Articoli di riviste: "FK-506 (Drug)"

1

Shaw, L. M., and K. L. Brayman. "FK-506 therapeutic drug monitoring." Clinical Chemistry 40, no. 12 (December 1, 1994): 2207–8. http://dx.doi.org/10.1093/clinchem/40.12.2207.

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2

Winkler, M., B. Ringe, J. Baumann, M. Loss, K. Wonigeit, and R. Pichlmayr. "Plasma vs whole blood for therapeutic drug monitoring of patients receiving FK 506 for immunosuppression." Clinical Chemistry 40, no. 12 (December 1, 1994): 2247–53. http://dx.doi.org/10.1093/clinchem/40.12.2247.

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Abstract By retrospective analysis of 13,000 blood samples obtained from 248 patients receiving FK 506 therapy, we compared the suitability of plasma with that of whole blood as the matrix for therapeutic drug monitoring of FK 506. The plasma concentrations did not correlate with the concentrations in whole blood (r = 0.56). In contrast to plasma samples (analyzed by enzyme immunoassay), FK 506 was detectable in all whole-blood samples (analyzed by enzyme immunoassay/microparticle enzyme immunoassay). The inter- and intraindividual variations of FK 506 measurements were greater in plasma than in whole blood. Moreover, plasma concentrations correlated only poorly with clinical events. There was a tendency to greater plasma concentrations being measured during episodes of toxicity, but no clear difference was evident between stable course and rejection. In whole-blood specimens, a correlation between reduced or increased FK 506 concentrations and rejection or toxicity, respectively, was observed. The discriminatory power of whole-blood values was greater for the differentiation between toxicity and stable course than between rejection and stable course. We therefore recommend whole blood rather than plasma as the matrix for therapeutic monitoring of FK 506 concentrations.

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3

Dumont, F. J., M. J. Staruch, S. L. Koprak, J. J. Siekierka, C. S. Lin, R. Harrison, T. Sewell, V. M. Kindt, T. R. Beattie, and M. Wyvratt. "The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin." Journal of Experimental Medicine 176, no. 3 (September 1, 1992): 751–60. http://dx.doi.org/10.1084/jem.176.3.751.

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FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

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4

Rokaw, M. D., M. E. West, P. M. Palevsky, and J. P. Johnson. "FK-506 and rapamycin but not cyclosporin inhibit aldosterone-stimulated sodium transport in A6 cells." American Journal of Physiology-Cell Physiology 271, no. 1 (July 1, 1996): C194—C202. http://dx.doi.org/10.1152/ajpcell.1996.271.1.c194.

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The immunosuppressants cyclosporin A (CyA), FK-506, and rapamycin (RAP) have multiple actions on target cells that appear to be mediated by interaction of drug-binding protein complexes. Both FK-506 and CyA, but not RAP, inhibit the Ca2(+)-dependent phosphatase, calcineurin, and in so doing have been found to inhibit Na(+)-K(+)-ATPase activity in various nephron segments. Of interest, FK-506 and RAP, but not CyA, are bound by the steroid receptor-associated FK-506-binding heat shock protein of 56 kDa, HSP56. To determine the physiological effect of this interaction on a steroid-mediated phenomenon, the effect of these agents on steroid-mediated Na+ transport in A6 cells was investigated. Aldosterone stimulation of Na+ transport and Na(+)-K(+)-ATPase activity are significantly inhibited by prolonged incubation with FK-506 and RAP. Although CyA inhibits basal Na(+)-K(+)-ATPase activity, it has no effect on aldosterone-induced Na+ transport or the aldosterone-induced increase in Na(+)-K(+)-ATPase activity. FK-506 inhibits the aldosterone-induced synthesis of G alpha i-3 protein but has no effect on glucocorticoid receptor number as quantified by Western blotting. The results suggest that FK-506 and RAP inhibit steroid-mediated Na+ transport at some pretranslational site. The common interaction of these agents with the steroid receptor-associated HSP56 might account for these findings.

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5

Di Padova, F. E. "Pharmacology of CsA and FK-506." Perspectives in Drug Discovery and Design 2, no. 1 (August 1994): 49–56. http://dx.doi.org/10.1007/bf02171736.

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6

Goulet, Mark T., Kathleen M. Rupprecht, Peter J. Sinclair, Matthew J. Wyvratt, and William H. Parsons. "The medicinal chemistry of FK-506." Perspectives in Drug Discovery and Design 2, no. 1 (August 1994): 145–62. http://dx.doi.org/10.1007/bf02171741.

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7

Petros, Andrew M., Gerd Gemmecker, Placido Neri, Edward T. Olejniczak, David Nettesheim, Robert X. Xu, Earl G. Gubbins, Harriet Smith, and Stephen W. Fesik. "NMR studies of an FK-506 analog, [U-carbon-13]ascomycin, bound to FK-506-binding protein." Journal of Medicinal Chemistry 35, no. 13 (June 1992): 2467–73. http://dx.doi.org/10.1021/jm00091a015.

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8

Kay, John E., Senam E. A. Doe, and C. Robin Benzie. "The mechanism of action of the immunosuppressive drug FK-506." Cellular Immunology 124, no. 1 (November 1989): 175–81. http://dx.doi.org/10.1016/0008-8749(89)90121-4.

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9

O'connor, Stephen P., Robert L. Ellsworth, Mary Nallin Omstead, Rosalind G. Jenkins, and Louis Kaplan. "The preparation of 14C-labeled FK-506." Journal of Labelled Compounds and Radiopharmaceuticals 31, no. 2 (February 1992): 103–8. http://dx.doi.org/10.1002/jlcr.2580310205.

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10

Jusko, William J. "Analysis of Tacrolimus (FK 506) in Relation to Therapeutic Drug Monitoring." Therapeutic Drug Monitoring 17, no. 6 (December 1995): 596–601. http://dx.doi.org/10.1097/00007691-199512000-00009.

