all
these cases, histological findings generally show damage to
elastic fibres giving them a typical appearance described as
"lumpy-bumpy" or "bramble-bush".
LICHEN PLANUS. Observations in some patients reported in the
1980s led to the suggestion that penicillamine might exacer-
bate or unmask lichen planus. However, there do not appear
to have been subsequent reports.
PEMPHIGUS. Pemphigus vulgaris and a number of variants in-
cluding pemphigus foliaceus, herpetiform pemphigus, pem-
phigus erythematosus,' benign mucous membrane
psmphigoid, cicatricial pemphigoid and combined pem-
phigus and pemphigoid features have been reported with
penicillamine therapy.
PSORIASIFORM ERUPTIONS Two patients with rheumatoid arthri-
tis developed psoriasiform eruptions during penicillamine
treatment. In one patient the eruption resolved when peni-
cillamine was stopped but worsened when treatment was re-
started.
SYSTEMIC SCLEROSIS Penicillamine has been used in the treat-
ment of scleroderma and systemic sclerosis (see under Uses,
below). However, systemic sclerosis-like lesions developed in
a 14-year-old boy with Wilson's disease who had been treated
with penicillamine for 11 year and the suitability of peni-
cillamine for this indication has therefore been questioned.
Genetic factors. There is increasing evidence that some pa-
tients may have a genetically determined increased suscepti-
bility to the adverse effects of penicillamine. Several studies
have suggested that rheumatoid arthritis patients with a poor
capacity for producing sulphoxides may be more susceptible
to the toxic effects of penicillamine. The poor sulphoxida-
tion capacity found in patients with primary biliary cirrhosis
could partly explain their high incidence of adverse reactions
to penicillamine. although Mitchison and colleagues found
no association between penicillamine toxicity and sulphoxi
dation status in a study of 20 such patients.
In addition to poor sulphoxidation, Emery and colleagues re-
ported increased toxicity in patients possessing the histocom-
patibility antigen HLA-DR3. Other studies have shown
associations between proteinuria and HLA antigens B8 and
DR3 myasthenia gravis and Bw35 and DRI. thrombocy-
tojwnia and HLA antigens DR4. Al, and C4BQO and
polymyositis or dermatomyositis and HLA antigens B18,
B35 and DR4. However, such associations are insufficiently
strong and testing procedures too expensive to make testing
-sulphoxidation status or HLA-typing useful for identifying
high-risk patients.
Systemic lupus erythematosus. A syndrome resembling
lupus erythematosus developed in 6 women with long-stand-
ing severe rheumatoid arthritis while being treated with peni-
cillamine these patients represented ap approximate
frequency of penicillamine-induced lupus erythematosus of
2%. All 6 had developed previous cutaneous reactions to gold
therapy. A case of bullous systemic lupus erythematosus as-
sociated with penicillamine administration has also been re-
ported.
Precautions
Penicillamine is contra-indicated in patients with lu-
pus erythematosus or a history of penicillamine-in-
duced agranulocytosis, aplastic anaemia, or severe
thromboSytopen7g. It should be used with care. if at
all. in patients with renal impairment.
Penicillamine should not be given with other drugs
capable of causing similar serious haematological or
renal adverse effects, for example gold salts, chloro-
quine or hydroxychloroquine, or immunosuppres-
sive drugs. Patients who are allergic to penicillin
may react similarly to penicillamine but cross-sensi-
tivity appears to be rare (see below).
Patients need to be carefully supervised and ob-
served for side-effects. In particular full blood
counts and urinalysis should be carried out; one rec-
ommendation is to perform such checks weekly for
the first 2 months of treatment and after any change
in dosage, and monthly thereafter. Treatment should
be withdrawn if there is a fall in white cell or platelet
count, or if progressive or serious proteinuria or hae-
maturia occur. Liver function tests have also been
recommended at 6-monthly intervals and renal func-
tion should be monitored.
Pyridoxine 25 mg daily may be given to patients on
long-term therapy, especially if they are on a re-
stricted diet. since penicillamine increases the re-
quirement for this vitamin.
Because of the effect of penicillamine on collagen
and elastin and a possible delay in wound healing, it
has been suggested that the dose should be reduced
to 250 mg daily for 6 weeks prior to surgery and
during the postoperative period until healing has
taken place.
