References on the Administration of Immunosuppressants Using ALZET® Osmotic Pumps

1. Cyclosporin

16221 Oller, J., Alfranca, A., Mendez-Barbero, N., Villahoz, S., Lozano-Vidal, N., Martin-Alonso, M., Arroyo, A. G., Escolano, A., Armesilla, A. L., Campanero, M. R., Redondo, J. M. C/EBPbeta and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling. Mol Cell Biol 2015; 35(-19-):3409-22. >>> Vascular Endothelial Growth Factor, Angiotensin II, Losartan, Cyclosporine; Saline; SC; Mice; Controls received mp w/ vehicle; animal info (Calcineurin (CN) B1 (Cnb1_/fl) conditional knockout mice, C57BL/6 mice); dose-response; vegf aka vascular endothelial growth factor; Dose (VEGF 25 ug/kg/day, AngII 1 ug/kg/min, CsA 5 mg/kg/day, Losartan 10 mg/kg/day);.

15213 Hamdi, H., Planat-Benard, V., Bel, A., Neamatalla, H., Saccenti, L., Calderon, D., Bellamy, V., Bon, M., Perrier, M.C., Mandet, C., Bruneval, P., Casteilla, L., Hagege, A.A., Puceat, M., Agbulut, O., Menasche, P. Long-Term Functional Benefits of Epicardial Patches as Cell Carriers. CELL TRANSPLANTATION 2014; 23(-1-):87-96. >>> Cyclosporine; SC; Rat; 2ML4; Animal info (female, Wistar); immunology;“Because of the planned long duration of the follow-up (6 months), concerns over daily injections of cyclosporine led us to use subcutaneously implanted microosmotic pumps preset to release the drug in a controlled fashion.” pg 93;.

14859 Cardinale, V., Renzi, A., Carpino, G., Torrice, A., Bragazzi, M.C., Giuliante, F., DeRose, A.M., Fraveto, A., Onori, P., Napoletano, C., Franchitto, A., Cantafora, A., Grazi, G., Caporaso, N., D'Argenio, G., Alpini, G., Reid, L.M., Gaudio, E., Alvaro, D., Alvaro, D. Profiles of Cancer Stem Cell Subpopulations in Cholangiocarcinomas. AMERICAN JOURNAL OF PATHOLOGY 2015; 185(--):1724-1739. >>> Cyclosporine; IP; Mice; 1004; Animal info (male, BALB/c, 13 weeks old); cancer (cholangiocarcinoma);.

14378 Sachewsky, N., Hunt, J., Cooke, M.J., Azimi, A., Zarin, T., Miu, C., Shoichet, M.S., Morshead, C.M., Morshead, C.M. Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. Disease Models&Mechanisms 2014; 7(--):953-961. >>> Cyclosporin; FK506; NIM811; Saline; SC; Mice; 2002; Controls received mp w/ vehicle; animal info (male, C57BL6J, 6-8 weeks old, 25-30g); pumps replaced every 2 weeks; ischemia (cerebral); post op. care (SC injection of warmed saline); behavioral testing (foot fault task);.

13281 Koellensperger, E., Niesen, W., Kolbenschlag, J., Gramley, F., Germann, G., Leimer, U. Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury. STEM CELLS INTERNATIONAL 2013; ;(-;-):U1-U10. >>> Cyclosporine; IP; Rat; 2ML4; Animal info (Sprague Dawley, model of toxic liver damage (two-thirds hepatectomy)); immunology; pumps replaced every 28 days; long-term study.

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2. Deoxyspergualin

3473 Suzuki, S., Nishimori, H., Kido, K., Arita, S., Tashiro, H., Ohdan, H., Quinones, D., Amemiya, H. Continuous administration of methyldeoxyspergualin prolongs xenograft survival in hamster-to-rat cardiac transplantation. Transplant. Proc 1993; 25(-1-):430-431. >>> Methyldeoxyspergualin; IP; rat; 2001; 2ML2; immunology.

2061 Nishikawa, K., Shibasaki, C., Takahashi, K., Takeuchi, T. Treatment schedule dependency of antitumor effect of deoxyspergualin. Jpn. J. Antibiot 1991; 44(-9-):917-925. >>> Deoxyspergualin; Saline; IP; mice; 2001; comparison of injections vs. mp; cancer; detailed formulation information; time-dependent systemic toxicity characterized;'continuous infusion produced higher efficacy'over injections.

