Anti-inflammatory Agents: Present and Future

This is an overview of the “Anti-inflammatory agents: Present and Future” paper similar to the handout that was given in class. Overall, the paper was somewhat repetitive and, as was mentioned in class, did not go into some of the serious issues associated with the use of some of these therapies.

-COX inhibitors:

• COX enzymes synthesize prostaglandins and thromboxanes, which participate in vasodilation, blood clotting, cell growth, and many other functions
• COX-1 is constitutive while COX-2 is inducible
• COX-2 inhibitors have decreased GI effects but increased cardiovascular effects

-Resolvins:

• Products of omega-3 fatty acid oxidation
• Lower infiltrating neutrophils and macrophages
• Decrease gene expression of TNF-alpha and IL-1beta

-Glucocorticoids:

• Suppress expression of cytokine-induced genes, T-cell growth factors, INF-gamma, NOX synthase, COX-2, and intracellular adhesion molecules
• Increase expression of anti-inflammatory molecules
• Chronic use is associated with organ toxicity

-Biologicals:

• Anti-cytokine therapies (block IL-1, TNF, IL-6, IL-12, IL-17, IL-18, or IL-23) are used to reduce inflammation by preventing responses such as T-cell activation
• Cytokines are more potent than hormones and can be produced by many cells
• Chemokines drive migration of immune cells while promoting angiogenesis, and can also be blocked to reduce inflammation
• Issue is innate immune response is important in defense against illness and cytokines can help with repair
• Synergistic action of cytokines means inhibiting only one is sufficient
• Effective at very low doses

-B cell depletion:

• Prevents antigen presenting and therefore T-cell activation

-Protease inhibitors:

• Proteases break down proteins and can activate cytokines
• Reduce inflammation by preventing proinflammatory cytokines from activating

-Small-molecule inhibitors of signal transduction:

• Kinases phosphorylate intracellular proteins to activate
• Example is to inhibit p38, which is important in cytokine, chemokine, COX-2 and NOX synthase production
• Tyrosine kinase inhibition reduces dendritic cell activation and proinflammatory cytokine production
• Possible renal or hepatic toxicity

-Statins:

• Reduce cholesterol levels
• Some work better than others in reducing inflammation
• Lower CRP and cardiovascular events were lowered
• Reduce cytokine production, adhesion molecules, and dendritic cell maturation
• Increase IL-10 production

-Histone Deacetylase inhibitors:

• Histone deacetylase maintains nuclear histones in deacetylated state to hold DNA
• Prevent transcription of certain genes and reduce production of cytokines
• Effective at very low doses

-Anti-coagulants and Thrombolytics:

• Activated protein C is the only approved therapy for sepsis
• Reduce cytokine production and endothelial activation by thrombin

-Activated Complement inhibitors:

• Reduce cytokine, chemokine, and adhesion molecule production

-PPARs (Peroxisome proliferator-activator receptors):

• Reduce expression of proinflammatory cytokines and adhesion molecules
• Used to treat type 2 diabetes
• Could increase cardiovascular events

-Prostaglandin (PGE) Agonists and Phosphodiesterase-4 (PDE-4) inhibitors:

• PGE2 is also immunosuppressive by inhibiting INF-gamma and IL-2
• Inhibitors of PDE-4 prevent breakdown of cAMP and are therefore anti-inflammatory
• Increased levels of cAMP lowers TNF-alpha

-Using small RNA molecules to downregulate gene expression holds promise

The paper “Anti-inflammatory Agents: Present and Future” stated the benefits of many treatments without listing the adverse effects. However, there can be serious side effects to using these various methods to treat inflammation. TGN1412 is a medication that binds to, and is a strong agonist for, the T-cells’ CD28 receptor. It was created with the intention of treating B cell chronic lymphocytic leukemia and rheumatoid arthritis. The disastrous Phase I clinical trial for this drug is an extreme example of the damage some of these therapies can cause. The clinical trials for this medication began in 2006, and were halted when many of the subjects had to be hospitalized with multiple organ dysfunction. These same effects were not seen in the pre-clinical trials on rabbits and monkeys, further proof that animal models do not accurately predict efficacy or safety in humans. Here is an article that I found about the clinical trials for this drug: http://www.i-sis.org.uk/LDTC.php