d-penicillamine: Chemistry and clinical use in rheumatic disease

doi:10.1016/0049-0172(86)90022-3

Seminars in Arthritis and Rheumatism

Volume 15, Issue 4, May 1986, Pages 261-281

https://doi.org/10.1016/0049-0172(86)90022-3 Get rights and content

Abstract

The discovery of d-penicillamine and its uses in medicine are reviewed. Chemical-physical properties are discussed, and the molecular structure of d-penicillamine and several of its reaction products are illustrated. Examples of its three main types of biochemical reactions—sulfhydryl-disulfide exchange, thiazolidine formation, and metal chelation are included. Trials of d-penicillamine in RA patients are reviewed critically. The administration of the drug is discussed in detail, including dosages, clinical and laboratory responses, patterns of adverse side effects or toxicity, drug-induced autoimmune diseases, indications and contraindications, and the monitoring and management of patients.

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Cited by (55)

Evaluation of thiol/disulfide homeostasis in rheumatoid arthritis and disease activity
2023, Clinical Biochemistry
Citation Excerpt :
These results suggest that thiol pools shift in the oxidative direction in patients with RA compared to healthy controls, and in patients with active disease compared to those in remission, and that the thiol antioxidant mechanism may have essential roles in the pathophysiology of RA. This hypothesis is supported by studies showing that d-penicillamine, a thiol-containing molecule [36,37], and myocrycin, a complex thiol-containing gold compound, may have beneficial therapeutic effects in the treatment of RA [38,39]. However, thiol molecules seem to represent possible therapeutic targets in the pathophysiology of RA; more extensive randomized controlled trials are needed to for a better understanding of the role of thiol balance in the development and progression of RA disease.
It has been suggested that the deterioration in the antioxidant defense system due to thiols may cause the pro-oxidant/antioxidant imbalance seen in rheumatoid arthritis (RA). This study was conducted to evaluate thiol/disulfide (−SH/−SS) homeostasis in patients with RA compared to healthy controls, and to validate the limited number of studies examining the relationship between Disease Activity Score-28 (DAS28) and thiol parameters.
A total of 100 individuals (mean age: 46.3 ± 12.03) consisting of 86 females and 14 males were included in the RA group, and a total of 100 individuals (mean age: 43.3 ± 10.96 years) consisting of 78 females and 22 males were included in the control group. DAS28 was used to assess RA disease activity. −SH/−SS homeostasis parameters were measured using the automated spectrophotometric method described by Erel and Neselioğlu.
While native thiol (−SH) (p:0.001), total thiol (−SH + −SS) (p < 0.0001) levels and −SH\(−SS + −SH) ratio (p: 0.018) were lower in the RA group compared to the healthy controls, disulfide (−SS) level (p: 0.005)), −SS\−SH (p: 0.001) and −SS\(−SS + -SH) (p: 0.002) ratios were found to be higher. In the control group and the group in remission (defined by DAS28 < 2.6), the median values of –SH (p:0.002) and −SS + −SH (p:0.0008) were found to be significantly higher, and the median value of –SS (p: 0.001) was found to be lower compared to the other DAS28 groups. While a negative correlation was found between DAS28 and –SH (r: −0.243, p: 0.007), a positive correlation was found between DAS28 and −SS (r: 0.316, p: 0.0003), −SS\−SH (r:0.229, p: 0.002) and −SS\(−SS + −SH) (r: 0.285, p: 0.0009).
The plasma thiol antioxidant pool was decreased in RA compared to healthy controls and those with active disease compared to those in remission.
Massive proteinuria for minimal change nephropathy secondary to treatment with D-penicilamine in a patient with Wilson's disease. Case report
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2012, Advances in Pharmacology
Citation Excerpt :
Even though it is an immune-mediated reaction, the time to onset is not shortened on rechallenge. Penicillamine is chemically reactive without metabolism; it can react with protein thiols to form mixed disulfides, and it reacts with aldehydes to form a thiazolidine ring (Howard-Lock et al., 1986). One of the signaling pathways between macrophages and T cells involves reaction of an aldehyde on macrophages with an amine on T cells, forming a reversible imine linkage (Rhodes, 1989).
If we could predict and prevent idiosyncratic drug reactions (IDRs) it would have a profound effect on drug development and therapy. Given our present lack of mechanistic understanding, this goal remains elusive. Hypothesis testing requires valid animal models with characteristics similar to the idiosyncratic reactions that occur in patients. Although it has not been conclusively demonstrated, it appears that almost all IDRs are immune-mediated, and a dominant characteristic is a delay between starting the drug and the onset of the adverse reaction. In contrast, most animal models are acute and therefore involve a different mechanism than idiosyncratic reactions. There are, however, a few animal models such as the nevirapine-induced skin rash in rats that have characteristics very similar to the idiosyncratic reaction that occurs in humans and presumably have a very similar mechanism. These models have allowed testing hypotheses that would be impossible to test in any other way. In addition there are models in which there is a delayed onset of mild hepatic injury that resolves despite continued treatment similar to the “adaptation” reactions that are more common than severe idiosyncratic hepatotoxicity in humans. This probably represents the development of immune tolerance. However, most attempts to develop animal models by stimulating the immune system have been failures. A specific combination of MHC and T cell receptor may be required, but it is likely more complex. Animal studies that determine the requirements for an immune response would provide vital clues about risk factors for IDRs in patients.
Other Traditional Disease-Modifying Antirheumatic Drugs: Monotherapy and Combination Therapy
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Other Traditional Disease-Modifying Antirheumatic Drugs: Monotherapy and Combination Therapy
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^☆: Supported by the Arthritis Society (Canada), National Science and Engineering Research Council, McMaster University Science and Engineering Research Board, and the Medical Research Council of Canada.

