Penicillamine

Penicillamine (3,3-dimethylcysteine) is a trifunctional amino acid containing carboxyl, amino and sulfhydryl groups, an analogue of the natural amino acid cysteine. Due to the asymmetrically located carbon atom, penicillamine can exist as D- and L-isomers. Penicillamine, obtained by controlled hydrolysis of penicillin, exists only in the form of the D-isomer, which is currently used in clinical practice.

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Indications for use and dosage

At the beginning of treatment, the drug is recommended to be prescribed once a day at a dose of 125-250 mg 1-2 hours before breakfast, and with fractional administration, the second dose of penicillamine should be taken 2-3 hours before dinner. This is due to the fact that food significantly reduces the absorption and bioavailability of the drug.

Penicillamine is prescribed after meals only if taking it before meals causes the development of symptoms of gastrointestinal lesions.

After 8 weeks, the dose is increased by 125-250 mg/day. It is believed that 8 weeks is the optimal time to evaluate the clinical efficacy of penicillamine treatment. An increase in the dose by 125 mg/day is indicated if nausea, vomiting, loss of appetite, and other signs of toxicosis occur. If the daily dose of penicillamine reaches 1 g, it is divided into two doses. During treatment, a fixed dose of the drug should not be used, but an attempt should be made to select the optimal dosage depending on the clinical efficacy.

When treating with penicillamine, it is recommended to prescribe vitamin B6 (pyridoxine) at a dose of 50-100 mg/day and multivitamin supplements, especially in patients with nutritional disorders. Although clinical signs of pyridoxine deficiency are extremely rare, there are descriptions of observations of patients with peripheral neuropathy, which could be stopped only by the introduction of pyridoxine.

During treatment, careful monitoring of patients is necessary, including clinical examination, blood tests (including platelet count) and urine tests every 2 weeks during the first few months of treatment and then at least once a month.

General characteristics

Being a water-soluble substance, penicillamine is well absorbed in the upper gastrointestinal tract, excreted in the urine as oxidized metabolites. It has the ability to remain in tissues for a long time after treatment is stopped.

Mechanism of action of penicillamine

The mechanism of action of penicillamine in rheumatic diseases is not fully understood. However, the drug is used in inflammatory rheumatic diseases, since it provides various immunological and anti-inflammatory effects when treating patients in vitro

1. The water-insoluble active sulfhydryl groups of D-penicillamine are capable of chelating heavy metals, including copper, zinc, and mercury, and participating in the sulfhydryl disulfide exchange reaction. This mechanism is thought to be responsible for D-penicillamine's ability to reduce copper levels in Wilson's disease.
2. The interaction of D-penicillamine with the aldehyde groups of collagen leads to disruption of the cross-linking of collagen molecules and an increase in the content of water-soluble collagen.
3. Interchain exchange of sulfhydryl (SH) groups of the D-penicillamine molecule and disulfide bonds leads to the formation of RF IgM polymer molecules, individual subunits of which are linked by SS bridges.

The anti-inflammatory effects of penicillamine are due to:

• selective inhibition of the activity of CD4 T-lymphocytes (T-helpers); suppression of the synthesis of gamma interferons and IL-2 by CD4 T-lymphocytes;
• suppression of RF synthesis, formation of CIC and dissociation of RF-containing immune complexes;
• antiproliferative effect on fibroblasts.

Side effects of penicillamine

During treatment with penicillamine, various side effects may develop.

Frequent, mild (do not require discontinuation of the drug):

• decreased taste sensitivity;
• dermatitis;
• stomatitis;
• nausea;
• loss of appetite.

Frequent severe (require discontinuation of treatment):

• thrombocytopenia;
• leukopenia; proteinuria/nephrotic syndrome.

Rare heavy:

• aplastic anemia;
• autoimmune syndromes (myasthenia gravis, pemphigus, systemic lupus erythematosus, Goodpasture's syndrome, polymyositis, dry Sjogren's syndrome).

The main factor limiting the use of penicillamine in rheumatology is frequent side effects. Some of them are dose-dependent and can be stopped by a short-term interruption of treatment or a reduction in the dose of the drug. Other side effects are associated with idiosyncrasy and are not dose-dependent. Most of the side effects of penicillamine develop in the first 18 months of treatment; side effects occur less frequently during other periods of treatment.

Clinical efficacy of penicillamine

Penicillamine is used in the treatment of active rheumatoid arthritis, including those with various systemic manifestations (vasculitis, Felty's syndrome, amyloidosis, rheumatoid lung disease); palindromic rheumatism; some forms of juvenile arthritis as a reserve drug.

The use of the drug is also effective in diffuse scleroderma.

The drug is not effective in AS.

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