tacrolimus and pirfenidone

Primary biliary cholangitis (PBC, primary biliary cirrhosis) is an autoimmune cholestatic liver disease characterized by chronic nonsuppurative destructive cholangitis and the presence of serum antimitochondrial antibodies. Ursodeoxycholic acid is the only drug approved by the US Food and Drug Administration to treat PBC. However, one-third of patients show incomplete responses to ursodeoxycholic acid and a poor prognosis. A number of old and new medications have been used in these patients, such as fibrates, glucocorticoids, immunosuppressants, obeticholic acid, mesenchymal stem cells, biological agents (anti-interleukin-12, cytotoxic T-lymphocyte antigen 4 immunoglobulin, anti-CD20), and antifibrotic drugs. This article reviews the therapeutic advances of these old and new medications in patients with PBC.

Topics: Abatacept; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cyclosporine; Enzyme Inhibitors; Fibric Acids; Glucocorticoids; Humans; Immunosuppressive Agents; Indoles; Liver Cirrhosis, Biliary; Mesenchymal Stem Cell Transplantation; Methotrexate; Mycophenolic Acid; Pyridones; Rituximab; Tacrolimus; Ursodeoxycholic Acid; Ustekinumab

Tacrolimus nephrotoxicity is thought to contribute to renal allograft dysfunction and subsequent failure, a process that is underpinned by alterations in mRNA expression of genes involved in matrix metabolism. The new anti-fibrotic pirfenidone was tested for its potential to reverse markers of renal dysfunction.. Rats were salt-depleted before tacrolimus and pirfenidone treatment. Serum creatinine, urinary protein/creatinine ratio, extracellular matrix deposition (ECM), and mRNA expression of genes involved in matrix turnover were assessed.. Tacrolimus reduced TGF-beta mRNA expression below control levels and treatment with pirfenidone at all doses did not alter this effect. Likewise, TIMP-1 mRNA expression was depressed by the addition of tacrolimus and pirfenidone caused a further decrease in expression. Collagen III, MMP-2, and MMP-9 expression was unchanged by tacrolimus, but pirfenidone reduced collagen III below control levels. ECM was slight (1-4%) and not significantly different between groups.. These findings suggest that pirfenidone can attenuate the limited fibrotic potential of tacrolimus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Collagen Type III; Collagenases; Fibrosis; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Kidney Diseases; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pyridones; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrolimus; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta