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1. Everolimus in kidney transplantation

Author

Cooper JE, Christians U, and Wiseman AC

Subjects
Medicine (General), R5-920
Abstract

James E Cooper¹, Uwe Christians², Alexander C Wiseman¹¹Division of Renal Diseases and Hypertension, Transplant Center, ²iC42 Integrated Solutions in Systems Biology for Clinical Research and Development, University of Colorado Denver, Aurora, CO, USAAbstract: Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.Keywords: mTOR inhibitors, kidney transplantation, everolimus

Published
2011

3. List of Contributors

Author

Arthur, J.M., primary, Banks, R.E., additional, Bennett, M.R., additional, Christians, U., additional, Devarajan, P., additional, Edelstein, C.L., additional, Elnagar, E., additional, Endre, Z.H., additional, Faubel, S., additional, Fick-Brosnahan, G., additional, Grubb, A., additional, Jain, S., additional, Jani, A., additional, Karakala, N., additional, Karumanchi, S.A., additional, Klawitter, J., additional, Klepacki, J., additional, Klein, J.B., additional, Merchant, M.L., additional, Parikh, C.R., additional, Thiessen Philbrook, H., additional, Reed, B.Y., additional, Vasudev, N.S., additional, and Walker, R.J., additional

Published
2017
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10. Author's Response: Targeting Treatments to Health Disparities

Author

Freedman, R., Noonan, K., McCarthy, L., Hunter, S.K., Christians, U., Wyrwa, A., Nakimuli-Mpungu, E., D'Alessandro, A., Zeisel, S.H., Hoffman, M.C., and Law, A.J.

Abstract

These initial data suggest that with prenatal vitamins and choline supplements, we might decrease one risk factor associated with poorer health outcomes disproportionally affecting Black families, ie, preterm birth. Dissemination of this research fulfills the principle of Justice in the Belmont Report, to ensure that participants from different racial, ethnic and socioeconomic groups receive benefits from research directed to their specific problems.

Published
2021
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11. Black American Maternal Prenatal Choline, Offspring Gestational Age at Birth, and Developmental Predisposition to Mental Illness

Author

Hoffman, M.C., Wyrwa, A., Zeisel, S.H., Noonan, K., Law, A.J., Nakimuli-Mpungu, E., McCarthy, L., Hunter, S.K., Freedman, R., D'Alessandro, A., and Christians, U.

Abstract

Black Americans have increased risk for schizophrenia and other mental illnesses with prenatal origins. Prenatal choline promotes infant brain development and behavioral outcomes, but choline has not been specifically assessed in Black Americans. Pregnant women (N = 183, N = 25 Black Americans) enrolled in a study of prenatal stressors and interactions with prenatal choline. Black American women had lower 16-week gestation plasma choline than Whites. Lower choline was not related to obesity, income, or metabolic genotypes. Pregnant women in rural Uganda have higher choline levels than Black American women. Black Americans' lower choline was associated with higher hair cortisol, indicative of higher stress. Lower maternal choline was associated with offsprings' lower gestational age at birth and with decreased auditory P50 inhibition, a marker of inhibitory neuron development. Behavioral development was assessed on the Infant Behavior Questionnaire-R-SF (IBQ-R) at 3 months. Lower Black American maternal gestational choline was associated with lower infant IBQ-R Orienting/Regulation, indicating decreased attention and relation to caregivers. Additional evidence for developmental effects of choline in Black Americans comes from a randomized clinical trial of gestational phosphatidylcholine supplementation versus placebo that included 15 Black Americans. Phosphatidylcholine increased gestational age at birth and newborn P50 inhibition and decreased Social Withdrawn and Attention problems at 40 months of age in Black Americans' offspring compared to placebo. Inhibitory and behavioral deficits associated with lower prenatal choline in offspring of Black American women indicate potential developmental predispositions to later mental illnesses that might be ameliorated by prenatal choline or phosphatidylcholine supplementation.