Anaesthesia. Penicillamine-induced myasthenia in a 57-
year-old woman led to prolonged postoperative apnoea ne-
cessitating artificial ventilation. The significance of this re-
port in planning anaesthesia for patients with rheumatoid
arthritis treated with penicillamine was discussed.
Penicillin allergy. Penicillamine is a degradation product of
penicillin and patients with penicillin allergy may theoretical-
ly have a cross-sensitivity lo penicillamine. Reactions due to
contamination of penicillamine with trace amounts of penicil-
lin have been eliminated by the use of synthetic penicilla-
mine. Results of a study in 4U patients with penicillin allergy'
suggested that while cutaneous cross-reactivity with peni-
cillamine had been documented, the risk of a severe allergic
reaction to penicillamine in penicillin-allergic patients was
probably quite low.
Pregnancy. Penicillamine teratogenicity has been re-
viewed.' Evidence of the embryotoxicity of maternal peni-
cillamine exposure in animal studies has been confirmed in
man by 5 reports of cutis laxa in neonates of mothers who had
taken penicillamine during pregnancy: 3 further reports of in-
tra-uterine brain injury were less characteristic. Nevertheless
most pregnancy outcomes were normal. No birth defects have
been reported when penicillamine was discontinued in early
pregnancy. Unless a safer therapy could be confirmed, peni-
cillamine management of women with Wilson's disease
should be continued throughout pregnancy since the benefits
outweighed the risks. However, for conditions for which there
were safer alternatives it would be prudent to discontinue
penicillamine during pregnancy.
Interactions
Penicillamine forms chelates with metal ions and
oral absorption of penicillamine may be reduced by
concomitant administration of iron and other metals.
antacids, and food. Penicillamine should be taken on
an empty stomach and it has been recommended
that there should be an interval of at least 2 hours
between the administration of penicillamine and
iron supplements.
Antacids, in a single-dose study in 6 healthy subjects, ad-
ministration of penicillamine by mouth immediately after
food, an oral dose of ferrous sulphate, or a dose of an antacid
mixture of aluminium hydroxide, magnesium hydroxide, and
simethicone. reduced the plasma concentrations of penicilla-
mine to 52%, 35%, and 66% respectively of those obtained
after administration in a fasting state. Results suggested that
the reduction in plasma-penicillamine concentrations was as-
sociated with decreased penicillamine absorption. lfan and
Welling' showed that the reduction of penicillamine plasma
concentrations by aluminium- and magnesium-containing
antacids was not similarly produced by sodium bicarbonate.
and thus the interaction was probably a result of chelation
rather than a pH effect.
Diazepam. For a report of exacerbation of intravenous di-
azepam-induced phlebitis by oral penicillamine, see under
Diazepam.
Gold. There have been conflicting reports on the effect of
previous gold therapy on the subsequent development of pen-
icillamine toxicity in patients with rheumatoid arthritis.
A multicentre trial group found no evidence of any interac-
tion between gold and penicillamine but Webley and
Coomes' found that although the overall incidence of side-
effects with penicillamine appeared unaffected by prior gold
therapy, bone-marrow depression and rashes were more com-
mon in those patients previously treated with gold. Hill' re-
ported that patients who had to stop gold therapy because of
adverse effects were more prone to develop major adverse ef-
fects lo penicillamine and a study by Dodd el al.' indicated
that patients who reacted adversely to gold were more likely
to develop side-effects to penicillamine. Dodd et al* also
found that the mean interval between finishing gold and be-
ginning penicillamine in patients who developed identical ad-
verse reactions to both drugs was significantly shorter than in
those who developed different side-effects or no side-effects:
this supported the theory that some adverse reactions to pen-
icillamine might result from the mobilization of gold previ-
ously stored in the tissues during gold therapy. An interval of
at least 6 months between gold and penicillamine therapy in
patients who had adverse reactions to gold was recommend-
ed. In contrast. Smith et a[. found no evidence that the inter-
val between gold and penicillamine therapy had any influence
on the subsequent development of penicillamine tonicity. A
genetic susceptibility in certain patients to react adversely to
either drug was suggested. However, in a prospective study by
Steven et al. prior gold, penicillamine. or levamisole treat-
ment had no influence on the subsequent efficacy or toxicity
of any one of these alternative drugs.
There has been a report of gold therapy causing a recurrence
of myasthenia that had previously occurred with penicilla-
nine.
