Pharmacokinetic and Biodistribution Studies of
Dexamethasone Prodrug
Introduction
Lupus is a chronic autoimmune disease that can damage many body systems, like skin, joints and also organs. In lupus, the immune system becomes hyperactive and autoantibodies are produced against nuclear antigens, including double stranded DNA (dsDNA), which is lethal for the people healthy tissues. When lupus causes inflammation in kidney, nephritis happened.
Lupus nephritis is a kind of glomerulonephritis, and itrsquo;s also the major cause of the morbidity and mortality in lupus patients. In which, the glomeruli become inflamed. Renal deposition of anti-dsDNA IgG-containing immune complexes induce inflammation and immune cell infiltration, which damages the renal functions and may leads to renal failure.
Current treatment of lupus nephritis includes different drug categories. Antimalarial drug is frequently used as the first-line treatment for patients with mild SLE. It is effective in preventing the occurrence of new mild SLE manifestations. However, hydroxychloroquine doesnrsquo;t have a good therapeutic effect in the nephritis or sever SLE. Cyclophosphamide, an alkylating agent, is the standard of care for lupus nephritis. Other immunosuppressive drugs, like mycophenolate and azathioprine, are also as effective as cyclophosphamide in the treatment of lupus nephritis. Although immunosuppressive agents show an excellent performance in the treatment of lupus nephritis, they are still suboptimal because of the expensive price.
Glucocorticoids(GCs) is another effective and common therapy for the lupus nephritis. Prednisone and other corticosteroids are generally prescribed to treat the inflammation. GCs are also used in combination with immunosuppressive agents for patients with significant organ involvement or refractory symptoms. However, its off-target toxicity limits its use. As lupus patients have to take GCs continuously for a long time, they are at high risk for developing GC-associated adverse side effects, including osteoporosis and immunosuppression. Patients requiring long-term glucocorticoids treatment should be monitored for the complications of hypertension, diabetes, myopathy, psychosis and cataracts.
To address this challenge and make GCs much safer for patients, a macromolecular prodrug of dexamethasone (P-DEX) was designed, which passively targets inflamed tissues and provides superior and sustained resolution of inflammation in several experimental animal inflammatory disease models. The nephrotropism, cell-mediated local sequestration, subcellular processing and activation of P-Dex contribute to its superior therapeutic efficacy and reduced systemic toxicities.
P-Dex can prevent albuminuria and reduce glomerular damage, which is same as the free Dex. However, P-Dex doesnrsquo;t reduce anti-dsDNA IgG levels and renal immune complexes. Thus, in contrast to Dex, P-Dex may prevent nephritis through a mechanism that is independent of production of pathogenic autoantibodies. P-Dex treatment also reduces the Dex toxicity. It does not affect bone quality and not reduce serum IgG levels. Therefore, the quantitatively study of its pharmacokinetics and biodistribution is necessary to further understand the nephrotropism of P-Dex.
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