Gold therapy for rheumatoid arthritis

Rheumatoid arthritis

It is generally agreed that RA is an inflammatory disease, of unknown causation, and one that is manifested, sometimes chronically, particularly in the peripheral joints of the body. The well-recognized symptoms of the disease, arising from inflammation, are the swellings of the joints and the incumbent physical disability and pain. Inflammation occurs first in the synovial membrane surrounding the joints and soon spreads to the synovium with progression of the disease. This has the result of eroding the articular cartilage on the bone joints that once damaged or removed means the bones directly rub against each other with concomitant bone erosion. Approximately 1-2% of the overall population of industrialized countries suffers from RA, although perhaps 10 times that number suffers from one of the approximately 150 known arthritic conditions. RA normally afflicts adults but not exclusively so. There is no pattern of inheritance with the disease, and females suffer RA more than males, in a ratio of 4:1. The pathogenesis of RA is linked to a breakdown of the body's immune system but the actual cause of RA is not known. However, a patient is diagnosed with RA if they have a combination of three factors, namely erosive joints, inflammation and the presence of the so-called rheumatoid factor (associated with the production of immunoglobulin).

Anti-arthritic Drugs

The first-generation gold compounds used for the treatment of RA are Au(I) thiolates such as aurothioglucose (1; marketed variously as Solganol®, Aureotan®, Auromyose®), disodium aurothiomalate (2; Myocrisin®, Myochrisin®, Mychrisis®, Miocrin®, Shiosol®, Tauredon®), tri-sodium

bis(thiosulphato)gold (3; Sanocrysin®, Sanochrisin®), aurothiopropanol sulphonate (4; Allochrysin®, Allochrysine®, Limiere®) and sodium gold 4-amino-2-mercaptobenzoic acid (5; Krysolgan®). Of these, drugs 1 and 2 are probably the most important. The chemical compositions of these drugs are shown in Figure 26.1. It should be noted that except for 3,29 the precise structures of these molecules are not known. In 1985, a new compound, a second-generation drug (2,3,4,6-tetra-O-acetyl-1-thio-^-D-glucopyranosyl) (triethylphosphine)gold(I) (6; Auranofin®, Aktil®, Crisinor®, Crisofin®, Ridaura®), was introduced as an orally active gold drug for the treatment of RA.

The first-generation gold complexes used to treat RA feature linear, two-coordinate Au(I) thiolates and, with the exception of 3, are polymeric. Crystal-lographic evidence for this is found in the structure of [Na2Cs(H)][{Au(SCH) (CO2)CH2CO2}2], an analogue of 2.30 The +I oxidation state of gold in these complexes is stabilized against disproportionation to Au(0) and Au(III) by the thiolate ligand. Importantly, the open geometry allows for exchange reactions with biological ligands, via three-coordinate intermediates. A common feature of drugs 1-5 is that they are water soluble, owing to the presence of hydrophilic

SO3Na n

Figure 26.1 Chemical structures of aurothioglucose (1), disodium aurothiomalate (2), tri-sodium of bis(thiosulphato)gold (3), aurothiopropanol sulphonate (4), gold(I) 4-amino-2-mercaptobenzoate (5) and [tetra-O-acetyl-^-D-(glucopyranosyl)thio]-triethyl-phosphine)gold(I) (6)

groups and/or charge, and this property directs their mode of administration to patients, i.e. via intramuscular injection.31,32 A disadvantage of the firstgeneration gold drugs is that they require frequent visits to the clinic as a doctor must administer the drug. Typically, doses are of the order of about 50 mg per week, at least initially, and usually decrease after an induction period. One potential problem with these gold drugs is that gold is accumulated in organs such as the kidney resulting in nephrotoxicity, which leads to a leakage of protein and blood into the urine; in severe cases, gold therapy must be stopped. Also, the beneficial effects of therapy may not be apparent for 6 months after the commencement of treatment and many patients suffer from other side effects of varying severity (see below) that may continue for a considerable time after Chrysotherapy has been discontinued.33 Over and above this, not all patients respond to Chrysotherapy.34

A relatively new gold-based drug that finds wide use is Auranofin (6).35 It has an effective linear P Au S geometry and has been structurally characterized by X-ray crystallography36 in contrast with many of the other gold-based drugs. Being lipophilic, Auranofin can be administered orally, in doses of 3 6 mg per day, so that this 'second-generation' drug has a considerable advantage in this respect over the aforementioned drugs that require regular visits to a doctor. The likely role of the phosphine ligand in Auranofin is to enhance the lipid solubility of the drug to facilitate its absorption in the gut. The different solubility profile of Auranofin results in a different biodistribution of gold throughout the body compared with that of the conventional water-soluble drugs, which are injected immediately into the blood stream. A possible advantage of this is that the concentration of gold in the kidneys, with harmful effects as alluded to earlier, is considerably less for Auranofin. This advantage notwithstanding, there are, common with the water-soluble gold-based drugs, a number of deleterious side effects associated with Chrysotherapy.

Patients undergoing Chrysotherapy may suffer from a wide variety of unpleasant and harmful side effects. These may include a metallic taste in the mouth, discolouration of the skin, dermatitis, diarrhoea, nausea, flushing, vomiting, bone marrow damage, etc. Such a range of difficulties begs the question, why use gold-based drugs? The answer to this question is quite straightforward: there is no cure for RA. Even though there are various classes of drugs available for the treatment of RA, it should be noted that treatment is designed to alleviate the symptoms of the disease, to reduce the swelling and pain, or even halt the progression of the disease, but there is no cure for RA. Amongst the classes of drugs employed in the treatment of RA are (i) Non-steroidal anti-inflammatory drugs (NSAIDS), which function by blocking the production of (bad) prostaglandins that promote inflammation and pain. Examples of NSAIDS include Advil® (ibuprofen), Feldene® (piroxicam) and Naprosyn® (naproxen). The major problem with NSAIDS is that they do not differentiate between the so-called good (that afford protection to the stomach lining and kidneys) and bad prostaglandins; (ii) COX-II enzyme inhibitors that target inflammatory arthritis. Examples include Celebrex® (celecoxib) and

Mobic® (meloxicam); (iii) Salicylates, such as Aspirin®, are well known to relieve the symptoms associated with RA; and (iv) Disease-Modifying Anti-Rheumatic DrugS (DMARDS) which function to impede the progression of the disease as the name suggests. Examples of DMARDS include Cytoxan® (cyclophosphamide), Novo-chloroquine® (chloroquine) and Rheumatrex® (methotrexate). Gold drugs used in Chrysotherapy are classed as DMARDS. Thus, there are a large variety of therapies available for managing RA and the gold drugs are but one of these. Given the long use of gold drugs, it is not surprising that some considerable effort has been devoted to elucidating the possible mechanism(s) of action of gold drugs as summarized in the next section.

26.4 Metabolism of Gold Drugs

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