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11

Clardy, Jon. "Structural studies on FK-506, cyclosporin A and their immunophilin complexes." Perspectives in Drug Discovery and Design 2, no. 1 (August 1994): 127–44. http://dx.doi.org/10.1007/bf02171740.

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12

DOE, SENAM E. A., C. ROBIN BENZIE, and JOHN E. KAY. "Early effects of the immunosuppressive drug FK-506 on signal transduction in lymphocytes." Biochemical Society Transactions 18, no. 3 (June 1, 1990): 451–52. http://dx.doi.org/10.1042/bst0180451.

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13

Takabayashi, Katsuhiko, Takao Koike, Kazuhiro Kurasawa, Ryutaro Matsumura, Toshiko Sato, Hisao Tomioka, Isao Ito, Takashi Yoshiki, and Sho Yoshida. "Effect of FK-506, a novel immunosuppressive drug on murine systemic lupus erythematosus." Clinical Immunology and Immunopathology 51, no. 1 (April 1989): 110–17. http://dx.doi.org/10.1016/0090-1229(89)90211-0.

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14

Patel, S. S., M. S. Patel, S. Salampure, B. Vishwanath, and N. M. Patel. "Development and Evaluation of Liposomes for Topical Delivery of Tacrolimus (Fk-506)." Journal of Scientific Research 2, no. 3 (August 24, 2010): 585. http://dx.doi.org/10.3329/jsr.v2i3.3258.

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In the present work Tacrolimus loaded liposomal systems were developed and evaluated for their topical delivery. Neutral multilamellar liposomes (MLVs) were prepared by thin film hydration method. The amount of drug loaded into vesicles ranged from 4.4 mg per 115mg to 8.2mg per 140mg of total lipid. Entrapment efficiency of tacrolimus in liposomes was studied by altering the amount of cholesterol ratio to lipid ratio. After performing stability study at different temperatures (4, 25, and 37°C) was affirms that drug leakage increased at higher temperature. The in-vitro permeation study shows significant reduced permeation with tacrolimus liposomes compared with free tacrolimus in propylene glycol. The animal study carried out on allergic contact dermatitis (ACD) model in rats showed that 0.03% tacrolimus liposomal gel exhibited similar activity when compared with 0.03% marketed tacrolimus ointment. It is also likely that tacrolimus liposomal gel which leads no visible or palpable residue when applied on skin would be more appealing to patients than conventional ointment. Overall study suggests that tacrolimus can be effectively incorporated in liposomes and can be used for the treatment of atopic dermatitis. Keywords: Tacrolimus; Multilamellar vesicle; Allergic contact dermatitis. © 2010 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved. DOI: 10.3329/jsr.v2i3.3258 J. Sci. Res. 2 (3), 587-598 (2010)

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15

Shitrit, David, Jacob E. Ollech, Ayelet Ollech, Ilana Bakal, Milton Saute, Gideon Sahar, and Mordechai R. Kramer. "Itraconazole Prophylaxis in Lung Transplant Recipients Receiving Tacrolimus (FK 506): Efficacy and Drug Interaction." Journal of Heart and Lung Transplantation 24, no. 12 (December 2005): 2148–52. http://dx.doi.org/10.1016/j.healun.2005.05.003.

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16

Acemoglu, Murat, Hendrik Andres, and Thomas Moenius. "Regio- and stereoselective preparation of ascomycin-d1 and FK 506-d1." Journal of Labelled Compounds and Radiopharmaceuticals 45, no. 5 (2002): 361–70. http://dx.doi.org/10.1002/jlcr.558.

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17

Kramer, Mordechai R., Anat Amital, Leonardo Fuks, and David Shitrit. "Voriconazole and itraconazole in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction." Clinical Transplantation 25, no. 2 (December 16, 2010): E163—E167. http://dx.doi.org/10.1111/j.1399-0012.2010.01373.x.

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18

O'Keefe, Stephen J., and Edward A. O'Neill. "Cyclosporin A and FK-506: Immunosuppression, inhibition of transcription and the role of calcineurin." Perspectives in Drug Discovery and Design 2, no. 1 (August 1994): 85–102. http://dx.doi.org/10.1007/bf02171738.

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19

White, James D., Jörg Deerberg, Steven G. Toske, and Takayuki Yakura. "Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin." Tetrahedron 65, no. 33 (August 2009): 6635–41. http://dx.doi.org/10.1016/j.tet.2009.06.030.

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20

Oyouni, AtifAbdulwahab A., Shalini Saggu, Ehab Tousson, Anand Mohan, and Abdullah Farasani. "Mitochondrial nephrotoxicity induced by tacrolimus (FK-506) and modulatory effects of Bacopa monnieri (Farafakh) of Tabuk Region." Pharmacognosy Research 11, no. 1 (2019): 20. http://dx.doi.org/10.4103/pr.pr_100_18.

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21

Schnider, Jonas T., Matthias Weinstock, Jan A. Plock, Mario G. Solari, Raman Venkataramanan, Xin Xiao Zheng, and Vijay S. Gorantla. "Site-Specific Immunosuppression in Vascularized Composite Allotransplantation: Prospects and Potential." Clinical and Developmental Immunology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/495212.

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Skin is the most immunogenic component of a vascularized composite allograft (VCA) and is the primary trigger and target of rejection. The skin is directly accessible for visual monitoring of acute rejection (AR) and for directed biopsy, timely therapeutic intervention, and management of AR. Logically, antirejection drugs, biologics, or other agents delivered locally to the VCA may reduce the need for systemic immunosuppression with its adverse effects. Topical FK 506 (tacrolimus) and steroids have been used in clinical VCA as an adjunct to systemic therapy with unclear beneficial effects. However, there are no commercially available topical formulations for other widely used systemic immunosuppressive drugs such as mycophenolic acid, sirolimus, and everolimus. Investigating the site-specific therapeutic effects and efficacy of systemically active agents may enable optimizing the dosing, frequency, and duration of overall immunosuppression in VCA with minimization or elimination of long-term drug-related toxicity.

