Rheumatoid arthritis penicillamine

Penicillamine, a metabolite of penicillin, is an analog of amino acid cystine. The D isomer has been used in rheumatoid arthritis. Penicillamine is rarely used today because of toxicity. 

D-Penicillamine can promote the elimination of copper (e.g., in Wilson disease) and of lead ions. It can be given orally. Two additional indications are cystinuria and rheumatoid arthritis. In cystinuria, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In rheumatoid arthritis, penicillamine can be used as a basal regimen (p.332). 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 p. 74), nephrotoxicity, bone marrow depression, and taste disturbances. 

The amino acids L-leucine, T-phenylalanine, L-tyrosine, and L-tryptophan all taste bitter, whereas their D-enantiomers taste sweet (5) (see Amino ACIDS). D-Penicillamine [52-67-5] a chelating agent used to remove heavy metals from the body, is a relatively nontoxic dmg effective in the treatment of rheumatoid arthritis, but T.-penicillamine [1113-41 -3] produces optic atrophy and subsequent blindness (6). T.-Penicillamine is roughly eight times more mutagenic than its enantiomer. Such enantioselective mutagenicity is likely due to differences in renal metaboHsm (7). (R)-ThaHdomide (3) is a sedative—hypnotic (3)-thaHdomide (4) is a teratogen (8). 

The mechanism of action of penicillamine, MTX, and hydroxychloroquine in the treatment of rheumatoid arthritis is unknown. 

Webb et al. [56] determined free penicillamine in the plasma of rheumatoid arthritis patients. Plasma ultrafiltrate was mixed with trichloroacetic acid and 4-aminobenzoic acid as internal standards, and HPLC mobile phase to determine total reduced penicillamine. Plasma was vortexed with trichloroacetic acid, the precipitated protein was removed after 15 min by centrifuging, and the supernatant solution was filtered and mixed with 4-aminobenzoic acid. In each instance, a 50-pL portion of solution was analyzed on a 25-cm column of Spherisorb-NH2 (5 pm) at 25 °C, with an electrochemical detector having dual porous graphite electrodes set at... 

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],... 

Layton, M.A., et al., "The Therapeutic Response to D-Penicillamine in Rheumatoid Arthritis Influence of Glutathione S-Transferase Polymorphisms," Rheumatology (Oxford), 38, 43-47 (1999). 

History of penicillamine-related aplastic anemia or agranulocytosis rheumatoid arthritis patients with a history or other evidence of renal insufficiency pregnancy breastfeeding. 

Children The efficacy of penicillamine in juvenile rheumatoid arthritis has not been established. 

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 is an analog of cysteine. Only the d-isomer is used. In patients with progressive rheumatoid arthritis which is refractory to treatment with gold compounds it may retard progression of articular cartilage and bone destruction. For these effects to become apparent a latency period of 3 4 month often is needed. Its mechanism is unknown but it supposedly interferes with the synthesis of DNA, collagen and mucopolysaccharides. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

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. 

Because penicillamine can cause severe adverse reactions, restrict its use in rheumatoid arthritis to patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy... 

The exact mechanisms of action of penicillamine in rheumatoid arthritis is not known. After oral administration it is partly metabolised and partly excreted unchanged. 

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. 

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... 

Penicillamine had a small effect on urinary glucaric acid excretion in patients with rheumatoid arthritis (923). This effect was thought to be the result of an indirect effect on hepatic metabolism and not to be related to disease activity. 

Vardi P, Brik R, Barzilai D, Lorber M, Scharf Y. Frequent induction of insulin autoantibodies by D-penicillamine in patients with rheumatoid arthritis. J Rheumatol 1992 19(10) 1527-30. 

Specific criteria for the diagnosis of rheumatoid arthritis in adults are listed in Table 16-1. In addition to the adult form of this disease, there is also a form of arthritis that occurs in children known commonly as juvenile rheumatoid arthritis, or by the more recent term juvenile idiopathic arthritis (JIA). Juvenile arthritis differs from the adult form of this disease—the age of onset (younger than 16 years) and other criteria help to differentiate these two types of rheumatoid joint disease.69,109 Drug treatment of adult and juvenile rheumatoid arthritis is fairly similar, however, with the exception that children may not respond as well to certain medications (e.g., hydroxychloroquine, gold compounds, penicillamine) compared to adults.79 80 Consequently, in this chapter most of the discussion of the management of rheumatoid arthritis is directed toward the adult form. 

Penicillamine (Cuprimine), a derivative of penicillin, is officially classified as a chelating agent that is often used in the treatment of heavy metal intoxication (e.g., lead poisoning). In addition, this drug has been used in patients with severe rheumatoid arthritis, and seems to be as effective as other DMARDs such as methotrexate, sulfasalazine, and gold therapy.68 98 Penicillamine, however, tends to be substantially more toxic than other DMARDs, and is therefore used rarely in the treatment of specific patients with rheumatoid arthritis.68... 

Mechanism of Action. The basis for the antiar-thritic effects of penicillamine is unknown. Reductions in serum immunoglobulin M-rheumatoid factor have been observed with penicillamine, and this drug has been shown to depress T-cell function.53 These and similar findings suggest that penicillamine works by suppressing the immune response in rheumatoid arthritis, but the exact mechanisms remain to be determined. 

Suarez-Almazor ME, Spooner C, Belseck E. Penicillamine for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2000 CD001460. 

W10. Wemick, R., Merryman, P., Jaffe, I., and Ziff, M., IgG and IgM rheumatoid factors in rheumatoid arthritis. Quantitative response to penicillamine therapy and relationship to disease activity. Arthritis Rheum. 26, 593-598 (1983). 

These agents bind the copper so that it is solublized and excreted in the urine. They are effective because of their high affinity for copper(II) over other metals in the body. Although both isomers of penicillamine bind copper equally well it has been found that the L-form is toxic. Interestingly D-penicillamine is also used to treat rheumatoid arthritis where it acts to reduce collagen crosslinking the enzymes responsible for this process are largely copper centred. 

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