Collagen Penicillamine

Brown Norway rat HgCl2 AU-salts D-Penicillamine Nevirapine HCB IC-glomerulonephritis Skin pathology, dermatitis Polyclonal IgE AutoAb (Type IV-collagen, ANA, 1 anti-ACh, thyroglobulin) Systemic inflamatory response with autoimmune symptoms... 

D-penidllamine can promote the elimination of copper (e.g., in Wilson s disease) and of lead ions. It can be given orally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal regimen (p. 320). 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), nephrotoxicity, bone marrow depression, and taste disturbances. 

Effects of peniciiiamine on coiiagen and eiastin Effects of penicillamine on collagen and eiastin make it advisable to consider a reduction in dosage to 250 mg/day when surgery is contemplated. 

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. 

In in vitro studies penicillamine inhibited angiotensin-con-verting enzyme (ACE) and carboxypeptidase (930). Penicillamine interferes with the functions of the copper-containing enzyme ceruloplasmin, and some of the penicillamine- and copper-containing complexes formed in vivo have a superoxide dismutase effect (931). In patients with scleroderma, penicillamine normalized collagen metabolism, by inhibiting beta-galactosidase activity (932). 

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. 

Acetylpenicillamine is a weaker chelating agent than penicillamine, has no effect on collagen cross-links, and is not effective in rheumatoid arthritis. It has been used in the treatment of mercury poisoning (1). 

The effect of penicillamine on collagen and elastin fibers, which causes characteristic skin lesions, also includes the vascular wall, but effects of vascular insufficiency have not been reported. 

When penicillamine is administered for a long time and in high doses (for example for Wilson s disease) it can cause a characteristic delayed skin eruption, with increased friability, hemorrhagic bullous lesions, and miliary papules (66,260-266). The lesions develop predominantly in those parts of the skin that are often exposed to trauma. This disorder is a manifestation of the effects of penicillamine on collagen and elastin. Occasionally, these eruptions imitate other rare... 

In the past, penicillamine, because of its effects on collagen synthesis, has been suspected of interfering with normal wound healing. Experience of 217 operations in 150 patients did not show such effects, and consequently, there does not seem to be a need for stopping penicillamine before surgery (278). On the other hand, a few reports have suggested that penicillamine can, at least in some patients, have deleterious effects on wound healing (177,279). 

Ulcerative lesions of the vagina can occur in patients taking penicillamine, as a manifestation of pemphigus or cicatricial pemphigoid, or following impaired collagen synthesis (SED-8, 533) (315). 

Camus JP, Koeger AC. D-PenidUamine et collagene. [D-penicillamine and collagen.] Ann Biol Clin (Paris) 1986 44(3) 296-9. 

Nimni ME. Penicillamine and collagen metabolism. Scand J Rheumatol Suppl 1979 (28) 71-8. 

Finally, a direct approach to inhibit fibroblasts has been considered. However, clinical trials with agents such as colchicine and penicillamine, which have some ability to suppress fibroblast collagen production, have not been successful (Cegla et al., 1975 Goodman and Turner-Warwick, 1978 Meier-Sydow et al., 1979 Liebetrau et al., 1982). 

The synthesis of collagen in vitro and in vivo in rats is inhibited by D-penicillamine, probably due to its ability to chelate Fe , a cofactor for proline hydroxylase (EC 1.14.11.2). ... 

The success of D-penicillamine as an antirheumatic drug have prompted the search for other thiols with improved risk/benefit relationship. Recently 5-thio-pyridoxine f5 was shown to have therapeutical value in rheumatoid arthritis. This thiol caused no increased urinary copper excretion, had no antipyridoxin effect, had no effect on skin collagen and did not enter into SH/SS exchange with the amino acid cystine. Thus, the redox potential and reactivity of thiopyridoxine appears to be somewhat different from that of D-penicillamine. 

The efficacy of penicillamine and cysteine in the treatment of rheumatoid arthritis was considered modest only further enhancement in potency and improvement of side-effects are needed. Sulfhydryl compounds possess an inhibitory effect on collagen synthesis but their immunochemical properties remain to be elucidated. 

Besides data pointing to inhibition of wound healing and — in animals — to specific damage to muscles and blood vessels, there is also some concern that aortic incompetence may develop in children receiving penicillamine. It may be that a penicillamine-induced collagen defect allows this lesion to develop, but at present it is impossible to be sure that the vahre lesion is not due to underlying disease (la SED VIII). 

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