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22

Kay, John E., and C. Robin Benzie. "T lymphocyte activation through the C28 pathway is insensitive to inhibition by the immunosuppressive drug FK-506." Immunology Letters 23, no. 2 (December 1989): 155–59. http://dx.doi.org/10.1016/0165-2478(89)90129-6.

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23

Shevchenko, V. P., I. Yu Nagaev, N. F. Myasoedov, H. Andres, T. Moenius, and A. Susan. "Synthesis of tritiated Cyclosporin A and FK-506 by metal-catalyzed hydrogen isotope exchange." Journal of Labelled Compounds and Radiopharmaceuticals 47, no. 7 (June 2004): 407–14. http://dx.doi.org/10.1002/jlcr.827.

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24

Chung, Shu-Ying, Fu-Chou Cheng, Ming-Shih Lee, Jing-Ying Lin, Ming-Cheng Lin, and Ming-Fu Wang. "Ginkgo biloba Leaf Extract (EGb761) Combined with Neuroprotective Agents Reduces the Infarct Volumes of Gerbil Ischemic Brain." American Journal of Chinese Medicine 34, no. 05 (January 2006): 803–17. http://dx.doi.org/10.1142/s0192415x06004302.

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Ginkgo biloba exerts many pharmacological actions. It possesses antioxidant properties, the ability of neurotransmitter/receptor modulation and antiplatelet activation factor. This research is designed to investigate the neuroprotective effects of long-term treatment with EGb761 (a standard form of the extract of Ginkgo biloba leaf) in combination with MgSO 4, FK506, or MK-801 on the infarct volume of male gerbils' brain induced by unilateral middle cerebral artery occlusion (MCAO). Thirty-five gerbils fed a standard diet were intragastrically given water or EGb761 (100 mg/kg/day) for one week. Five randomized groups were established: control ( n = 7), EGb 761 ( n = 8), EGb 761 + MgSO 4 ( n = 7), EGb 761 + FK 506 ( n = 7), and EGb 761 + MK -801 ( n = 6). The three drug-combination groups were injected with MgSO 4 (90 mg/kg), FK506 (0.5 mg/kg), or MK-801 (1 mg/kg), respectively 30 min before MCAO. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation for 24 hours. Postmortem infarct volumes were determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections. Results showed that the total infarct volumes of the four treated groups either EGb761 alone or in combination with drugs were lower than the control group by 36.1% (EGb761 alone), 40.3% ( EGb 761 + MgSO 4), 35.3% ( EGb 761 + FK 506), and 56.4% ( EGb 761 + MK -801), respectively ( p < 0.01). The main affected areas of the brain in the four treated groups were significantly focused between 4 and 6 mm from the frontal pole, when compared to the control group ( p < 0.01). All animals in the five groups had infarctions in both cortex and subcortex. These results indicate that long-term pre-treatment of EGb761 administered either alone or in combination with drugs significantly effective neuroprotection on infarct volume in gerbil ischemic brains.

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25

Wong, S. H. Y., B. Ghodgaonkar, P. Fong, B. Campbell, J. F. Burdick, and F. Boctor. "Supercritical Fluid Chromatography for Therapeutic Drug Monitoring of Immunosuppressants: Selectivity for Cyclosporine A, Fk 506 (Tacrolimus), and Rapamycin." Journal of Liquid Chromatography 17, no. 10 (June 1994): 2093–109. http://dx.doi.org/10.1080/10826079408013534.

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26

Lhoest, G., N. Maton, A. Laurent, and R. K. Verbeeck. "Isolation and identification of a FK-506 C36–C37 dihydrodiol from erythromycin-induced rabbit liver microsomes." Journal of Pharmaceutical and Biomedical Analysis 12, no. 2 (February 1994): 235–41. http://dx.doi.org/10.1016/0731-7085(94)90034-5.

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27

Yu, JS, S. Lee, HJ Eom, HR Kang, SR Lee, TK Lee, J. Baek, et al. "Protective effect of Korean red ginseng against FK-506-induced damage in LLC-PK1 cells." Planta Medica 81, S 01 (December 14, 2016): S1—S381. http://dx.doi.org/10.1055/s-0036-1596887.

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28

Cryan, John, Shirley H. Y. Hung, Gregory Wiederrecht, Nolan H. Sigal, and John J. Siekierka. "FKBP, the binding protein for the immunosuppressive drug, FK-506, is not an inhibitor of protein kinase C activity." Biochemical and Biophysical Research Communications 180, no. 2 (October 1991): 846–52. http://dx.doi.org/10.1016/s0006-291x(05)81142-8.

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29

Petros, A. M., R. T. Gampe, G. Gemmecker, P. Neri, T. F. Holzman, R. Edalji, J. Hochlowski, M. Jackson, and J. McAlpine. "NMR studies of an FK-506 analog [U-13C]ascomycin, bound to FKBP: conformation and regions of ascomycin involved in binding." Journal of Medicinal Chemistry 34, no. 9 (September 1991): 2925–28. http://dx.doi.org/10.1021/jm00113a037.

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30

Banholzer, R., A. P. Nair, H. H. Hirsch, X. F. Ming, and C. Moroni. "Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region." Molecular and Cellular Biology 17, no. 6 (June 1997): 3254–60. http://dx.doi.org/10.1128/mcb.17.6.3254.