Insulin. Unexplained hypoglycaemia in two type I diabetics
occurred 6 to 8 weeks after penicillamine treatment for rheu-
matoid arthritis was started. Both patients required a reduc-
tion in their insulin dose. It was possible that [he reaction was
the result of the induction of insulin antibodies'
Iron. Penicillamine plasma concentrations were reduced by
52% when penicillamine was administered after a dose of fer-
rous sulphate in healthy subjects. Patients stabilised on pen-
icillamine while on oral iron therapy were considered
unlikely to respond fully to penicillamine and would be ex-
posed to a large increase in penicillamine absorption with
possible adverse reactions if the iron was stopped.
Probenecid. Probenecid reduced the beneficial effects of
penicillamine in cystinuria; co-administration in hyperuricae-
mic cystinuric patients was contra-indicated.
Pharmacokinetics
Penicillamine is readily absorbed from the ga.stro-
intestinal tract and reaches peak concentrations in
the blood within I to 3 hours. It is reported to be
more than 80% bound to plasma proteins. It is
metabolised in the liver and excreted in the urine and
faeces mainly as metabolites. Elimination is bipha-
sic with an initial elimination half-life of about I to
3 hours followed by a slower phase, suggesting
gradual release from tissues.
Uses and Administration
Penicillamine is a chelator which aids the elimina-
tion from the body of certain heavy-metal ions. in-
cluding copper, lead. and mercury, by forming
stable soluble complexes with them that are readily
excreted by the kidney. It is used in the treatment of
Wilson's disease (to promote the excretion of cop-
per), in heavy-metal poisoning such as lead poison-
ing, in cystinuria (to reduce urinary concentrations
of cystine). in severe active rheumatoid arthritis, and
in chronic active hepatitis.
Penicillamine is administered by mouth and should
be taken on an empty stomach. A low initial dose
increased gradually to the minimum optimal main-
tenance dosage may reduce the incidence of side-
effects as well as provide closer control of the con-
dition being treated.
In the treatment of Wilson's disease, a dose of 1.5
to 2 g daily in divided doses may be given initially.
The optimal dosage to achieve a negative copper
balance should be determined initially by regular
analysis of 24-hour urinary copper excretion and
subsequently by monitoring free copper in the se-
rum, A maintenance dose of 0.75 to I g daily may be
adequate once remission is achieved and should be
continued indefinitely; the UK manufacturers rec-
ommend that a maintenance dose of 2 g daily should
not be continued for more than a year. In children, a
suggested close is up to 20 mg per kg body-weight
daily (minimum 50U mg daily) in divided doses. A
dose of up to 20 mg per kg daily is also suggested
for the elderly.
In the management of lead poisoning, penicilla-
niine may be given in doses of 1 to 2 g daily in di-
vided doses until the urinary lead concentration is
stabilised at less than 0.5 mg per day. A recom-
mended dose for children is 20 to 25 mg per kg daily
in divided doses. A dose of 20 mg per kg daily is
suggested for the elderly.
In cystinuria. doses of penicillamine are adjusted
according to cystine concentrations in the urine. For
the treatment of cystinuria and cystine calculi, the
dose is usually in the range of I to 4 g daily in divid-
ed doses: a suggested dose for children is up to
30 mg per kg daily in divided doses. For the preven-
tion of cystine calculi, lower doses of 0.25 to I gat
bedtime may be given. An adequate fluid intake is
essential to maintain urine flow during penicilla-
mine administration for cystinuria.
In the treatment of severe active rheumatoid ar-
thritis an initial dose of penicillamine 125 to
250 mg daily is increased gradually by the same
amount at intervals of 4 to 12 weeks. Remission is
usually achieved with maintenance doses of 500 to
750 mg daily in divided doses, but up to 1.5 g daily
may be required (one UK manufacturer has reported
that up to 2 g daily may be required by a few pa-
tients). Improvement may not occur for several
months: the USA manufacturers suggest that peni-
cillamine should be discontinued if there is no re-
sponse after treatment for 3 to 4 months with I to
1.5 g daily; in the UK a trial for 12 months is sug-
gested. After remission has been sustained for 6
months an attempt may be made gradually to reduce
the dose by 125 to 250 mg daily every 2 to 3 months
hut relapse may occur. Lower doses may be required
in the elderly who may be more susceptible to devel-
oping adverse effects. Initial doses of 50 to 125 mg
daily have been recommended gradually increased
to a maximum of I g daily if necessary. In children
the maintenance dose is 15 to 20 mg per kg daily: a
suggested initial dose is 2.5 to 5 mg per kg or 50 mg
daily for one month increased gradually at 4-weekly
intervals.