Published
2021
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12. POS0383 EFFECTS OF TOFACITINIB THERAPY ON ARGININE AND METHIONINE METABOLITES IN ASSOCIATION WITH VASCULAR PATHOPHYSIOLOGY IN RHEUMATOID ARTHRITIS: A METABOLOMIC APPROACH

Author

Soós, B., primary, Hamar, A., additional, Pusztai, A., additional, Czókolyová, M., additional, Végh, E., additional, Szamosi, S., additional, Pethö, Z., additional, Gulyás, K., additional, Kerekes, G., additional, Szekanecz, É., additional, Szántó, S., additional, Szücs, G., additional, Christians, U., additional, Klawitter, J., additional, Seres, T., additional, and Szekanecz, Z., additional

Published
2021
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33. Development and validation of a sensitive assay for the quantification of imatinib using LC/LC-MS/MS in human whole blood and cell culture

Author

Klawitter, J., Zhang, Y.L., Anderson, N., Serkova, N.J., Christians, U., and Publica

Abstract

We developed and validated a semi-automated LC/LC-MS/MS assay for the quantification of imatinib in human whole blood and leukemia cells. After protein precipitation, samples were injected into the HPLC system and trapped onto the enrichment column (flow 5 mL/min); extracts were back-flushed onto the analytical column. Ion transitions [M+H](+) of imatinib (m/z=494.3 -> 394.3) and its internal standard trazodone (372.5 -> 176.3) were monitored. The range of reliable response was 0.03-75 ng/mL. The inter-day precisions were: 8.4% (0.03 ng/mL), 7.2% (0.1 ng/mL), 6.5% (1 ng/mL), 8.2% (10 ng/mL) and 4.3% (75 ng/mL) with no interference from ion suppression. Autosampler stability was 24 hs and samples were stable over three freeze-thaw cycles. This semi-automated method is simple with only one manual step, uses a commercially available internal standard, and has proven to be robust in larger studies.

Published
2009

36. Worsening of long-term myocardial function after successful pharmacological pretreatment with cyclosporine

Author

Laudi S, Weimann J, Haschke M, Saskia Trump, Schmitz V, Christians U, Kaisers U, and Steudel W

Subjects
Male, Cardiotonic Agents, Time Factors, Dose-Response Relationship, Drug, Heart Ventricles, Myocardial Infarction, Myocardial Reperfusion Injury, Pilot Projects, Stroke Volume, Organ Size, Myocardial Contraction, Ventricular Function, Left, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Random Allocation, Cyclosporine, Ventricular Pressure, Animals
Abstract

Pretreatment with cyclosporine (CsA) decreases infarct size 24h after myocardial ischemia/reperfusion (I/R). The goal of this study was to determine effects of CsA pretreatment on long-term cardiac function after I/R-injury. Rats were randomly assigned to group-1: vehicle-only, group-2: CsA-5mg/kg/day, and group-3: CsA-12.5mg/kg/day given orally for three days prior to I/R-injury (30 min of left anterior descending coronary artery occlusion). Post-I/R survival and cardiac function were evaluated 14 days after I/R-injury by echocardiography and invasive hemodynamic measurements. Rats with I/R-injury showed increased left ventricular pressure (LVEDP) compared to rats without I/R-injury (p0.005). Although CsA initially decreased infarct size, no differences of LVEDP were seen 14 days after I/R-injury (vehicle: 21.2+/-8.9 mmHg, CsA-5mg/kg/day: 21.5+/-0.7 mmHg, CsA-12.5mg/kg/day: 20.5+/-9.4 mmHg). Ejection fraction and fractional shortening were decreased compared to baseline, but showed no differences between groups. On day 14, a dose-dependent increase in left ventricular end diastolic diameter was seen (p0.001). CsA pretreatment was associated with a dose-dependent decrease in post-I/R-survival (vehicle: 56%, CsA-5mg/kg/day: 32%, CsA-12.5mg/kg/day: 16%; p=0.017). CsA pretreatment did not improve long-term cardiac function despite decreased infarct size 24h after I/R-injury, but increased post-I/R mortality significantly. Poor cardiac function after CsA pretreatment might be caused by left ventricular dilation.

Published
2006

40. Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors

Author

Christians, U., Gottschalk, S., Miljus , J., Hainz, C., Benet, L., Leibfritz, D., https://orcid.org/0000-0002-0867-7222, and Serkova, N.

