Anti-arthritic

Gucosamine (chitosamine) 2-Ami no-2-deoxy glucose Anti arthritic in osteoarthritis Well-tolerated No direct toxic effects have been reported. 

As auranofin demonstrates both anti-arthritic and antitumor effects, many analogs differing in the thiolate and the phosphine residues have been characterized [18, 21, 51-53]. Like auranofin, these complexes are generally linear at the two-coordinate gold center. Di- i-(diethylphosphinoethylthio)digold(I) is a complex that... 

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). 

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. 

ARRY-438162 is a recently disclosed potent and selective ATP non-competitive MEK1/2 inhibitor that is in Phase lb clinical trials as an anti-arthritic agent [24]. ARRY-438162 inhibited the MEK1/2 enzyme with an IC50 = 12 nM and pERK in cells with an IC50 = 11 nM. ATP non-competitive inhibition may be responsible for equipotent inhibition of MEK1/2 in vitro and pERK in cells. The compound was selective against a panel of 220 other kinases. 

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... 

Lactoferrin Cow Anti-arthritic gastrointestinal tract infections... 

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. 

Anti-arthritic effect. Oral administration of AJA, a cannabinoid acid devoid of psychoactivity, reduced joint tissue damage in rats with adjuvant arthritis. Peripheral blood monocytes (PBM) and synovial fluid monocytes (SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AJA (0-30 mM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for messenger RNA (mRNA), and supernatants were collected for cytokine assay. Addition of AJA to PBM and SFM in vitro reduced both steady-state levels of interleukin-ly (IL-ly) mRNA and secretion of IL-ly in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 mM AJA (p < 0.05 vs untreated controls, n = 7). AJA did not influence tumor necrosis factor-a (TNF-a) gene expression in or secretion from PBM . 

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). 

It seems likely that the future will see major developments in the use of metal complexes as bacteriocidal, viricidal, immunosuppressive, anti-arthritic and biocidal agents. One class of complexing agents that appears to have particular promise are the macrocyclic antibiotics, macrocyclic polyethers, polyamines and cryptates . In this group the ligand wraps around a metal ion to form a lipid-soluble complex... 

Evans, C.H., Robbins, P.D., Ghivizzani, S.C., Herdon, J.H., Kang, R., Bahnson, A.B. et al. (1996) Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Hum. Gene Ther., 7, 1261-1280. 

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. 

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. 

---