In the management of chronic active hepatitis, an
initial dose of penicillamine 500 mg daily in divided
doses may be given after liver function tests have
indicated that the disease has been controlled by
corticosteroids: the dose is gradually increased over
3 months to 1.25 g daily with a concurrent reduction
in the corticosteroid dose.
Acetylpenicillamine has been used in mercury poi-
soning.
Chronic active hepatitis. Penicillamine has been tried in
chronic active hepatitis as an alternative to pro-
longed conicosteroid maintenance therapy once control of
the disease is achieved. The dose of penicillamine is increased
over several months to a suitable maintenance dose with a
concurrent reduction in the corticosteroid dose.
Cystinuria. Cystinuria is an inherited disorder of renal ami-
no acid excretion in which there is excessive excretion of cys-
tine (cysteine disulphide), along with ornithine, lysine, and
arginine. The low solubility of cystine leads to the formation
of cystine stones in the kidney, resulting in pain, haematuria,
renal obstruction, and infection. Treatment is primarily aimed
at reducing the urinary concentration of cystine to below its
solubility limit of 300 to 400 mg per litre at neutral pH. Pa-
tients with cystinuria excrete from 400 to 1200 mg cystine
daily and should be advised to drink at least 3 litres of water
daily, including at night, to maintain a dilute urine. Cystine is
more soluble in alkaline urine and urinary alkalinisers such as
sodium bicarbonate, sodium citrate, or potassium citrate may
he used: however, high doses are required and calcium stone
formation may be promoted. In patients where these meas-
ures are ineffective or not tolerated penicillamine may be
used: it complexes with cysteine to form a more soluble
mixed disulphide, therefore reducing cystine excretion, pre-
venting cystine stone formation, and promoting the gradual
dissolution of existing stones. Adverse effects are common
and tiopronin, which has a similar action, may be used as an
alternative. Surgical removal may be necessary for estab-
Ushed stones but lithotripsy is not very effective.
Lead poisoning. Penicillamine may be used lo treat asymp-
tomatic lead intoxication and to achieve desirable lead-tissue
levels in patients with symptomatic lead poisoning once they
have received treatment with sodium calcium edetate and
dimercaprol.
Primary biliary cirrhosis. Copper accumulation in the liv-
er has been noted in patients with long-lasting cholestatic liv-
er disorders such as primary biliary cirrhosis and
initial studies indicated that penicillamine might be of ben-
efit by increasing the urinary excretion of copper and reduc-
ing liver-copper concentrations. It was also suggested that (he
immunological action of penicillamine might influence the
course of the diseased However, preliminary results indicat-
ing that penicillamine improved survival in patients with pri-
mary biliary cirrhosis' were not supported by further
studies' in which penicillamine did not significantly affect
the overall survival or prevent progression of the disease. A
review by James* concluded that the value of penicillamine in
the treatment of primary biliary cirrhosis was not proven,
there was possibly a marginal decrease in mortality in an in-
termediate symptomatic group of patients but the incidence of
side-effects was probably too high to justify further long and
elaborate clinical studies.
Rheumatoid arthritis. Rheumatoid arthritis and ju-
venile chronic arthritis are generally treated using the
same methods. Initial drug therapy is usually with ah NSAID,
which provides symptomatic relief. Penicillamine is one of a
diverse group of disease modifying antirheumatic drugs used
in an attempt to suppress the rate of cartilage erosion or alter
the course of the disease. However, early enthusiasm for pen-
icillamine has been somewhat curtailed by a high incidence
of adverse effects. During long-term therapy as many as 50%
of patients taking penicillamine have been reported to with-
draw from treatment as a consequence of adverse effects'
Low doses of penicillamine to reduce the incidence of side-
effects have been tried and while doses as low as 125 mg daily
have been claimed to be effective in some patients with rheu-
matoid arthritis, a 36-week multicentre double-blind study'
involving 225 patients concluded that a dose of penicillamine
500 mg daily was only slightly more effective than placebo.