Abstract

Co-administration of the calcineurin inhibitor cyclosporine and the mTOR inhibitors sirolimus or everolimus increases the efficacy of immunosuppression after organ transplantation. However, clinical studies showed enhancement of cyclosporine toxicity. To characterize the biochemical mechanisms involved, we assessed the time-dependent effects of cyclosporine in combination with mTOR inhibitors on energy production (ex vivo31P-MRS), glucose metabolism (ex vivo13C-MRS), and reactive oxygen species (ROS) formation (using the fluorescent agent 2′,7′-dichlorofluorescein diacetate) in perfused rat brain slices. Cyclosporine alone inhibited energy production (ATP: 75±9), the Krebs cycle (4-13C-glutamate from 1-13C-glucose: 61±27), and oxidative phosphorylation (NAD+: 62±25) after 4 h of perfusion. After 10 h, activation of anaerobic glycolysis (3-13C-lactate: 140±17) compensated for inhibition of mitochondrial energy production and lowered the intracellular pH. ROS formation was increased after 4 h (285±55 of untreated control), but not after 10 h. mTOR inhibitors alone inhibited lactate production. When combined with cyclosporine, sirolimus enhanced cyclosporine-induced inhibition of energy metabolism (ATP: 64±9) and ROS formation (367±46). Most importantly, sirolimus inhibited cytosolic glycolysis and therefore compensation for cyclosporine-induced ATP reduction after 10 h. In contrast to sirolimus, everolimus antagonized cyclosporine-induced inhibition of mitochondrial energy metabolism (ATP: 91±7) and ROS formation (170±49). The antioxidant tocopherol antagonized all cyclosporine effects on cell metabolism. Cyclosporine time-dependently inhibited mitochondrial metabolism and increased ROS, followed by compensation involving anaerobic glycolysis. Everolimus antagonized cyclosporine-induced mitochondrial dysfunction, whereas sirolimus inhibited compensatory anaerobic glycolysis, thus enhancing cyclosporine's negative effects. ROS play the key role in mediating the negative effects of cyclosporine on cell energy metabolism.

Published
2004

44. Emerging technologies: Polymer-free phospholipid encapsulated sirolimus nanocarriers for the controlled release of drug from a stent-plus-balloon or a stand-alone balloon catheter

Author

Lemos Neto, P.A. (Pedro), Farooq, V. (Vasim), Takimura, C.K. (Celso), Gutierrez, P.S. (Paulo), Virmani, R. (Renu), Kolodgie, F. (Frank), Christians, U. (Uwe), Kharlamov, A.N. (Alexander ), Doshi, M. (Manish), Sojitra, P. (Prakash), Beusekom, H.M.M. (Heleen) van, Serruys, P.W.J.C. (Patrick), Lemos Neto, P.A. (Pedro), Farooq, V. (Vasim), Takimura, C.K. (Celso), Gutierrez, P.S. (Paulo), Virmani, R. (Renu), Kolodgie, F. (Frank), Christians, U. (Uwe), Kharlamov, A.N. (Alexander ), Doshi, M. (Manish), Sojitra, P. (Prakash), Beusekom, H.M.M. (Heleen) van, and Serruys, P.W.J.C. (Patrick)

Abstract

Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions. This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks.

Published
2013
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48. Active drug transport of immunosuppressants - New insights for pharmacokinetics and pharmacodynamics

Author

Christians, U., Strom, T., Zhang, Y.L., Steudel, W., Schmitz, V., Trump, Saskia, Haschke, M., Christians, U., Strom, T., Zhang, Y.L., Steudel, W., Schmitz, V., Trump, Saskia, and Haschke, M.

Abstract

Immunosuppressants have a narrow therapeutic index, and pharmacokinetic variability negatively affects long-term outcome of transplantation. Recently, it has become clear that active transport is a major determinant of the inter-and intraindividual variability of the pharmacokinetics and pharmacodynamics of immunosuppressants. Active transport plays a key role in (1) the poor correlation between oral doses and systemic exposure of cyclosporine, tacrolimus, sirolimus, and everolimus, (2) tissue distribution including distribution into lymphocytes, (3) hepatic and intestinal metabolism, (4) the pharmacokinetic variability of immunosuppressants after oral dosing, (5) drug-drug interactions, (6) disease-drug interactions, and (7) age, gender, and ethnicity-based differences in pharmacokinetics of immunosuppressants. Those new insights may significantly improve patient management and long-term Outcome not only by reducing pharmacokinetic variability and avoidance of drug-drug interactions but also by identification of sensitive patient populations. They will also significantly impact preclinical and clinical development strategies of new immunosuppressants.

Published
2006

50. Pre-clinical Experimental Therapeutics and Pharmacology

Author

Jensen, R. L., primary, Gilliespie, D., additional, Ajewung, N., additional, Faure, R., additional, Kamnasaran, D., additional, Poirier, D., additional, Tamura, K., additional, Wakimoto, H., additional, Rabkin, S. D., additional, Martuza, R. L., additional, Shah, K., additional, Hashizume, R., additional, Aoki, Y., additional, Serwer, L. P., additional, Drummond, D., additional, Noble, C., additional, Park, J., additional, Bankiewicz, K., additional, James, D. C., additional, Gupta, N., additional, Agerholm-Larsen, B., additional, Iversen, H. K., additional, Jensen, K. S., additional, Moller, J., additional, Ibsen, P., additional, Mahmood, F., additional, Gehl, J., additional, Corem, E., additional, Ram, Z., additional, Daniels, D., additional, Last, D., additional, Shneor, R., additional, Salomon, S., additional, Perlstein, B., additional, Margel, S., additional, Mardor, Y., additional, Charest, G., additional, Fortin, D., additional, Mathieu, D., additional, Sanche, L., additional, Paquette, B., additional, Li, H.-F., additional, Hariono, S., additional, Dasgupta, T., additional, Kim, J.-S., additional, Haas-Kogan, D., additional, Weiss, W. A., additional, James, C. D., additional, Waldman, T., additional, Nicolaides, T., additional, Ozawa, T., additional, Rao, S., additional, Sun, H., additional, Ng, C., additional, De La Torre, J., additional, Santos, R., additional, Prados, M., additional, Butowski, N., additional, Michaud, K., additional, Solomon, D. A., additional, Prados, M. D., additional, Pandya, H., additional, Gibo, D., additional, Debinski, W., additional, Vinchon-Petit, S., additional, Jarnet, D., additional, Jadaud, E., additional, Feuvret, L., additional, Garcion, E., additional, Menei, P., additional, Chen, R., additional, Yu, J.-C., additional, Liu, C., additional, Jaffer, Z. M., additional, Chabala, J. C., additional, Winssinger, N., additional, Rubenstein, A. E., additional, Emdad, L., additional, Kothari, H., additional, Qadeer, Z., additional, Binello, E., additional, Germano, I., additional, Hirschberg, H., additional, Baek, S.-K., additional, Kwon, Y. J., additional, Sun, C. H., additional, Li, S. C., additional, Madsen, S., additional, Liu, T., additional, Wang, S.-W., additional, Gibo, D. M., additional, Fan, Q.-W., additional, Cheng, C., additional, Hackett, C., additional, Feldman, M., additional, Houseman, B. T., additional, Oakes, S. A., additional, Debnath, J., additional, Shokat, K. M., additional, Sai, K., additional, Chen, F., additional, Qiu, Z., additional, Mou, Y., additional, Zhang, X., additional, Yang, Q., additional, Chen, Z., additional, Patel, T. R., additional, Zhou, J., additional, Piepmeier, J. M., additional, Saltzman, W. M., additional, Banerjee, S., additional, Kaul, A., additional, Gianino, S. M., additional, Christians, U., additional, Gutmann, D. H., additional, Wu, J., additional, Shen, R., additional, Puduvalli, V., additional, Koul, D., additional, Alfred Yung, W. K., additional, Yun, J., additional, Sonabend, A., additional, Stuart, M., additional, Yanagihara, T., additional, Dashnaw, S., additional, Brown, T., additional, McCormick, P., additional, Romanov, A., additional, Sebastian, M., additional, Canoll, P., additional, Bruce, J. N., additional, Piao, L., additional, Joshi, K., additional, Lee, R. J., additional, Nakano, I., additional, Madsen, S. J., additional, Chou, C. C., additional, Blickenstaff, J. W., additional, Sun, C.-H., additional, Zhou, Y.