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We analyzed the effect of rapamycin on autocrine mast cell tumor lines with abnormally stable interleukin-3 (IL-3) transcripts due to a defect in mRNA degradation. Rapamycin inhibited IL-3 mRNA expression specifically, while transcripts of IL-4 and IL-6 were not affected. As indicated by the use of the transcriptional inhibitor actinomycin D or by reporter constructs, inhibition was posttranscriptional and resulted from destabilization of the mRNA. Transcripts from transgenes lacking the AU-rich 3' untranslated region were refractory to drug-induced degradation, suggesting that these 3' sequences contain the target of the rapamycin effect. Rapamycin did not promote IL-3 mRNA degradation in cells of a tumor variant lacking expression of FKBP12, the binding protein of rapamycin. Experiments with wortmannin indicated that rapamycin does not act via p70S6 kinase. FK-506, another ligand of FKBP12 affecting the phosphatase calcineurin, did not antagonize but shared the effect of rapamycin. Our data fit a model whereby both FKBP12 and calcineurin target an unknown regulator of IL-3 mRNA turnover.

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Bansal, Puneet, and Anil Kumar. "P1-194: Novel drug strategies and molecular mechanisms of lycopene, FK-506 and venlafaxine against 3-NP induced Huntington's-like symptoms in rats." Alzheimer's & Dementia 8, no. 4S_Part_5 (July 2012): P174—P175. http://dx.doi.org/10.1016/j.jalz.2012.05.472.

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32

Tran, Quang Hieu Dé, Elizabeth Guay, Suzanne Chartier, and Jacqueline Tousignant. "Tacrolimus in Dermatology." Journal of Cutaneous Medicine and Surgery 5, no. 4 (July 2001): 329–35. http://dx.doi.org/10.1177/120347540100500409.

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Background: Tacrolimus (FK 506), a metabolite of the fungus Streptomyces tsukubaensis, is an anti-T-cell drug. It acts by inhibiting the production of IL-2, IL-3, IL-4, TNFα, and GM-CSF. More potent and with slightly less secondary effects than cyclosporine, it has been the object of considerable interest, especially in conditions that could benefit from the latter. Objective: In psoriasis, a placebo-controlled double-blind study has shown oral tacrolimus at 0.1 mg/kg/day to be effective in controlling recalcitrant lesions. In human, small studies have reported tacrolimus ointment to be effective in controlling acute contact dermatitis. Short-term trials of topical tacrolimus in the treatment of atopic dermatitis have recently shown excellent results in both adults and children. In animal studies of hair growth disorders, topical tacrolimus induces anagen and protects from chemotherapy-induced alopecia. Animal studies with the ointment for the prevention of skin graft rejection, lupus dermatoses, and skin papilloma formation have also shown to be promising. Conclusions: There are case reports of pyoderma gangrenosum, Sezary's syndrome, and Behçet's disease successfully treated with oral tacrolimus but, because of their small number, they remain anecdotal at this point.

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Furue, Masutaka, Atsushi Osada, and Kunihiko Tamaki. "Inhibition of contact hypersensitivity by an anti-allergic drug, azelastine, is likely to be mediated by its novel immunosuppressive effects distinct from FK-506." Journal of Dermatological Science 6, no. 1 (August 1993): 75. http://dx.doi.org/10.1016/0923-1811(93)91148-n.

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WOO, J., C. S. K. ROSS, J. I. MILTON, and A. W. THOMSON. "Immunosuppressive activity of FK-506 in rats: flow cytometric analysis of lymphocyte populations in blood, spleen and thymus during treatment and following drug withdrawal." Clinical & Experimental Immunology 79, no. 1 (June 28, 2008): 109–14. http://dx.doi.org/10.1111/j.1365-2249.1990.tb05136.x.

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Vannucchi, AM, A. Grossi, A. Bosi, D. Rafanelli, M. Statello, S. Guidi, R. Saccardi, and P. Rossi-Ferrini. "Effects of cyclosporin A on erythropoietin production by the human Hep3B hepatoma cell line." Blood 82, no. 3 (August 1, 1993): 978–84. http://dx.doi.org/10.1182/blood.v82.3.978.978.

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Abstract (sommario):

Abstract There is evidence that the inadequate erythropoietin (Epo) production observed in patients undergoing allogeneic bone marrow transplantation (BMT) might be ascribed to an inhibitory effect caused by the immunosuppressive drug cyclosporin A (CsA). In this in vitro study, we have evaluated the effects of CsA on the release of Epo in the culture medium by the human Hep3B hepatoma cell line. In cultures incubated with both CsA and the nonimmunosuppressive CsA analog MeAla-6, but not with the CsA-unrelated immunosuppressive agent FK-506, the levels of Epo in the medium were significantly reduced in comparison with controls, at concentrations (0.01 to 1.6 mumol/L) not affecting total protein synthetic rate nor the constitutive secretion of alpha- fetoprotein. Hep3B cells were found to contain a CsA-binding molecule, with an M(r) of 18 Kd, as assessed by high performance liquid chromatography (HPLC) and ligand-blotting analysis. CsA did not affect the expression of the Epo gene, as judged by Northern blot analysis, but caused a significant amount of Epo to remain unsecreted within the cells; almost all (97% of total) of the intracellular Epo was associated with the plasma membrane subcellular fraction. We conclude that: (1) CsA is able to inhibit Epo release in vitro by Hep3B cells, further supporting the hypothesis that the drug might have a role in the inappropriately low Epo levels observed in BMT patients; (2) the inhibitory effect appears to be specific and not caused by a general impairment of protein synthesis and/or secretion; and (3) the reduced Epo levels found in the medium of CsA-treated Hep3B cultures are supposed to be the consequence of an inability of the cells to correctly process Epo molecules for the secretory pathway.

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Vannucchi, AM, A. Grossi, A. Bosi, D. Rafanelli, M. Statello, S. Guidi, R. Saccardi, and P. Rossi-Ferrini. "Effects of cyclosporin A on erythropoietin production by the human Hep3B hepatoma cell line." Blood 82, no. 3 (August 1, 1993): 978–84. http://dx.doi.org/10.1182/blood.v82.3.978.bloodjournal823978.