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3. FK506

14401 Shin, K., Lim, A., Zhao, C., Sahoo, D., Pan, Y., Spiekerkoetter, E., Liao, J.C., Beachy, P.A., Shin, K. Hedgehog Signaling Restrains Bladder Cancer Progression by Eliciting Stromal Production of Urothelial Differentiation Factors. CANCER CELL 2014; 26(--):521-533. >>> FK506; SC; Mice; 2004; Controls received mp w/ vehicle; animal info (male, GilCreER/WT; SMPflox/flox, 8-10 weeks old); cancer (bladder); used wound clips;.

14378 Sachewsky, N., Hunt, J., Cooke, M.J., Azimi, A., Zarin, T., Miu, C., Shoichet, M.S., Morshead, C.M., Morshead, C.M. Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. Disease Models&Mechanisms 2014; 7(--):953-961. >>> Cyclosporin; FK506; NIM811; Saline; SC; Mice; 2002; Controls received mp w/ vehicle; animal info (male, C57BL6J, 6-8 weeks old, 25-30g); pumps replaced every 2 weeks; ischemia (cerebral); post op. care (SC injection of warmed saline); behavioral testing (foot fault task);.

14372 Rojanathammanee, L., Floden, A.M., Manocha, G.D., Combs, C.K., Combs, C.K. Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition. Journal of Neuroinflammation 2015; 12(--):U14-U26. >>> FK506; tat-VIVIT; tat-VEET; DMSO; HEPES; SC; Mice (transgenic); 1004; Controls received mp w/ vehicle; animal info (male, APP/PS1, 12 months old); neurodegenerative (Alzheimer's); behavioral testing (t maze); peptides; FK506, tat-VIVIT are NFAT inhibitors; VEET is a negative control scrambled peptide;.

13718 Bentzinger, C.F., von Maltzahn, J., Dumont, N.A., Stark, D.A., Wang, Y.X., Nhan, K., Frenette, J., Cornelison, D.D.W., Rudnicki, M.A., Rudnicki, M.A. Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength. Journal of Cell Biology 2014; 205(--):97-111. >>> FK506; Mice (transgenic); Animal info (C57BL6); FK-506 aka tacrolimus; FK506 is an immunosuppressant.

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4. Methyldeoxyspergualin

3473 Suzuki, S., Nishimori, H., Kido, K., Arita, S., Tashiro, H., Ohdan, H., Quinones, D., Amemiya, H. Continuous administration of methyldeoxyspergualin prolongs xenograft survival in hamster-to-rat cardiac transplantation. Transplant. Proc 1993; 25(-1-):430-431. >>> Methyldeoxyspergualin; IP; rat; 2001; 2ML2; immunology.

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5. Rapamycin

16171 Scarpace, P. J., Matheny, M., Strehler, K. Y., Toklu, H. Z., Kirichenko, N., Carter, C. S., Morgan, D., Tumer, N. Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats. J Gerontol A Biol Sci Med Sci 2016; 71(-7-):891-9. >>> Rapamycin; DMSO; PEG 400; CSF/CNS; Rat; Controls received mp w/ vehicle; animal info (male, F344 x Brown Norway, 24 months old); pumps replaced after 14 days; ALZET brain infusion kit used; 10% DMSO used; 90% PEG 400 used; post op. care (rats kept warm until recovered); used aCSF filled pump for 14 days, then replaced with rapamycin or vehicle for 28 day infusion; obesity; Dose (30 ug/day); Brain coordinates (1.3 mm posterior to bregma, 1.9 mm lateral to the midsaggital suture and to a depth of 3.5mm);.

16045 Toklu, H. Z., Bruce, E. B., Sakarya, Y., Carter, C. S., Morgan, D., Matheny, M. K., Kirichenko, N., Scarpace, P. J., Tumer, N. Anorexic response to rapamycin does not appear to involve a central mechanism. Clin Exp Pharmacol Physiol 2016; 43(-9-):802-7. >>> Rapamycin; DMSO; PEG 400; CSF/CNS (third ventricle); Rat; Controls received mp w/ vehicle; animal info (male, F344 Brown Norway, 23-25 months old); 10% DMSO used; used PE-50 tubing; pumps initially filled with aCSF - after one week recovery, pumps replaced with rapamycin or vehicle pump; Dose (30 ug/day); Brain coordinates (1.1 mm posterior to Bregma and 1.6 mm ventral from the skull surface on the midline (medial s- sure), with the nose bar set at 4 mm below the ear bars (below zero)) pg 805;.