-H., additional, Tome, C. M. L., additional, Wykosky, J., additional, Palma, E., additional, Nduom, E., additional, Machaidze, R., additional, Kaluzova, M., additional, Wang, Y., additional, Nie, S., additional, Hadjipanayis, C., additional, Saito, R., additional, Nakamura, T., additional, Sonoda, Y., additional, Kumabe, T., additional, Tominaga, T., additional, Lun, X., additional, Zemp, F., additional, Zhou, H., additional, Stechishin, O., additional, Kelly, J. J., additional, Weiss, S., additional, Hamilton, M. G., additional, Cairncross, G., additional, Rabinovich, B. A., additional, Bell, J., additional, McFadden, G., additional, Senger, D. L., additional, Forsyth, P. A., additional, Kang, P., additional, Jane, E. P., additional, Premkumar, D. R., additional, Pollack, I. F., additional, Yoo, J. Y., additional, Haseley, A., additional, Bratasz, A., additional, Powell, K., additional, Chiocca, E. A., additional, Kaur, B., additional, Johns, T. G., additional, Ferruzzi, P., additional, Mennillo, F., additional, De Rosa, A., additional, Rossi, M., additional, Giordano, C., additional, Magrini, R., additional, Benedetti, G., additional, Pericot, G. l., additional, Magnoni, L., additional, Mori, E., additional, Thomas, R., additional, Tunici, P., additional, Bakker, A., additional, Pradarelli, J., additional, Kaka, A., additional, Alvarez-Breckenridge, C., additional, Pan, Q., additional, Teknos, T., additional, Cen, L., additional, Ostrem, J. L., additional, Schroeder, M. A., additional, Mladek, A. C., additional, Fink, S. R., additional, Jenkins, R. B., additional, Sarkaria, J. N., additional, Madhankumar, A. B., additional, Slagle-Webb, B., additional, Park, A., additional, Pang, M., additional, Klinger, M., additional, Harbaugh, K. S., additional, Sheehan, J. M., additional, Connor, J. R., additional, Chen, T. C., additional, Wang, W., additional, Hofman, F. M., additional, Drummond, D. C., additional, Noble, C. O., additional, Park, J. W., additional, Zhou, Y., additional, Marks, J. D., additional, Alonso, M. M., additional, Gomez-Manzano, C., additional, Cortes-Santiago, N., additional, Roche, F. P., additional, Fueyo, J., additional, Johannessen, T.-C. A., additional, Grudic, A., additional, Tysnes, B. B., additional, Nigro, J., additional, Bjerkvig, R., additional, Joshi, A. D., additional, Parsons, W., additional, Velculescu, V. E., additional, Riggins, G. J., additional, Bindra, R. S., additional, Jasin, M., additional, Powell, S. N., additional, Fu, J., additional, Shen, R.-J., additional, Colman, H., additional, Lang, F. F., additional, Jensen, M. R., additional, Friedman, G. K., additional, Haas, M., additional, Cassady, K. A., additional, Gillespie, G. Y., additional, Nguyen, V., additional, Murphy, L. T., additional, Beauchamp, A. S., additional, Hollingsworth, C. K., additional, Mintz, A., additional, Garg, S., additional, Kridel, S., additional, Conrad, C. A., additional, Madden, T., additional, Ji, Y., additional, Priebe, W., additional, Seleverstov, O., additional, Purow, B. W., additional, Grant, G. A., additional, Wilson, C., additional, Campbell, M., additional, Humphries, P., additional, Li, S., additional, Li, J., additional, Johnson, A., additional, Bigner, D., additional, Dewhirst, M., additional, Pokorny, J. L., additional, Kitange, G. J., additional, Carlson, B. L., additional, Suphangul, M., additional, Petro, B., additional, Mukhtar, L., additional, Baig, M. S., additional, Villano, J., additional, Mahmud, N., additional, Keir, S. T., additional, Reardon, D. A., additional, Watson, M., additional, Shore, G. C., additional, Bigner, D. D., additional, Friedman, H. S., additional, and Gururangan, S., additional

Published
2010
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