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Abstract (sommario):

There is evidence that the inadequate erythropoietin (Epo) production observed in patients undergoing allogeneic bone marrow transplantation (BMT) might be ascribed to an inhibitory effect caused by the immunosuppressive drug cyclosporin A (CsA). In this in vitro study, we have evaluated the effects of CsA on the release of Epo in the culture medium by the human Hep3B hepatoma cell line. In cultures incubated with both CsA and the nonimmunosuppressive CsA analog MeAla-6, but not with the CsA-unrelated immunosuppressive agent FK-506, the levels of Epo in the medium were significantly reduced in comparison with controls, at concentrations (0.01 to 1.6 mumol/L) not affecting total protein synthetic rate nor the constitutive secretion of alpha- fetoprotein. Hep3B cells were found to contain a CsA-binding molecule, with an M(r) of 18 Kd, as assessed by high performance liquid chromatography (HPLC) and ligand-blotting analysis. CsA did not affect the expression of the Epo gene, as judged by Northern blot analysis, but caused a significant amount of Epo to remain unsecreted within the cells; almost all (97% of total) of the intracellular Epo was associated with the plasma membrane subcellular fraction. We conclude that: (1) CsA is able to inhibit Epo release in vitro by Hep3B cells, further supporting the hypothesis that the drug might have a role in the inappropriately low Epo levels observed in BMT patients; (2) the inhibitory effect appears to be specific and not caused by a general impairment of protein synthesis and/or secretion; and (3) the reduced Epo levels found in the medium of CsA-treated Hep3B cultures are supposed to be the consequence of an inability of the cells to correctly process Epo molecules for the secretory pathway.

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KASS, LEONARD, DORETTE Z. ELLIS, JANICE PELLETIER, NATHAN E. TABLEMAN, and SAMUEL C. EDWARDS. "Inhibition of the calcineurin-like protein phosphatase activity in Limulus ventral eye photoreceptor cells alters the characteristics of the spontaneous quantal bumps and the light-mediated inward currents, and enhances arrestin phosphorylation." Visual Neuroscience 15, no. 6 (November 1998): 1039–49. http://dx.doi.org/10.1017/s0952523898156031.

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Changes in intracellular calcium are involved in phototransduction processes in both vertebrate and invertebrate photoreceptors. During this phototransduction process in the Limulus ventral eye, there is a biochemical change in the protein phosphatase, calcineurin, such that it becomes capable of activation by calcium and calmodulin. Here we show that the calcium/calmodulin-dependent calcineurin-like activity in light-adapted ventral eye was completely inhibited by the CaN autoinhibitory peptide, CaN A457–482 and the Merck analog of the membrane-permeable, immunosuppressant drug, FK 506, L-683, 590, but not an inactive analogue, L-685, 818. Whole-cell, voltage-clamp recordings of spontaneous quantal bump activity present in dark-adapted photoreceptors injected with either CaN A457–482 (500 μM) or superfused with L-683, 590 (20 μM) or L-685, 818 revealed that both CaN A457–482 and L-683, 590, but not L-685, 818, caused rapid decreases in quantal bump amplitude, rise time and fall time, resulting in smaller, sharper bumps. This was correlated with enhanced phosphorylation of arrestin in light-adapted ventral eye photoreceptors exposed to L-683, 590 or less reliably okadaic acid. Both CaN A457–482 and L-683, 590 markedly affected the light-stimulated inward currents recorded from light-adapted ventral photoreceptors, causing a “terracing” of the inward current, and an intensity-dependent delay in the time required to reach peak amplitude. Consequently, inhibition of calcineurin markedly affects two major rhodopsin-dependent electrophysiological processes, and implicates CaN as an integral component in the phototransduction cascade.

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Lopatynska-Mazurek, Malgorzata, Lukasz Komsta, Ewa Gibula-Tarlowska, and Jolanta H. Kotlinska. "Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7083. http://dx.doi.org/10.3390/ijms22137083.

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Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

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Lemster, B., L. L. Huang, W. Irish, J. Woo, P. B. Carroll, K. Abu-Elmagd, H. R. Rilo, et al. "Influence of FK 506 (Tacrolimus) On Circulating CD4+T Cells Expressing Cd25 and Cd45ra Antigens in 19 Patients with Chronic Progressive Multiple Sclerosis Participating in an Open Label Drug Safety Trial." Autoimmunity 19, no. 2 (January 1994): 89–98. http://dx.doi.org/10.3109/08916939409009536.

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40

Chow, Kai Uwe, Daniel Nowak, Soo-Zin Kim, Bernd Schneider, Martina Komor, Simone Boehrer, Paris S. Mitrou, Dieter Hoelzer, Eckhart Weidmann, and Wolf-Karsten Hofmann. "In Vivo Drug-Response in Patients with Leukemic Non-Hodgkin’s Lymphomas Is Predicted by In Vitro Chemosensitivity Testing and Gene Expression Profiling." Blood 104, no. 11 (November 16, 2004): 2273. http://dx.doi.org/10.1182/blood.v104.11.2273.2273.

