Anti-inflammatory Cytokine Inhibitors

Title Anti-inflammatory Nitro- and Thio-fatty Acids 

Ferrante el al., US Patent 6,924,309 (August 2, 2005) Assignee Children, Youth and Women s Health Service Incorporated (North Adelaide, AU) and Peptech Limited (AU) 

Invention Significance The lipoxygenase pathway of arachidonic acid is 

Octadecan-l-ol (1.92mmol) and triphenylphosphine (2.10mmol) were dissolved in 25 ml CH2C12, then cooled in an ice bath, and treated with CBr4 (1.90 mmol). The mixture was stirred overnight at ambient temperature and was then concentrated. The residue was purified by flash column chromatography using silica gel with hexane and the product was isolated in 96% yield as a waxy solid, mp = 26-28°C. 

A solution of NaOH (3.4 mmol) and Bu4NI (0.43 mmol) in 10 ml water was added to a solution of the Step 2 product (1.70 mmol) and methyl acrylate (5.13 mmol) dissolved in 10 ml CH2C12, then refluxed 24 hours. The solution was cooled and the layers separated. The organic phase was washed twice with 25 ml water, dried, and concentrated. The residue was purified by flash column chromatography using diethyl ether/hexane, 5 95, and the product isolated in 76% yield as a waxy solid. 

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First identified as an inhibitor of IFN-y synthesis in THi cells, IL-10 is an important immunoregulatory cytokine. It is an anti-inflammatory cytokine that was first called... 

Several anti-inflammatory cytokines that are known from the immune system inhibit NF-kB in the nervous system, but how these molecules act in the neuron is not well understood. One possibility might be the induction of IkB transcription. Some molecules have dual activity in regulating NF-kB, depending on their concentrations. A recent review has summarized the inhibitors of NF-kB in the nervous system (Kaltschmidt et al, 2005). 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Echinacea (Echinacea purpurea) Uses immune system stimulant prevention/Rx of colds, flu as supportive th apy for colds chronic infxns of the resp tract lower urinary tract Action Stimulates phagocytosis cytokine production T resp cellular activity topically exerts anesthetic, antimicrobial, anti-inflammatory effects Efficacy Not established may X severity duration of URI Available forms Caps w/ powdered herb equivalent to 300-500 mg, PO, tid pressed juice 6-9 mL, PO, once/d tine 2-4 mL, PO, tid (1 5 dilution) tea 2 tsp (4 g) of powdered herb in 1 cup of boiling water Noles/SE Fever, taste p -version, urticaria, angioedema Contra w/ autoimmune Dz, collagen Dz, progressive systemic Dz (TB, MS, collagen-vascular disorders), HIV, leukemia, may interfere w/ immunosuppressive therapy Interactions t Risk of disulfiram-like reaction W/ disulfiram, metronidazole T risk of exacerbation of HIV or AIDS W/ chinacea amprenavir, other protease inhibitors X effects OF azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, econazole vag cream, muromonab-CD3, mycophenolate, prednisone, tacrolimus EMS Possible immunosuppression... 

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