15777 Zongming Jiang, Shaoyong Wu, Xiujuan Wu, Junfeng Zhong, Anqing Lv, Jing Jiao, Zhonghua Chen. Blocking mammalian target of rapamycin alleviates bone cancer pain and morphine tolerance via u-opioid receptor. International Journal of Cancer 2016; 138(--):2013-2020. >>> Rapamycin; CTOP; LY297002; DMSO; saline; CSF/CNS (intrathecal); Rat; Controls received mp w/ saline; animal info (Wistar, 200-250g); 50% DMSO used; cancer (breast; bone); dose-response (pg 2015); behavioral testing (hindpaw withdrawal latency); Rapamycin is an mTOR antagonist; CTOP is an MOR antagonist; LY297002 an a PI3K inhibitor;.

14931 Fields, J., Dumaop, W., Elueteri, S., Campos, S., Serger, E., Trejo, M., Kosberg, K., Adame, A., Spencer, B., Rockenstein, E., He, J.J., Masliah, E., Masliah, E. HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders. JOURNAL OF NEUROSCIENCE 2015; 35(--):1921-1938. >>> Rapamycin; CSF/CNS; Mice; 1007D; Animal info (GFAP-Tat tg, 7-8 months old); neurodegenerative (HIV-associated neurocognitive disorder);“Because Rapam poorly crosses into the CNS, it was infused intracerebrally into the lateral ventricle of 9-month-old mice at a concentration of 20 mg/kg.” pg 1923; Rapamycin is an autophagy activator;.

13522 Li, H.L., Lee, J.Y., He, C.Y., Zou, M.H., Xie, Z.L. Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 2014; 306(-2-):E197-E209. >>> Rapamycin; Mice; Control animals received mp w/ vehicle; animal info (C57BL/6, 12 wks old, male).

12666 Paliouras, G.N., Hamilton, L.K., Aumont, A., Joppe, S.E., Barnabe-Heider, F., Fernandes, K.J.L. Mammalian Target of Rapamycin Signaling Is a Key Regulator of the Transit-Amplifying Progenitor Pool in the Adult and Aging Forebrain. Journal of Neuroscience 2012; 32(-43-):15012-15026. >>> Rapamycin; epidermal growth factor; DMSO; CSF/CNS; Mice (pregnant); 1007D; Control animals received mp w/ vehicle; animal info (C57BL/6, female, 2, 10, 18 mo old); ALZET brain infusion kit 3 used.

12332 Klucken, J., Poehler, A.M., Ebrahimi-Fakhari, D., Schneider, J., Nuber, S., Rockenstein, E., Schloetzer-Schrehardt, U., Hyman, B.T., McLean, P.J., Masliah, E., Winkler, J. Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway. Autophagy 2012; 8(-5-):754-766. >>> Bafilomycin, A1; rapamycin; CSF/CNS; Mice; 1007D; Animal info (wt, alpha synuclein, 9 mo old); neurodegenerative (Parkinson's disease).

12260 Yang, S.B., Tien, A.C., Boddupalli, G., Xu, A.W., Jan, Y.N., Jan, L.Y. Rapamycin Ameliorates Age-Dependent Obesity Associated with Increased mTOR Signaling in Hypothalamic POMC Neurons. Neuron 2012; 75(-3-):425-436. >>> Rapamycin; PEG 400; DMSO; cremophor; CSF/CNS; Mice; 1004; Animal info (C57BL/6, 2, 12 mo old); ALZET brain infusion kit used; 10% DMSO used; 60% PEG 400 used; 30% cremophor used.

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What researchers are saying ...

“Nonspecific toxicity is a common problem associated with in vivo application of antisense oligonucleotides.However, by employing certain strategies including the use of partial rather than complete phosphorothioate modification, reducing the length of the oligonucleotide, and using a steady continuous infusion rather than bolus injections, we were able to minimize such toxicity (Van Kampen & Stoessl, 2000a).” (p. 309) Van Kampen et al., Neuroscience 2003;116:307-314.