¹: From the Laboratories for Inorganic Medicine, Institute for Materials Research, and the Rheumatic Diseases Unit, McMaster University, Hamilton, Ontario, Canada.

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d-penicillamine: Chemistry and clinical use in rheumatic disease☆

Abstract

Br Med J

Dtsh Med Wochenschr

J Nucl Med

Rec Trav Chim Pays Bas

J Am Chem Soc

Arthritis Rheum

Clin Res

Arthritis Rheum

Penicillamine, a characteristic degradation product of penicillin

Nature

Penicillamine, its anologs and homologs

Brief History of the Study of Penicillin

Structure and conformation of amino acids containing sulfur. I. Crystal and molecular structure of l-β,β-dimethylcysteine (penicillamine) hydrochloride monohydrate

Acta Crystallogr

d-penicillamine—production and properties

Angew Chem Int Ed

The crystal structure of racemic dl-penicillamine and a spectroscopic study of d-(−)-penicillamine

J Cryst Spectr Res

The total synthesis of penicillin V

J Am Chem Soc

J Am Chem Soc

Liebigs Ann Chem Uber die Anlagenung von Schwefelverbindungen an die β,β-Dimethylacrylsaure—Synthesen der β,β-Dimethyl-α-aminopropionsaure

dl-Penicillamin

Synthetische Versuche in der Penicillin-Reihe (II)

Synthetische Versuche in der Penicillinreihe IV

Synthetische Versuche in der Penicillinreihe V

Synthetische Versuche in der Penicillinreihe VI

Penicillamine: A new oral therapy for Wilson's disease

Am J Med

Effects of penicillamine on cystinuria

Br Med J

Controlled trial of d-penicillamine in severe rheumatoid arthritis

Lancet

Lancet

Long term follow-up of 235 cases of juvenile rheumatoid arthritis treated with d-penicillamine

A comparative study of gold and penicillamine in the management of seronegative juvenile chronic arthritis

Management of scleroderma

A controlled trial of d-penicillamine therapy in primary biliary cirrhosis

Lancet

The syndrome of primary biliary cirrhosis

J Rheumatol

2,5,5-Trimethylthiazolidine-4-carboxylic acid, a D-(−)-penicillamine directed pseudometabolite of ethanol. Detoxication mechanism for acetaldehyde

J Med Chem

Treatment of lead poisoning with oral penicillamine

Br Med J

Mercury poisoning from an unsuspected source

Br J Ind Med

Acrodynia treated with d-penicillamine

Am J Dis Child

d-penicillamine in Morphoea

Lancet

Postgrad Med J Oct

Penicillamine for the treatment of Darier's disease and other disorders of keratin formation

Lancet

Dissociation of human serum macroglobulins

Science

Labelling products of penicillamine with technetium-99m

A kit for the preparation of basic 99mTc penicillamine for renal scanning

Int J Appl Radiat Isot

Inhibition of the growth of the rat by l-penicillamine and its prevention by aminoethanol and related compounds

J Biol Chem

Structural and spectroscopic studies of dipotassium 3,3,3′,3′-tetramethylcystinate trihydrate, K2[C10H18N2O4S2]3H2O

Can J Chem

Ultraviolet spectra of alky disulfudes and their relation to alkali cleavage of disulfide bonds

J Am Chem Soc

Metal binding in chelation therapy: X-ray crystal structure of a copper(I)-copper(II) complex of d-penicillamine

J Chem Soc Chem Commun

Inhibition of collagen gelation by action of the Superoxide radical

Arthritis Rheum

Action of singlet oxygen on collagen

Indian J Biochem Biophys

Effect of oxygen derived free radicals on hyaluronic acid

Arthritis Rheum

Free radicals and inflammations: Reaction of synovial fluid Superoxide dismutase

Science

Free radicals and inflammation: Reaction of synovial fluid by Superoxide dismutase

FEBS Lett

Orgotein, the drug version of bovine Cu-Zn Superoxide dismutase II. A summary account of clinical trials in man and animals

Labelling products of penicillamine with technetium-^99m

A kit for the preparation of basic ^99mTc penicillamine for renal scanning

Structural and spectroscopic studies of dipotassium 3,3,3′,3′-tetramethylcystinate trihydrate, K₂[C₁₀H₁₈N₂O₄S₂]3H₂O