Inflammatory disease treatment

Advancement in autoimmune and inflammatory disease treatment and diagnosis represents a critical worldwide need ranking in importance only behind management of cardiovascular disease and cancer to the medical practitioner. The list of related diseases is long major classes include rheumatoid arthritis, asthma, diabetes type 1, multiple sclerosis, and inflammatory bowel disease. 

Asthma is a chronic inflammatory disease. Therefore steroids represent the most important and most frequently used medication. Already after the fust treatment, steroids reduce cellular infiltration, inflammation, and the LAR, whereas changes in the EAR require prolonged treatment to lower the existent IgE levels. The mechanisms of steroid actions are complex and only incompletely understood. Besides their general antiinflammatory properties (see chapter glucocorticoids), the reduction of IL-4 and IL-5 production from T-lymphocytes is particularly important for asthma therapy. The introduction of inhaled steroids, which have dramatically limited side effects of steroids, is considered one of the most important advancements in asthma therapy. Inhaled steroids (beclomethasone, budesonide, fluticasone, triamcinolone, momethasone) are used in mild, moderate, and partially also in severe asthma oral steroids are used only in severe asthma and the treatment of status asthmaticus. Minor side effects of most inhaled steroids are hoarseness and candidasis, which are avoided by the prodrug steroid ciclesonide. 

Aspirin has been remarkably successful in the treatment of the pain and swelling of inflammatory disease and in fact, an estimated 45,000 tons of aspirin are still consumed each year. This success resulted in the syntheses of many other aspirin-like drugs , now referred to as NSAIDs. Aspirin, however, continues to have a unique use in the prevention of thrombosis. Since it produces irreversible inhibition of COX-1 by acetylation of serine at position 530 in the active site, a daily low dose of aspirin will cause a cumulative inhibition of COX-1 in platelets, in the portal circulation. A gradual inhibition of platelet aggregation occurs, reducing the possibility of occlusion of coronary or cerebral vessels by platelet thrombi. However, there are no systemic... 

NSAIDs are used as the first-line treatment of rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis and other inflammatory diseases, and are thus amongst the most widely used dtugs in the developed world. This widespread use inevitably entailed a considerable associated morbidity, in particular a high incidence of gastric toxicity. In the USA alone, perforations, ulcers and bleeds lead to the hospitalisation of 100,000 patients per year, and about 15% of these die while under intensive care. 

Synthetic steroid with strong glucocorticoid-agonistic activity. Dexamethasone is over 10 times more potent than cortisol due to a higher binding affinity for glucocorticoid receptor and a decreased clearance rate of the compound. Due to its potency, dexamethasone is widely used in the clinics for the treatment of inflammatory diseases. 

Glucocorticoids are widely used to treat a variety of inflammatory and immune diseases. With the recognition that airway inflammation is present even in patients with mild asthma, treatment with glucocorticoids is now the mainstay of asthma therapy. Consequently, by far the most common use of glucocorticoids today is in the treatment of asthma and inhaled glucocorticoids have now become established as first-line treatment in adults and children with persistent asthma, the commonest chronic airway inflammatory disease. 

The effect of prolonged antioxidant therapy in relation to normal physiological processes (for example, redox cycling, cell-cell signalling, transcription factor activation) must be assessed. It is conceivable that the overload of one antioxidant by dietary supplementation (for example, a-tocopherol) may shift the levels of other antioxidants (for example, by decreasing ascorbate and /3-carotene concentrations), with unknown consequences. To assess the potential for lipid-soluble antioxidant treatment in inflammatory diseases such as RA, further investigations into these questions will be needed. 

The first covers each of the major cell types and classes of inflammatory mediators. The second covers each of the major organ systems and the diseases involving the immune and inflammatory responses that can aflfect them. The series will thus include clinical aspects along with basic science. The third covers diflPerent classes of drugs that are currently being used to treat inflammatory disease or diseases involving the immune system, as well as novel classes of drugs under development for the treatment of such diseases. 

CXCR2 is a member of the CXC family of chemokine receptors. IL-8 activates this receptor, and an antagonist would potentially be useful for the treatment of inflammatory diseases. Baxter et al. [58] describe the parallel optimization of binding and functional potency, physicochemical properties, ADME properties, and PK. The thiol of the HTS hit was varied with typical replacements (i.e., OH, NH2, SMe, NHAc, etc.), but this only led to inactive compounds. Variation of the substituent at N(2) showed that a benzyl moiety was required (Ph, Me substituents gave inactive compounds). Variation of the C(5) substituent showed that -substituents produced optimal activity. The optimized lead has substantially improved CXCR2 binding and functional activity as well as an excellent PK profile (Scheme 13). 

When present, the urethral discharge is watery and less purulent than that seen with acute gonococcal urethritis. Complications resulting from lack of treatment or inadequate treatment include epididymitis (in males), and pelvic inflammatory disease including associated complications... 

TABLE 77-4. Treatment Regimens for Pelvic Inflammatory Disease... 

Beigi R, Wiesenfeld H. Pelvic inflammatory disease new diagnostic criteria and treatment. Obstet Gynecol Clin North Am 2003 30(4) 777-793. 

Methotrexate is a valuable drug that is commonly used in the treatment of inflammatory diseases, autoimmune diseases, and proliferative dieases. Its true potency can only be realized by the proper, quantitative analysis of the time-dependent inhibition of DHFR by this compound. 

Today there are two selective COX2 inhibitors that are in clinical use for the treatment of inflammatory diseases, Vioxx1 and Celebrex. The structures of these drugs are shown in Figure 6.23 together with the structures of DuP697 and NS-398. 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

Mclnnes, I. and Grade, J. 2004. Interleukin-15 a new cytokine target for the treatment of inflammatory diseases. Current Opinion in Pharmacology 4(4), 392-397. 

Other studies describe similar beneficial effects for PUFA-enriched diets to treat Crohn s disease, other inflammatory bowel diseases such as ulcerative colitis, as well as psoriasis, asthma, systemic lupus erythematosus, and multiple sclerosis [57], Thus, immunomodulation by PUFAs appears to be a promising intervention for the treatment of many autoimmune and inflammatory diseases. 

Pathway selective ER ligands have been reported that selectively inhibit nuclear factor kB (NF-kB) mediated gene expression [71], Since NF-kB is a pivotal regulator of pro-inflammatory gene expression, ligands that selectively inhibit the NF-kB pathway could be developed for the treatment of chronic inflammatory diseases such as arthritis, atherosclerosis, sepsis, and inflammatory bowel disease... 

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