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Abstract Only a few approaches are available to address the mechanisms of cell death in vivo which are induced by anticancer treatment in patients with malignancies. In this study in vitro chemosensitivity testing of primary peripheral blood leukemic cells of five patients suffering from different leukemic Non-Hodgkin’s lymphomas (atypical CLL, typical CLL, Immunocytoma, Mantle Cell Lymphoma, Prolymphocytic Leukemia (PLL)) was combined with the analysis of the in vivo rate of apoptosis by flow-cytometry (Annexin V and depolarisation of mitochondrial membrane potential (MMP) by JC-1). Furthermore, changes in expression patterns of apoptosis related proteins during chemotherapeutic treatment were detected by Western Blot. Gene expression profiling (HG-U133A, Affymetrix, Santa Clara, CA) was employed to identify common marker genes of in vivo drug response. In vitro chemosensitivity was tested using the cytotoxic agents which the patients were scheduled to receive and was strongly correlated with effective reduction of leukemic lymphoma cells in patients resulting in complete remissions in all five cases. Due to the rapid clearance of apoptotic tumor cells in vivo neither the analysis of the in vivo rate of apoptosis and depolarisation of MMP nor the assessment of expression of regulators of apoptosis showed concordant results concerning the drug response. However, assessment of gene expression during therapy could identify a set of 30 genes to significant discriminate between samples from patients before treatment compared to samples from the same patients after receiving cytotoxic therapy. Among these 30 genes we found a high proportion of genes associated with apoptotic cell death and cell proliferation signalling including complement lysis inhibitor (clusterin, CLU, SP40), beta-catenin interacting protein (ICAT), peroxisome proliferator activated receptor alpha (PPARα), TNF alpha converting enzyme (ADAM 17 / TACE), homeo box A3 (HOXA), inositol polyphosphate 5 phophatase (PPI 5 PIV, SHIP1), FK 506 binding protein (FKBP 38) and inhibitor of p53 induced apoptosis alpha (NME 6). Clusterin is able to mediate apoptosis via p53 and increases drug-induced cell death when overexpressed as detected in our treated samples. The downregulation of NME 6 during chemotherapeutic treatment may enhance this effect. These results indicate that in vitro chemosensitivity testing and gene expression profiling can successfully be utilised to predict in vivo drug response in patients with leukemic NHL’s and can be used to explore new pathway models of drug-induced cell death in vivo which are independent of different lymphoma subtypes and different treatment regimens.

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41

Yue, Gang, Robert S. Edinger, Hui-Fang Bao, John P. Johnson, and Douglas C. Eaton. "The effect of rapamycin on single ENaC channel activity and phosphorylation in A6 cells." American Journal of Physiology-Cell Physiology 279, no. 1 (July 1, 2000): C81—C88. http://dx.doi.org/10.1152/ajpcell.2000.279.1.c81.

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Rapamycin and FK-506 are immunosuppressive drugs that bind a ubiquitous immunophilin, FKBP12, but immunosuppressive mechanisms and side effects appear to be different. Rapamycin binds renal FKBP12 to change renal transport. We used cell-attached patch clamp to examine rapamycin's effect on Na+ channels in A6 cells. Channel NP o was 0.5 ± 0.08 ( n = 6) during the first 5 min but fell close to zero after 20 min. Application of 1 μM rapamycin reactivated Na+ channels ( NP o = 0.47 ± 0.1; n=6), but 1 μM FK-506 did not. Also, GF-109203X, a protein kinase C (PKC) inhibitor, mimicked the rapamycin-induced reactivation in a nonadditive manner. However, rapamycin did not reactivate Na+ channels if cells were exposed to 1 μM FK-506 before rapamycin. In PKC assays, rapamycin was as effective as the PKC inhibitor; however, epithelial Na+ channel (ENaC) phosphorylation was low under baseline conditions and was not altered by PKC inhibitors or activators. These results suggest that rapamycin activates Na+ channels by binding FKBP12 and inhibiting PKC, and, in renal cells, despite binding the same immunophilin, rapamycin and FK-506 activate different intracellular signaling pathways.

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42

Edinger, Robert S., Simon C. Watkins, David Pearce, and John P. Johnson. "Effect of immunosuppressive agents on glucocorticoid receptor function in A6 cells." American Journal of Physiology-Renal Physiology 283, no. 2 (August 1, 2002): F254—F261. http://dx.doi.org/10.1152/ajprenal.00337.2001.

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Immunosuppressive agents such as FK-506 and rapamycin inhibit aldosterone- stimulated Na+ transport in A6 cells. Concentration dependence is consistent with the known affinities of these agents for immunophilins. The inhibition was also dependent on time, requiring preincubation with FK-506 or rapamycin before inhibition was seen. The present studies were designed to determine whether this inhibition was pretranscriptional and whether it was due to an effect on either receptor translocation or nuclear accumulation. Because transport effects of steroids in A6 cells are mediated by glucocorticoid receptors (GRs), we examined the transcriptional response of GR-regulated reporters transfected into these cells. Preincubation of cells with FK-506 and rapamycin completely blocked reporter gene activation, whereas preincubation with cyclosporin A partially inhibited this activation. A minimum of 8 h of preincubation was required before the effect was seen. Using a transiently transfected green fluorescent protein-GR construct, we examined the effect of FK-506 and rapamycin on GR translocation. GR translocation induced by dexamethasone was extremely rapid (<5 min) and was largely unaffected by FK-506 or rapamycin but was completely blocked by geldanamycin. Digital deconvolutions revealed a punctate nuclear accumulation of GR, which was still seen after preincubation with immunosuppressive agents. These agents clearly inhibit steroid action by blocking GR-stimulated gene transcription, but this effect is not mediated by altered translocation or nuclear accumulation of receptors. Inhibition of steroid-regulated gene transcription by immunosuppressive agents may explain the electrolyte abnormalities seen in patients receiving these drugs.

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43

Tumlin, J. A., J. T. Someren, C. E. Swanson, and J. P. Lea. "Expression of calcineurin activity and alpha-subunit isoforms in specific segments of the rat nephron." American Journal of Physiology-Renal Physiology 269, no. 4 (October 1, 1995): F558—F563. http://dx.doi.org/10.1152/ajprenal.1995.269.4.f558.

