Complexes antiarthritic activity

Gold sodium thiomalate provides a stimulus for liver, kidney and possibly other cells to change the body distribution of zinc and copper. Proteins such as metalloproteins, superoxide dismutase and metallothioneins19 help the cell carry out this task. These essential metals are important in the physiological processes relevant to rheumatoid arthritis, and thus it also appears possible that the gold complexes may mediate their antiarthritic activity through an effect on the metabolism of zinc and copper. 

Roccal benzaikonium chloride, rocepafant [inn] (BN S0730) is a complex diazepine. a PLATELET-ACTTVATING FACTOR RECEPTOR ANTAGONIST. It haS ANTIALLERGIC properties, experimental antiarthritic activity, and has been investigated for treatment of drug-induced retinopathy. 

Fig. 11.2. Ligands whose copper complexes have demonstrated antiarthritic activity.

The nature of the phosphine ligand (R3P) influenced the extent of oral absorption of the complex and antiarthritic activity was found to be closely related to the gold serum concentrations (Fig. 3). The maximum absorption and activity occurred when the phosphine was EtsP. EtaPAuCl was initially selected for clinical trial but diarrhoea proved to be a troublesome side-effect and it was abandoned in favour of the tetraacetylated thioglucose derivative, auranofin (9). Under the tradename Ridaura this was approved by the FDA for clinical use in the USA in May 1985. 

Fig. 3. The correlation between the antiarthritic activity (in rat model, assessed by the reduction in paw volume of uninjected leg on day 16, oral doses of compound equivalent to 10 mg Au kg ) and serum Au concentration for the series of complexes RjPAuCI ( ) and R3PAuSGlu(A) (where SGlu is p-D-thioglucose). Data om Ref. 46...

A very large number of copper compounds have been tested for antiinflammatory activity, and various copper complexes of antiarthritic drugs have been found to be more effective than the parent drugs alone (including aspirin, D-penicillamine, ketoprofen and gold thiomalate).25... 

One compound which did not work well in our system was our original model, a-phenylacrylic acid. A number of these aryl propionic acids are valuable as nonsteroidal antiarthritics. Here, as is typically the case, only one enantiomer is active and thus a process to prepare one isomer directly was needed. We tried hard to solve this problem, even using ruthenium-ligand systems, but without success. It took Professor Noyori with his BINAP-ruthenium complex to solve this problem [4]. This is just another example in the history of invention. The one who makes the first discovery seldom makes the second. On a grander stage, this may explain why there are so few double Nobel Laureates. 

The list of compounds presented in Table 6.4 includes copper complexes of well-known antiarthritic drugs, including salicylic acid, aspirin, diflunisal, niflumic acid, D-penicillamine, hydrocortisone, dexamethasone, dimethyl-sul-phoxide, clopirac, ketoprofen, ibuprofen, (+ )-naproxen, indomethacin, me-fenamic acid, thiomalic acid, phenylbutazone, lonazolac, isoxicam and azo-propazone. While there has been much discussion concerning the qualitative and quantitative activities of these complexes [136, 152-156, 164, 187], it is... 

The lack of gastric irritation [270], the presence of antiulcer activity, and the enhanced anti-inflammatory activity of these complexes make this class of potentially useful antiarthritic drugs particularly promising, since the arthritic syndrome is likely to include gastric ulcers [259, 260]. 

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