ABSTRACT
We review the crystal structures, electrospray ionization mass spectra (ESI-MS) data and chiral HPLC data for the racemic and optically pure mononuclear AuL2 complexes, and for racemic [AuLI]n and optically pure [AgLII]n polymers (LI = thiomalate, LII = D-penicillamine). We postulate an equilibrium between polymeric, mononuclear and free ligand species for [AuLII]n (gold sodium thiomalate or GST). The ESI-MS results clearly show a tetrameric principal species in the 1:1 gold polymers, [AuLI]n. For the 1:1 silver: D-penicillamine complex, [AgLII]n, a non-molecular crystal of double helical structure, the ESI-MS results show multi-ligand-silver species, including tetramers, pentamers and hexamers. Other, relevant gold, silver and copper complexes are compared.
ABSTRACT
Use of chiral molecules in clinical practice may cause problems because different chiral forms of a drug (enantiomers) may have different biological activities--yet clinicians have little awareness of these risks. After discussion of the chemical conventions used to describe chirality, examples of the influence of chirality on the efficacy and toxicity of antirheumatic drugs are given. It is recommended that single enantiomers should be used in biological experiments and clinical trials.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Gold Sodium Thiomalate/chemistry , Penicillamine/chemistry , StereoisomerismABSTRACT
In order to study the effect of gold compounds on the action of thrombin in vivo, experiments were performed to measure platelet survival and the weight of thrombus formation in experimental models of intra-aortic thrombosis by two indwelling aortic catheter methods. We have called these the long and short catheter methods. Platelet survival was reduced in all gold-treated and control animals which had indwelling aortic catheters. In the long catheter model, New Zealand White male rabbits were treated with one of the following: gold sodium thiomalate, sterile water, gold thioglucose, gold sodium thiosulfate, disodium thiomalate. Gold sodium thiomalate-treated rabbits had a reduced weight of experimentally induced intra-aortic thrombi compared with animals treated with sterile water or equimolar concentrations of gold thioglucose, gold sodium thiosulfate, or disodium thiomalate. This reduction in thrombus weight in the animals treated with gold sodium thiomalate was not reflected by changes in platelet survival or fibrinolysis. The serum gold levels achieved in these in vivo experiments was in the range of 5.0 X 10(-5) to 1.0 X 10(-4) M. These values are comparable to levels which can be achieved in human subjects immediately after a gold injection. In the short catheter model, New Zealand White male rabbits were treated with either gold sodium thiomalate, gold thioglucose, disodium thiomalate, or auranofin. Controls were given either water or 0.05% chlorocresol. Water-treated and gold sodium thiomalate-treated animals were also given 51Cr-labeled platelets and 125I-fibrinogen before insertion of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Gold Sodium Thiomalate/therapeutic use , Thrombosis/drug therapy , Animals , Catheterization/methods , Disease Models, Animal , Fibrinolysis/drug effects , Gold/blood , Gold Sodium Thiomalate/blood , Hemoglobins/drug effects , Leukocyte Count/drug effects , Male , Microscopy, Electron , Platelet Count/drug effects , Rabbits , Thrombosis/bloodABSTRACT
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.
Subject(s)
Penicillamine/therapeutic use , Rheumatic Diseases/drug therapy , Arthritis, Rheumatoid/drug therapy , Autoimmune Diseases/chemically induced , Drug Eruptions/etiology , Gold Sodium Thiomalate/therapeutic use , Hematologic Diseases/chemically induced , Humans , Kidney Diseases/chemically induced , Kinetics , Molecular Conformation , Penicillamine/administration & dosage , Penicillamine/adverse effects , Penicillamine/metabolism , Scleroderma, Systemic/drug therapy , Spondylitis/drug therapy , Structure-Activity Relationship , Taste Disorders/chemically inducedABSTRACT
One hundred fourteen patients with definite or classic rheumatoid arthritis were followed prospectively between January 1976 and April 1981 to monitor their toxicity pattern to D-penicillamine. The influence of previous sodium aurothiomalate therapy on the toxicity pattern of D-penicillamine is described. There was no significant difference in overall outcome of the patients treated with D-penicillamine with respect to adverse effects, whether they had previous gold toxicity, previous gold therapy but no toxicity, or no previous gold therapy. The time from gold toxicity to the start of D-penicillamine therapy was greater in those who did not develop D-penicillamine toxicity compared with those who did. This difference just reached statistical significance. Total gold salt received had no effect on eventual outcome of D-penicillamine treatment, and the toxicity pattern of D-penicillamine in those patients who had previous gold therapy was similar to those patients who had never received gold therapy.
