Autoimmune therapy

StmcturaHy related to nitrofurantoias are Dantrolene [7261-97-4] (38), a peripherally acting muscle relaxant, and its analogues (39), which can be used as an antidote against succiaylcholine-iaduced myopathy and ia autoimmune myasthenia gravis therapy (136,137). 

As discussed above, the vast majority of autoimmune diseases is associated with chronic inflammation. The therapy thus rests on two principles ... 

Immune defense mechanisms can become deleterious for an individual when they are not controlled properly. Then they can cause disease. In such situations therapy is aimed to dampen immune reactions. Important examples are sqttic shock, allergy, autoimmune diseases, and chronic inflammatory diseases such as rheumatoid arthritis. Also, the success of organ transplantation... 

Immunosuppressive agents are indicated for the therapy of systemic autoimmune diseases (e.g., systemic lupus... 

First trials with CD3 antibodies for therapy of autoimmune diseases (insulin-dependent diabetes mellitus psoriatic arthritis... 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

Lithium is associated with hypothyroidism in up to 34% of patients, and hypothyroidism may occur after years of therapy. Lithium appears to inhibit thyroid hormone synthesis and secretion. Patients with underlying autoimmune thyroiditis are more likely to develop lithium-induced hypothyroidism. Patients may require LT4 replacement even if lithium is discontinued. 

Besides anemia associated with cancer and CKD, anemia of chronic disease can result from inflammatory processes and occurs commonly in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. In treating these types of anemia of chronic disease, the most important principle is treating the underlying disease. These patients also may have iron deficiency and should be treated in the manner already discussed. Erythropoietin therapy such as epoetin-alfa therapy at a dose of 150 units/kg three times a week also may be used in these patients. 

Furlan, R., Butti, E., Pluchino, S., and Martino, G. 2004. Gene therapy for autoimmune diseases. Current Opinion in Molecular Therapeutics 6(5), 525-536. 

The overall effect of Li+ on the hematopoietic system is of stimulation of the immune system. Not surprisingly then, Li+ is reported to exacerbate the activity of a number of autoimmune diseases, such as psoriasis [212] and rheumatoid arthritis [213], and to result in the production of autoantibodies in some patients [214]. However, there is no evidence that Li+ s stimulation of the immune system leads to any reduction in the occurrence of viral or bacterial infections in patients on Li+ therapy. 

Penicillamine onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia. Glomerulonephritis may occur, which manifests as proteinuria and hematuria. Penicillamine is usually reserved for patients who are resistant to other therapies because of the rare but potentially serious induction of autoimmune diseases (e.g., Goodpasture s syndrome, myasthenia gravis). 

Pituitary failure (secondary hypothyroidism) is an uncommon cause resulting from pituitary tumors, surgical therapy, external pituitary radiation, postpartum pituitary necrosis, metastatic tumors, tuberculosis, histiocytosis, and autoimmune mechanisms. 

Initiation factors initiate kidney damage and can be modified by drug therapy. Initiation factors include diabetes mellitus, hypertension, autoimmune disease, polycystic kidney disease, and drug toxicity. 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

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. 

---