A dose of 125 mg daily was not significantly different from
either the 500 mg dose or placebo. In patients with juvenile
rheumatoid arthritis it has been suggested that gold' therapy
may be preferred to penicillamine since there is greater expe-
rience with gold and its efficacy is better established.
Scleroderma. Despite the lack of conclusive evidence in its
favour penicillamine, which affects the cross-linking of colla-
gen, has been widely thought to be of benefit in scleroderma
and perhaps in some visceral manifestations of sys-
lemic sclerosis. If used, treatment should probably be be
gun early and continued for several years: therapy for 6 to 12
months is required before any benefit can be observed. A dose
of 250 to 500 mg of penicillamine daily has been used.
Wilson's disease. Wilson's disease, or hepatolenticular de-
generation. is a rare autosomal disorder of copper accumula-
tion. Excretion of excess copper, which normally occurs via
the bile. is impaired in Wilson's disease and total body copper
progressively increases. The excess copper accumulates in
the liver, brain, and other organs including the kidneys and
corneas, and eventually causes tissue damage.
Effective treatment of Wilson's disease depends upon estab-
lishing a negative copper balance thereby preventing deposi-
tion of more copper and mobilising for excretion excess
copper already deposited and this is achieved with copper-
reducing drugs. Once negative copper balance has been
achieved, maintenance treatment must be continued lifelong.
Dietary restriction of copper is not generally considered to be
an important part of the treatment of Wilson's disease; pa-
tients may be advised to avoid copper-rich foods, such as liver
and shellfish, during the first year of treatment and to restrict
their consumption thereafter. Symptomatic recovery from
copper overload occurs slowly, but is usually complete if
treatment is started early enough, and a normal life expectan-
cy can be achieved. However, once irreversible organ damage
such as liver cirrhosis has occurred, treatment can only pre-
vent further deterioration: those presenting with end-stage
liver disease do not benefit from copper-reducing therapy, and
liver transplantation is necessary (although successful medi-
cal treatment has been reported in children). The drugs used
in the treatment of Wilson's disease are penicillamine, trien-
tine, and zinc. Ammonium tetrathiomolybdate is under inves-
tigation.
Penicillamine reduces copper concentrations mainly by
chelating copper which is then excreted in the urine. Two
molecules of penicillamine combine with one atom of copper.
Penicillamine also reduces the affinity of copper for proteins
and polypeptides thus allowing removal of copper from tis-
sues and induces synthesis of metallothionein in the liver, a
protein that combines with copper to form a non-toxic prod-
uct. Trieniine is a less potent copper chelator than penicilla-
mine that competes for copper bound to serum albumin. Zinc
induces synthesis of metallothionein in the intestine, a protein
that has a higher affinity for copper than for zinc, so that ab-
sorption of copper from the gastro-intestinal tract is blocked.
It is usually given as the acetate as this form is less irritating
io the stomach than the sulphate. Ammonium tetrathiomotyb-
date forms a complex with protein and copper. When it is giv-
en with food it blocks the intestinal absorption of copper, and
when taken between meals it combines with albumin- and
caeruloplasmin-bound copper.
CHOICE OF DRUG. Penicillamine is generally regarded as the
drug of choice for the initial management of Wilson's disease
as it produces a rapid reduction in copper levels. However, in
patients with neurological symptoms there may be a worsen-
ing of symptoms on initiation of penicillamine (possibly due
to transiently increased brain and blood copper concentra-
tions). Some practitioners therefore suggest zinc initially;
/inc is not suitable in those requiring rapid reduction of cop-
per levels as it has a slow onset of action. Trientine. which
may also exacerbate neurological symptoms, is used in pa-
tients intolerant of penicillamine. Ammonium tetrathiomo-
lybdate is under investigation for the initial reduction of
copper levels; it may be particularly suitable for patients with
neurological symptoms.
Once a negative copper balance is achieved, maintenance
therapy must be continued for life. Penicillamine, trientine,
and zinc are all used for maintenance treatment. Patients tak-
ing penicillamine are also given pyridoxine to prevent defi-
ciency (see under Precautions, above). The adverse effects of
penicillamine may be a problem during long-term use and
V.inc. which has low toxicity, is often preferred. Zinc is also
used in patients in the asymptomatic stage of the disease.
References.