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Penicillamine, sold under the brand name of Cuprimine among others, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...
, and various heavy metal poisonings. It is taken by mouth. Penicillamine was approved for medical use in the United States in 1970. It is on the World Health Organization's List of Essential Medicines.


Medical uses

It is used as a chelating agent: * In Wilson's disease, a rare genetic disorder of
copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pink ...
metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine. * Penicillamine was the second line treatment for
arsenic poisoning Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, ...
, after
dimercaprol Dimercaprol, also called British anti-Lewisite (BAL), is a medication used to treat acute poisoning by arsenic, mercury, gold, and lead. It may also be used for antimony, thallium, or bismuth poisoning, although the evidence for those uses is ...
(BAL). It is no longer recommended. In cystinuria, a hereditary disorder in which high urine cystine levels lead to the formation of cystine stones, penicillamine binds with cysteine to yield a mixed
disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
which is more soluble than cystine. Penicillamine has been used to treat scleroderma. Penicillamine can be used as a
disease-modifying antirheumatic drug Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroida ...
(DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy, although it is rarely used today due to availability of
TNF inhibitor A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthrit ...
s and other agents, such as tocilizumab and tofacitinib. Penicillamine works by reducing numbers of T-lymphocytes, inhibiting
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
function, decreasing IL-1, decreasing
rheumatoid factor Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune com ...
, and preventing
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
from cross-linking.


Adverse effects

Common side effects include rash, loss of appetite, nausea, diarrhea, and low blood white blood cell levels. Other serious side effects include liver problems, obliterative bronchiolitis, and
myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
. It is not recommended in people with lupus erythematosus. Use during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
may result in harm to the baby. Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...
. Bone marrow suppression, dysgeusia, anorexia,
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
, and
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine. Other possible adverse effects include: * Nephropathy * Hepatotoxicity * Membranous glomerulonephritis *
Aplastic anemia Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red bloo ...
(idiosyncratic) * Antibody-mediated
myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
and
Lambert–Eaton myasthenic syndrome Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. Around 60% of those with LEMS have an underlying malignancy, most commonly small-cell lung cancer; it is therefore regard ...
, which may persist even after its withdrawal * Drug-induced
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
*
Elastosis perforans serpiginosa Elastosis perforans serpiginosa is a unique perforating disorder characterized by transepidermal elimination of elastic fibers and distinctive clinical lesions, which are serpiginous in distribution and can be associated with specific diseases.Free ...
* Toxic myopathies * Unwanted breast growth *Oligospermia


Chemistry

Penicillamine is a tri
functional Functional may refer to: * Movements in architecture: ** Functionalism (architecture) ** Form follows function * Functional group, combination of atoms within molecules * Medical conditions without currently visible organic basis: ** Functional sy ...
organic compound, consisting of a
thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
, an
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
, and a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
. It is structurally similar to the α-
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...
, but with geminal dimethyl
substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as '' side ...
s α to the thiol. Like most amino acids, it is a colorless solid that exists in the zwitterionic form at physiological pH. Penicillamine is a chiral drug with one stereogenic center and exist as a pair of enantiomers. Refer the image for the structure of penicillamine enantiomers. The (S)-enantiomer, the eutomer, is antiarthritic while the distomer (R)-penicillamine is extremely toxic. Of its two
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
s, L-penicillamine (having ''R'' absolute configuration) is toxic because it inhibits the action of
pyridoxine Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disor ...
(also known as vitamin B6). That enantiomer is a
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
of
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
but has no
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
properties itself. A variety of penicillamine–copper complex structures are known.


History

John Walshe first described the use of penicillamine in Wilson's disease in 1956. He had discovered the compound in the urine of patients (including himself) who had taken
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny Brown and Cumings) of its efficacy, as they held that Wilson's disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that
dimercaprol Dimercaprol, also called British anti-Lewisite (BAL), is a medication used to treat acute poisoning by arsenic, mercury, gold, and lead. It may also be used for antimony, thallium, or bismuth poisoning, although the evidence for those uses is ...
should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of D-penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine and tetrathiomolybdate. Penicillamine was first synthesized by
John Cornforth Sir John Warcup Cornforth Jr., (7 September 1917 – 8 December 2013) was an AustralianBritish chemist who won the Nobel Prize in Chemistry in 1975 for his work on the stereochemistry of enzyme-catalysed reactions, becoming the only Nobel ...
under supervision of Robert Robinson. Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.


Cost

In the United States, Valeant raised the cost of the medication from about US$500 to US$24,000 per month in 2016.


References


External links

* {{Portal bar, Medicine Amino acids Antirheumatic products Chelating agents Enantiopure drugs Human drug metabolites Nephrotoxins Non-proteinogenic amino acids Thiols World Health Organization essential medicines Wikipedia medicine articles ready to translate Disease-modifying antirheumatic drugs