Antifungals tacrolimus

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

Drugs that may affect nelfinavir include anticonvulsants, azithromycin, azole antifungals, efavirenz, delavirdine, HMG-CoA reductase inhibitors, indinavir, interleukins, nevirapine, rifabutin, rifampin, ritonavir, saquinavir, St. John s wort. Drugs that may be affected by nelfinavir include amiodarone, antiarrhythmics (amiodarone, quinidine), azithromycin, benzodiazepines, efavirenz, ergot alkaloids, delavirdine, didanosine, fentanyl, indinavir, lamivudine methadone, nonsedating antihistamines, oral contraceptives, phenytoin, pimozide, quinidine, rifabutin, saquinavir, sildenafil, sirolimus, tacrolimus, zidovudine. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

Drugs that might be affected by amprenavir include antiarrhythmics, anticonvulsants, azole antifungals, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, cyclosporine, ergot alkaloids, fentanyl, HMG-CoA reductase inhibitors, indinavir, methadone, nelfinavir, oral contraceptives, pimozide, rifabutin, ritonavir, saquinavir, sildenafil, tacrolimus, trazodone, tricyclic antidepressants, warfarin, and zidovudine. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Uses Candidiasis tinea Infxns Action Antifungal alters cell wall permeability Dose PO Prophylaxis One troche dissolved in mouth tid Rx 1 troche dissolved in mouth 5 x d for 14 d Vag 1% cream 1 applicator full hs for 7 d 2% cream 1 applicator full hs for 3 d Tabs 100 mg vaginally hs for 7 d or 200 mg (2 tabs) vaginally hs for 3 d or 500-mg tabs vaginally hs once Topical Apply bid 10—14 d Caution [B, (C if PO), ] Not for systemic fungal Infxn Contra Component allergy Disp Cream, soln, lotion, vag tabs, vag cream SE Topical Local irritation PO N/V Interactions T Effects OF cyclosporine, tacrolimus X- effects OF spermicides EMS None OD Unlikely... 

ADEFOVIR DIPIVOXIL 1. ANTIBIOTICS -aminoglycosides, vancomycin 2. ANTICANCER AND IMMUNOMODULATING DRUGS - cidosporin, tacrolimus 3. ANTIFUNGALS-amphotericin, 4. ANTIPROTOZOALS-pentamidine 5. ANTIVIRALS - cidofovir, foscarnet sodium, tenofovir Possible t efficacy and side-effects Competition for renal excretion Monitor renal function weekly... 

The interaction of tacrolimus with fluconazole has been retrospectively evaluated in 19 kidney and pancreas/kid-ney transplant recipients (90). Both intravenous and oral fluconazole altered the blood concentration of tacrolimus. Five subjects did not have a significant interaction and 15 did. No patient had nephrotoxicity or transplant rejection related to antifungal therapy. 

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). ... 

Rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Rapamycin has a chemical structure partially similar to that of tacrolimus (Fig. 2). It was first isolated from Streptomyces hygro-scopicus strains found in soil obtained on Rapa Nui (Easter Island), hence the name rapamycin [19, 20]. This compound was initially investigated as an antifungal agent and later found to have immunosuppressive activity [21]. Rapamycin also binds to FKBP, but its immunosuppressive mechanisms are distinct from those of tacrolimus and cyclosporin in that it does not act via the calcineurin pathway [22, 23]. The immunosuppressive effects of rapamycin result from its inhibition of T-cell [23, 24] and B-cell [25] proliferation. The key effect on those cells results from the blocking of the signals of several cytokines (IL-2 and IL-4), leading to interruption of the cell cycle from the G, to the S phase. Unlike tacrolimus, the complex of rapamycin and FKBP-12 does not inhibit the dephosphorylase... 

Nakagawa, H., Etoh, T, Yokota, Y, Ikeda, F, Hatano, K., Teratani, N., Shimomura, K., Mine, Y, and Amaya, T. (1966). Tacrolimus has antifungal activities against Malassezia furfur isolated from healthy adults and patients with atopic dermatitis. Clin. Drug. Invest. 12, 244-250. 

Anticancer drugs etoposide, doxorubicin, vincristine Ca + channel blockers dUtiazem, verapamil HIV protease inhibitors indinavir, ritonavir Antibiotics/antifungals erythromycin, ketoconazole Hormones testosterone, progesterone Immunosuppressants cyclosporine, FK506 (tacrolimus)... 

A4 Amiodarone, azole antifungals, cimetidine, clarithromycin, cyclosporine, erythromycin, fluoroquinolones, grapefruit juice, HIV protease inhibitors, metronidazole, quinine. SSRIs, tacrolimus Antiarrhythmics, antidepressants, azole antifungals, benzodiazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone. paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca anticancer agents... 

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. 

Antifungal azoles The co-prescription of posaconazole with tacrolimus has been evaluated in 14 lung transplant recipients with cystic fibrosis. Posaconazole inhibited CYP3A4-mediated tacrolimus metabolism, resulting in a threefold reduction in tacroh-mus dosage requirements [95. ... 

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