Tacrolimus immunosuppressive action

Tacrolimus, another antibiotic with immunosuppressant actions, does not bind to cyclophilin, but acts similarly to cyclosporine to inhibit caldneurin. 

DOC organ or tissue transplantation (+/- mycophenolate +/- steroids +/- cytotoxic drugs). Tacrolimus has been used alternatively to cyclosporine in renal and liver transplants. Mycophenolate, an inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity. 

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

Pharmacology Tacrolimus is a macrolide immunosuppressant that prolongs the survival of the host and transplanted graft and inhibits T-lymphocyte activation, although the exact mechanism of action is not known. 

Pharmacology Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. The mechanism of action of tacrolimus in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. Pharmacokinetics ... 

Echinacea (Echinacea purpurea) Uses immune system stimulant prevention/Rx of colds, flu as supportive th apy for colds chronic infxns of the resp tract lower urinary tract Action Stimulates phagocytosis cytokine production T resp cellular activity topically exerts anesthetic, antimicrobial, anti-inflammatory effects Efficacy Not established may X severity duration of URI Available forms Caps w/ powdered herb equivalent to 300-500 mg, PO, tid pressed juice 6-9 mL, PO, once/d tine 2-4 mL, PO, tid (1 5 dilution) tea 2 tsp (4 g) of powdered herb in 1 cup of boiling water Noles/SE Fever, taste p -version, urticaria, angioedema Contra w/ autoimmune Dz, collagen Dz, progressive systemic Dz (TB, MS, collagen-vascular disorders), HIV, leukemia, may interfere w/ immunosuppressive therapy Interactions t Risk of disulfiram-like reaction W/ disulfiram, metronidazole T risk of exacerbation of HIV or AIDS W/ chinacea amprenavir, other protease inhibitors X effects OF azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, econazole vag cream, muromonab-CD3, mycophenolate, prednisone, tacrolimus EMS Possible immunosuppression... 

Sirolimus (Rapamune) is structurally related to tacrolimus. It is approved for use as an adjunctive agent in combination with cyclosporine for prevention of acute renal allograft rejection. It blocks IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine-threonine kinase. This mechanism of action is different from those of tacrolimus and cyclosporine. This allows sirolimus to augment the immunosuppressive effects of these drugs. 

Although it is not chemically related to cyclosporine, tacrolimus (6.7) has a similar mechanism of action. Tacrolimus is an immunosuppressant macrolide antibiotic derived from Streptomyces tsukubaenis. Like cyclosporine, tacrolimus inhibits the same cytoplasmic phosphatase, calcineurin, which catalyzes the activation of a T-cell-specific transcription factor (NF-AT) involved in the biosyntheses of interleukins such as IL-2. Sirolimus (6.8) is a natural product produced by Streptomyces hydroscopicus, it blocks the ability of T cells to respond to cytokines. 

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. 

Mechanism of Action. Cyclosporine and tacrolimus (see below) are known as calcineurin inhibitors because they inhibit a specific protein (calcineurin) in lymphoid tissues. This inhibition ultimately suppresses the production of IL-2, a cytokine that plays a critical role in immune response by promoting the growth and proliferation of activated T lymphocytes and other immune cells, such as NK. cells (see Fig. 37—1).5,52 Thus, cyclosporine is one of the premier immunosuppressants because of its relative selectivity for T cells and its inhibition of a key mediator of the immune response (IL-2).41 This relatively specific inhibition is often advantageous when compared with other nonse-lective drugs such as azathioprine, cyclophosphamide, and glucocorticoids that inhibit virtually all the cells and chemical mediators involved in the immune response. 

Mechanism of Action. Unlike other immunosuppressants (cyclosporine, tacrolimus), sirolimus does not interfere directly with cytokine production. Instead, sirolimus inhibits the function of a specific enzyme commonly known as the mammalian target of rapamycin (mTOR).37,42 This enzyme plays a key role in signaling pathways that promote the growth and proliferation of T and B cells.37,45 By inhibiting this enzyme, sirolimus causes cell division to stop at a specific stage (Gl), thereby limiting the ability of these cells to mount an attack on transplanted tissues.65... 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

Cyclosporine binds to an intracellular protein, cyclophilin. Cyclophilins and similar binding proteins are now referred to collectively as immunophilins and their enzymatic activities are relevant to the actions of immunosuppressants such as cyclosporine and tacrolimus. This complex inhibits the phosphatase activity of calcineurin, which in turn prevents dephosphorylation and translocation of NFAT. NFAT is required to induce a number of cytokine genes, including that for interleukin-2, which serves as a T-cell growth and differentiation factor (Krensky et al., 2005 Matsuda and Koyasu, 2000). Cyclosporine also increases expression of TGF-p, which is a potent inhibitor of IL-2 stimulated cell proliferation and generation of cytotoxic T lymphocytes (Khanna et al., 1994). 

FK506 (tacrolimus) (23) is a 23-membered macrocyclic lactone isolated from Streptomyces tsukubaensis and is structurally related to rapamycin. It displays antifungal and immunosuppressive activities. It is marketed as an immunosuppressant that can be used in transplant therapy and several autoimmune disorders. Rapamycin and FK506 share the same common cellular receptor FKBP, but they present a different mechanism of action. Similar to cyclosporine A, FK506 suppresses T-cell activation at the level of lymphokine production and prevents the expression of the interleukin 2 receptor (IL-2R). ... 

Based on the different mechanism of action from cyclosporin and tacrolimus, rapamycin has been investigated as an adjunctive immunosuppressant agent for prevention of rejection after organ transplantation in combination with these agents. 

FK506 (tacrolimus), a natural product of Streptomyces tukubaensis, is a 23-membered macrolide antibiotic that contains a unique hemiketal-masked, a,P-diketo amide moiety (Fig. 1) [1]. It has a mode of action and toxicity profile similar to those of cyclosporin A (CsA), an immunosuppressive cyclic undecapeptide produced by Tolypocladium inflatum (Fig. 1), which has been used clinically for two decades to prevent rejection on transplantation of organs, such as kidney, heart, liver, and bone marrow. The use of CsA has led to a remarkable increase of survival of all organ allografts and has fueled a dramatic increase in the number of kidney, liver, cardiac, and bone marrow transplants [2]. Thus, CsA has revolutionized transplantation surgery, both in terms of efficiency and quality of life of the patient. FK506 is said to be a more potent immunosuppressant than CsA and was approved for the treatment and prevention of kidney transplant rejection. 

C5 H,9N0,3, Mr914.19, cryst., mp. 183-185°C, [aJu -58.2° (CH3OH), a 31-membered peptide lactone in which a long-chain carboxylic acid is cyclized with l- pipecolic acid as a bridge and produced by Strepto-myces hygroscopicus. R. has antifungal, antineoplastic, and immunosuppressive activities, it is structurally related to FK-506 and exhibits a similar mechanism of action in the development of the immune response. R. was first marketed in 1999 in combination with cyclosporin and tacrolimus for use in transplantation medicine. The first total synthesis of R. was realized in 1993. 

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