Anti-arthritic activity

There is some evidence that auranofin may also be biologically de-acetylated during its absorption from the gut [58]. It is unfortunate that so many in vitro studies to determine possible mechanisms for the anti-arthritic activity of auranofin have not considered (tetra) desacetyl-auranofin as the first likely active metabolite, with its far greater hydrophilicity than the administered auranofin (which is only a pro-drug). 

Enhanced glucocorticosteroid activity (three to five times that of cortisone) and reduced mineralocorticoid activity at the projected therapeutic dose were demonstrated by the collaborators of Schering Corporation using appropriate assays. Anti-arthritic activity and the absence of any significant associated salt retention were quickly demonstrated for both prednisone and prednisolone. 

Introduction of the 16a-hydroxyl group into 9-fluoro-hydrocortisone and 9-fluoro-prednisolone has been shown by Bernstein et al. [16] to result in complete suppression of the salt-retaining properties of these steroids, without appreciably impairing their glucocorticoid activity. Moreover, studies in man have demonstrated the anti-arthritic activity of 9-fluoro-16a-hydroxy-prednisolone and have confirmed its lack of salt-retaining activity. Subsequently, Lederle reported that the anti-inflammatory potency was lowered, but salt retention was eliminated. 

It has been claimed that 2,3,5-trihydroxybenzoic acid X) and its triacyl derivatives possess antihyaluronidase and anti-arthritic activities , but later work by the same authors suggests that they are inactive as analgesic or anti-arthritic drugs . 2,3,4-Trihydroxybenzoic acid XI) is inactive at 200 mg/kg subcutaneously and 3,4,5-trihydroxybenzoic acid XII) is active at a subcutaneous dose of 118 mg/kg in a mouse vascular permeability test . 

Apart from the acute anti-inflammatory activity described in the preceding section, taraxasterol acetate was also tested for chronic activity in the model of Freund s adjuvant-induced rat arthritis. When 80 mg/kg of this compound were administered i.p., a 57% decrease with respect to the control value for the injected limb was observed at 18 h. After 21 days, the secondary reaction, which is measured on the non-injected limb, was reduced by 78%. Given the fact that in this condition the injected limb suffered a comparable reduction of 67%, it seems that taraxasterol acetate did not act by modifying immune mechanisms [64]. Duwiejua et al. [66] also reported appreciable anti-arthritic activity for glutin-3-one 44% and 74% reductions in the ipsilateral and contralateral paw swelling, respectively, after 10 days. 

In 1938, before Cu complexes were used in therapy, it was reported that patients with rheumatoid arthritis had higher than normal total serum Cu concentrations which returned to normal levels with remission. Had this increase in total serum Cu been recognized as an increase in serum Cu complexes, this increase might have been considered to be a physiologic response to this disease when Cu complexes were subsequently found to have anti-arthritic activity in man and anti-inflammatory activity in animal models of inflammation. 

Vetal, S., Bodhankar, S.L., Mohan, V., and Thakurdesai, P.A. 2013. Anti-inflammatory and anti-arthritic activity of type-A procyanidine polyphenols from bark of Cinnamomum zeylanicum in rats. Food Science and Human Wellness, 2 59-67. 

Shaw, C. Gold Complexes with Anti-arthritic, Anti-tumour and Anti-HIV Activity In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed. The Royal Society of Chemistry Cambridge, 1999, pp 26-57. 

Of interest here is that certain drugs and prodrugs that contain an isoxazole ring are metabolized to a cyano enol, e.g., leflunomide (11.122, R = CF3, R = H), a prodrug of the potential anti-arthritic agent 2-cyano-3-hydroxy-A-[4-(trifluoromethyl)phenyl]but-2-enamide (11.123). After oral administration of 50 mg/kg of 11.122 to rats, the plasma concentration of the prodrug peaked at 1 pg/ml and dropped rapidly, whereas the concentration of the active metabolite 11.123 was maintained at ca. 100 pg/ml for 24 h [147]. This... 

Studies on isolation from adrenal cortex and the synthesis of cortisone (in 28 steps), an anti-arthritic hormone, was accomplished in the 1940s by Woodward and others. Cortisone was used as an important military medicine during World War II. Carl Djerassi from Stanford University directed the research at the Syntex Laboratories, which led to the synthesis of the first oral contraceptive pill for women. Koji Mori is very active in the field of the synthesis of pheromones. 

Malfait AM, Gallily R, SumariwaUa PF, The non-psycho active cannabis-constituent cannabidiol is an oral anti-arthritic therapeutic in murine coUagen-induced arthritis. Prod Nat Acad Sci USA 97 9561—9566, 2000. 

Other modifications of the molecule (e.g., introduction of a double bond or a substituent in position 1) have given rise to very powerful anti-inflammatory and anti-arthritic drugs that are used in dermatology (triamcinolone, betamethasone, dexa-methasone cf. Chapter 8) (Figure 4.5). These compounds have greatly reduced residual mineralocorticoid activity. 

A new class of compounds is reported to have dual inhibitory properties. They have a y-sultam skeleton and show potent inhibitory effects towards both COX-2 and 5-lipoxygenase as well as production of IL-1 in in vitro assays. These compounds have also proved to be effective in several animal arthritic models without any ulcerogenic activity. Among these compounds S-2474 ((E)-(5)-(3,5-di-fe/t.-butyl-4-hydroxy-benzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide) was selected as an anti-arthritic drug candidate and is now under clinical investigations (Inagaki et al., 2000). 

Because of its analogy to PPi and an ability to chelate metals, the BP structure has served as a pharmacophore for drug design in various areas. In addition, as detailed in Chapter I—1, "...in some cases a new clinical activity observed for an old drug is sufficiently potent and interesting to justify the immediate use of the drug in the new indication... . Some of the cases that follow fall into this class, and include especially antiparasitic, anti-arthritic, and antirestenosis applications. 

In particular, the non-naturally occurring amino acid L-tert-leucine has received significant attention due to several pharmaceutically active compounds into which it is incorporated[1). HIV-protease inhibitors developed by Novartis and Abbott are based on L-tert-leudne 2, 3. Roche has developed the anti-arthritic compound Ro 31-9790 based on its potent inhibition of collagenase 41 and a key component in the synthesis of Ro 31-9790 is the methylamide of L-tert-leucine. Boehringer Ingelheim developed a series of compounds that inhibit the ribonucleotide redudase of Herpes... 

Cinchophen (2-phenylquinoline-4-carboxylic acid, Atophan, XLIII) has been used in the treatment of gout and arthritic conditions, but fell into disrepute as it caused toxic hepatic cirrhosis with a high mortality in sensitive individuals. It must nevertheless be mentioned as it represents another class of chemical compound which possesses anti-inflammatory activity. 

Analgesic activities of copper complexes, as well as their antipyretic and anti-inflammatory activities, offer some explanation for their remarkably successful treatments of arthritic and other degenerative diseases of man [138]. 

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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