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Calcineurin activity and alpha-subunit expression were studied in microdissected proximal tubules (S2), medullary thick ascending limbs (MTAL), cortical collecting ducts (CCD), connecting tubules (CNT), and outer medullary collecting ducts (OMCD). We have shown that cyclosporin A (CsA) and FK-506 inhibit sodium-potassium-adenosinetriphosphatase (Na-K-ATPase) activity in CCD, OMCD, and MTAL but did not uncover the mechanism for resistance of proximal tubule segments to these drugs. Because cells expressing high calcineurin activity are relatively resistant to the biological effects of CsA and FK-506, we hypothesized that the resistance of proximal tubules may be linked to increased calcineurin expression. Consequently, we measured calcineurin activity in microdissected tubules using a calcineurin-specific substrate. Calcineurin activity in S2 proximal tubule segments was 10-fold higher than in CCD, CNT, OMCD, or MTAL. FK-506 (6.0 ng/ml) inhibited calcineurin activity in CCD, CNT, and MTAL but not S2; 250 ng/ml FK-506 inhibited S2 calcineurin activity by 50%. Likewise, high concentrations of CsA (25 micrograms/ml) and FK-506 (250 ng/ml) inhibited S2 Na-K-ATPase activity by 77 and 73%, respectively. To investigate whether the resistance of S2 segments might be due to differential expression of calcineurin alpha-subunit isoforms, we determined the isoform expression by Western blot analysis using isoform-specific antibodies against the alpha 1-, alpha 2-, and alpha 3-isoforms. We found that alpha 1 expression in S2 was significantly greater than in the CCD and MTAL, whereas alpha 2 expression in the S2 was significantly less than in CCD and MTAL. No alpha 3 was detected in any nephron segment tested.(ABSTRACT TRUNCATED AT 250 WORDS)

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44

Dušková, M., L. Dušek, M. Čìž, A. Lojek, and H. Slavíková. "The Influence of Some Immunosuppressive Drugs on the Metabolic Activity of Human Phagocytes and Lymphocytes in vitro." International Journal of Immunopathology and Pharmacology 11, no. 3 (September 1998): 155–62. http://dx.doi.org/10.1177/039463209801100305.

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The effect of azathioprine, cyclosporine A and FK 506 on the production of reactive oxygen species by polymorphonuclear leukocytes (Iuminol-dependent chemiluminescence) and on the blast transformation of lymphocytes ([3H]thymidine incorporation) was studied in dose-response experiments under in vitro conditions. Although there were no significant effects of immunosuppressives on non-stimulated blast transformation, FK 506 and cyclosporine A significantly inhibited the blast transformation stimulated by concanavaline A and protein A and the effects made it possible to build 2nd-order polynomial dose-response models. Azathioprine was found to be a relatively weak inhibitor of [3H]thymidine incorporation in lymphocytes (76% of control value). Spontaneous production of reactive oxygen species by polymorphonuclear leukocytes was significantly inhibited, particularly by FK 506 (1–100 ng.ml−1) in comparison to the control value, while there was no effect of the immunosuppressives on this system activated either by starch grains or zymosan. Only the highest applied concentrations of azathioprine (100 ng.ml−1) and cyclosporine A (1000 ng.ml−1) led to a significant decline in spontaneous phagocytosis. The direct effect of immunosuppressives on activated production of reactive oxygen species by neutrophiles was not proved.

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45

Hodge, Shekema, Juliette de Rosayro, Amanda Glenn, Ifeoma C. Ojukwu, Stephen Dewhurst, Harold M. McClure, Norbert Bischofberger, Daniel C. Anderson, Sherry A. Klumpp, and Francis J. Novembre. "Postinoculation PMPA Treatment, but Not Preinoculation Immunomodulatory Therapy, Protects against Development of Acute Disease Induced by the Unique Simian Immunodeficiency Virus SIVsmmPBj." Journal of Virology 73, no. 10 (October 1, 1999): 8630–39. http://dx.doi.org/10.1128/jvi.73.10.8630-8639.1999.

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ABSTRACT The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing.

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46

Siekierka, John J. "Probing T-cell signal transduction pathways with the immunosuppressive drugs, FK-506 and rapamycin." Immunologic Research 13, no. 2-3 (June 1994): 110–16. http://dx.doi.org/10.1007/bf02918272.

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47

Poolos, Nicholas P. "Hypoxia Results in GABAergic Channelopathy." Epilepsy Currents 5, no. 6 (November 2005): 234–35. http://dx.doi.org/10.1111/j.1535-7511.2005.00073.x.

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AMPA/Kainate Receptor–mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain Sanchez RM, Dai W, Levada RE, Lippman JJ, Jensen FE J Neurosci 2005;25:3442–3451 Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABAA receptor (GABAAR)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs), because the upregulation of CaN activation and GABAAR inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABAAR β2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonylbenzo[ f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.

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Esteves, Iracema, Juliana F. Fernandes, Andreza Feitosa Ribeiro, Fabio P. S. Santos, Ricardo Helman, Claudio Castro Junior, Vinicius R. P. Mattos, et al. "The Clinical and Therapeutic Drug Monitoring of Oral and Intravenous Busulfan in Patients with Acute Leukemia That Underwent to Stem Cell Transplantation with a Test Dose of Busulfan." Blood 124, no. 21 (December 6, 2014): 5841. http://dx.doi.org/10.1182/blood.v124.21.5841.5841.

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Abstract Introduction: Busulfan (Bu) is used in the conditioning regimen for hematopoietic stem cell transplantation (HSCT). Therapeutic drug monitoring (TDM) of Bu with subsequents adjustments doses based on a “target” therapeutic concentration may reduce toxicity after HSCT. Objectives: To evaluatethe impact of TDM of Bu and clinical outcomes in patients with acute leukemia that underwent to allogeneic matched related donor (MRD) and allogeneic matched unrelated donor (MUD) HSCT. Patients and methods: From January 2009 to January 2014, we prospectively analyzed 42 patients with diagnosis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who underwent TDM of Bu (IV or oral) before transplantation (test dose) and TDM on 1st day of conditioning regimen. Samples were collected at 0, 30’, 60’ and subsequently every hour until 6 hours after administration of busulfan. The plasma was extracted by HPLC (High Performance Liquid Chromatography). All the patients that were submitted to TDM had a test dose 15 days to 48 hours before transplantion. The dose of Bu was adjusted during the first day of the conditioning regimen based on test dose. At the same time we analyzed 21 patients in the retrospective group who did not underwent TDM (from 2004 to 2010). Results: In the retrospective group (n=21), all of them underwent to MRD transplantation. Six (46.2%) were in first complete remission (CR1), 18(85.7%) patients received Bu and cyclophosphamide (BuCy) and the mean of age was 38 years (18-55 Yo). The median of CD34+ cells was 5.4 x 106/kg. The second group consisted by patients that received oral Bu (n= 21): 7 (33.3%) underwent to MUD transplantation, 14 (66.6%) to MRD transplantation, 8 (44.4%) patients were second complete remission (CR2), 4 (22.2%) had active disease status with a mean age of 32.7 years (14-58 Yo). Fifteen (71.4%) received BuCy and 16 (76.2%) received cells from peripheral blood. The median of CD34+ cells was 5.8 x106/kg. The median area under the curve (AUC) in 24 hours was 4950 μMol.min (3196.6- 8212 μMol.min). The third group was IV Bu (n= 21): 7 (33.3%) patients underwent MRD and 14 (66.6%) MUD transplantation, 7 (33.3%) patients were CR1, 7 (33.3%) had active disease or prior HSCT with a mean of age 52.7 years (20-74 Yo). The majority of patients received fludarabine and Bu (n=18; 85.7%) as conditioning and bone marrow was the main source. Immunosuppression was based on FK-506 and methotrexate (90.5% of patients). The median of AUC in 24 hours was 5690 μMol.min (3539.6- 8881.8 μMol.min). The cumulative incidence (CI) of sinusoidal obstructive syndrome (SOS) in the retrospective group and IV Bu were 9.5% for both, while in the group oral Bu it was at 19% (p = 0.566). The median AUC of Bu received during conditioning for those who died of SOS was lower in oral Bu than IV Bu (4872 uMol.min vs 5732 uMol.min respectively). The CI of acute graft-versus-host disease (aGVHD) at D+100 was 38.1% in the retrospective group, 40.6% in oral Bu and 42.9% in IV Bu. Chronic GVHD was 13.6% in oral Bu, 34% in IV Bu and 42.9% in the retrospective group (p = 0.142). The CI of relapse at D+100 was 19% in IV Bu, 4.8% in the retrospective group and oral Bu did not have this event. The IC of death at D+100 was 34.9% in group oral Bu, 9.5% in IV Bu and 14.3% in the retrospective (p = 0.102). The CI of relapse at 1.5 years was 35.8% in the IV Bu, 34.8% in oral Bu and 14.3% in the retrospective group. The CI of death at 1.5 years was 9.5% in group IV Bu, 53.5% in oral Bu and 34.3% in the retrospective (p = 0.015). Among patients who died until D+100, the median of AUC was 5732 μMol.min (5578.5-6818.5 μMol.min) during the conditioning for IV Bu and 4872 μMol.min (3448-8212 μMol.min) for oral Bu. The range between the AUC was large and there was no correlation with patients who died. Conclusion: In acute leukemia SOS had an impact on mortality at D+100 after HSCT (p <0.005). We observed increased incidence of SOS in oral Bu when compared to IV Bu and the classification of this toxicity was severe in 100% of cases when used oral Bu. We conclude that, regardless formulation, both oral or IV busulfan should be monitored with pharmacokinetics and adjustments of doses. Disclosures No relevant conflicts of interest to declare.

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Li, Dailin, Sam Xian Jun Cheng, Gilberto Fisone, Michael J. Caplan, Yoshiyuki Ohtomo, and Anita Aperia. "Effects of okadaic acid, calyculin A, and PDBu on state of phosphorylation of rat renal Na+-K+-ATPase." American Journal of Physiology-Renal Physiology 275, no. 6 (December 1, 1998): F863—F869. http://dx.doi.org/10.1152/ajprenal.1998.275.6.f863.

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Several indirect lines of evidence suggest that protein kinases and phosphatases modulate the activity of renal Na+-K+-ATPase. The aim of this study was to examine whether such regulation may occur via modulation of the state of phosphorylation of Na+-K+-ATPase. Slices from rat renal cortex were prelabeled with [32P]orthophosphate and incubated with the inhibitors of protein phosphatase (PP)-1 and PP-2A, okadaic acid (OA) and calyculin A (CL-A), respectively, the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), or the PP-2B inhibitor, FK-506. Phosphorylation of Na+-K+-ATPase α-subunit was evaluated by measuring the amount of [32P]phosphate incorporation into the immunoprecipitated protein. Incubation with either OA, CL-A, or PDBu caused four- to fivefold increases in the amount of [32P]phosphate incorporation into immunoprecipitated Na+-K+-ATPase α-subunit. OA and PDBu had a synergistic effect on the state of phosphorylation of Na+-K+-ATPase α-subunit. FK-506 did not affect Na+-K+-ATPase phosphorylation, neither alone nor in the presence of PDBu. Each of the drugs, OA, CL-A, and PDBu, inhibited the activity of Na+-K+-ATPase in microdissected proximal tubules. PDBu potentiated OA-induced inhibition of Na+-K+-ATPase activity. Inhibition of Na+-K+-ATPase required a lower dose of CL-A than of OA. On the basis of the inhibitory constant values of CL-A and OA for PP-1 and PP-2A, it is concluded that the tubular effect is mainly due to inhibition of PP-1. The PP-1 activity in rat renal cortex was ∼1.5 nmol Pi ⋅ mg protein−1 ⋅ min−1. Using a monoclonal anti-α antibody that fails to recognize the subunit when Ser23 is phosphorylated by PKC, we demonstrated that the dose response of PDBu inhibition of Na+-K+-ATPase correlated with the dose response of phosphorylation of the enzyme. The results suggest that the state of phosphorylation and activity of proximal tubular Na+-K+-ATPase are determined by the balance between the activities of protein kinases and phosphatases.

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Karpas, A., M. Lowdell, S. K. Jacobson, and F. Hill. "Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506." Proceedings of the National Academy of Sciences 89, no. 17 (September 1, 1992): 8351–55. http://dx.doi.org/10.1073/pnas.89.17.8351.

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