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9. Additional file 1 of Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

Author

Hedrick, Sidnee L., Luo, Dan, Kaska, Sophia, Niloy, Kumar Kulldeep, Jackson, Karen, Sarma, Rupam, Horn, Jamie, Baynard, Caroline, Leggas, Markos, Butelman, Eduardo R., Kreek, Mary Jeanne, and Prisinzano, Thomas E.

Abstract

Additional file 1. File includes synthetic experimental details, 1H NMR spectra, 13C NMR spectra, and HPLC chromatograms of 14, 16, 20–22, and 25, 26 and 28–30.

Published
2021
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14. Enhancing Anti-Tumor Immunity and Responses to Immune Checkpoint Blockade By Suppressing Interleukin-10 in Chronic Lymphocytic Leukemia

Author

Rivas, Jacqueline R., primary, Alhakeem, Sara S., additional, Eckenrode, Joseph M., additional, Zhang, Yinan, additional, Collard, James P., additional, Hildebrandt, Gerhard C., additional, Fleischman, Roger A., additional, Chen, Li, additional, Thorson, Jon S., additional, Leggas, Markos, additional, and Bondada, Subbarao, additional

Published
2019
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29. Gefitinib Enhances the Antitumor Activity and Oral Bioavailability of Irinotecan in Mice

Author

Stewart, Clinton F., primary, Leggas, Markos, additional, Schuetz, John D., additional, Panetta, John C., additional, Cheshire, Pamela J., additional, Peterson, Jennifer, additional, Daw, Najat, additional, Jenkins, Jesse J., additional, Gilbertson, Richard, additional, Germain, Glen S., additional, Harwood, Franklin C., additional, and Houghton, Peter J., additional

Published
2004
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30. Mrp4 Confers Resistance to Topotecan and Protects the Brain from Chemotherapy

Author

Leggas, Markos, primary, Adachi, Masashi, additional, Scheffer, George L., additional, Sun, Daxi, additional, Wielinga, Peter, additional, Du, Guoqing, additional, Mercer, Kelly E., additional, Zhuang, Yanli, additional, Panetta, John C., additional, Johnston, Brad, additional, Scheper, Rik J., additional, Stewart, Clinton F., additional, and Schuetz, John D., additional

Published
2004
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31. Interactions between Hepatic Mrp4 and Sult2a as Revealed by the Constitutive Androstane Receptor and Mrp4 Knockout Mice

Author

Assem, Mahfoud, primary, Schuetz, Erin G., additional, Leggas, Markos, additional, Sun, Daxi, additional, Yasuda, Kazuto, additional, Reid, Glen, additional, Zelcer, Noam, additional, Adachi, Masashi, additional, Strom, Stephen, additional, Evans, Ronald M., additional, Moore, David D., additional, Borst, Piet, additional, and Schuetz, John D., additional

Published
2004
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32. Localization and Functional Characterization of the Rat Oatp4c1 Transporter in an In Vitro Cell System and Rat Tissues.

Author

Kuei-Ling Kuo, Haining Zhu, McNamara, Patrick J., and Leggas, Markos

Subjects
ION transport (Biology), IMMUNOGLOBULINS, PLASMA cells, CARRIER proteins, ANIMAL models in research, IMMUNOBLOTTING, IMMUNOHISTOCHEMISTRY
Abstract

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. However, our in vitro studies with MDCKII cells showed that upon transfection rat Oatp4c1 polarizes to the apical membrane. In this report, we validated the trafficking and function of Oatp4c1 in polarized cell systems as well as its subcellular localization in rat kidney. Using several complementary biochemical, molecular and proteomic methods as well as antibodies amenable to immunohistochemistry, immunofluorescence, and immunobloting we investigated the expression pattern of Oatp4c1 in polarized cell systems and in the rat kidney. Collectively, these data demonstrate that rat Oatp4c1 traffics to the apical cell surface of polarized epithelium and localizes primarily in the proximal straight tubules, the S3 fraction of the nephron. Drug uptake studies in Oatp4c1-overexpressing cells demonstrated that Oatp4c1-mediated estrone-3-sulfate (E3S) uptake was pH-dependent and ATP-independent. These data definitively demonstrate the subcellular localization and histological location of Oatp4c1 and provide additional functional evidence that reconciles expression-function reports found in the literature. [ABSTRACT FROM AUTHOR]

Published
2012
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33. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

Author

Favie, L.M.A., Groenendaal, F., Broek, M.P.H. van den, Rademaker, C.M.A., Haan, T.R. de, Straaten, H.L.M. van, Dijk, P.H., Heijst, A. van, Dudink, J., Dijkman, K.P., Rijken, M., Zonnenberg, I.A., Cools, F., Zecic, A., Lee, J.H. van der, Nuytemans, D.H.G.M., Bel, F. van, Egberts, T.C.G., Huitema, A.D.R., Brouwer, M.J., Mulder-de Tollenaer, S.M., Jebbink-Akkerman, L.J.M.G., Liem, D., Steiner, K., Simons, S.H.P., Jonge, R.C.J. de, Bos, A.A., Sonnaert, M., Camfferman, F.A., PharmaCool Study Grp, Clinical sciences, Growth and Development, Neonatology, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, General Paediatrics, AGEM - Inborn errors of metabolism, APH - Methodology, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pediatric surgery, Leggas, Markos, and Pediatrics

Subjects
Male, Physiology, Enzyme Metabolism, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], INFANTS, Hypothermia, Pathology and Laboratory Medicine, Biochemistry, Body Temperature, Drug Metabolism, Hypothermia, Induced, Medicine and Health Sciences, Metabolites, Therapeutic hypothermia, Prospective Studies, Enzyme Chemistry, education.field_of_study, Asphyxia Neonatorum, Brain Diseases, Analgesics, Multidisciplinary, PRETERM, Agricultural and Biological Sciences(all), Morphine, GENTAMICIN PHARMACOKINETICS, Drugs, General Medicine, POPULATION PHARMACOKINETICS, Physiological Parameters, Anesthesia, SAFETY, Medicine, Female, medicine.symptom, General Agricultural and Biological Sciences, medicine.drug, Research Article, Science, Population, Genetics and Molecular Biology, Loading dose, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Signs and Symptoms, All institutes and research themes of the Radboud University Medical Center, Pharmacokinetics, Diagnostic Medicine, medicine, Journal Article, Humans, Pain Management, Dosing, education, HYPOXIC-ISCHEMIC ENCEPHALOPATHY, perinatal asphyxia, GLUCURONIDATION, Pharmacology, business.industry, Biochemistry, Genetics and Molecular Biology(all), Infant, Newborn, Biology and Life Sciences, Neonates, PHARMACODYNAMICS, medicine.disease, Perinatal asphyxia, Opioids, Metabolism, DRUG-METABOLISM, Pharmacodynamics, General Biochemistry, Enzymology, ASPHYXIATED NEWBORNS, business, Genetics and Molecular Biology(all), Developmental Biology
Abstract

ObjectiveMorphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.Study designTerm and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.Results244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, pConclusionsClearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.Trial registrationwww.trialregister.nl NTR2529.

Published
2019

34. Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.

Author

Leggas M, Stewart CF, Woo MH, Fouladi M, Cheshire PJ, Peterson JK, Friedman HS, Billups C, and Houghton PJ

Subjects
Animals, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Astrocytoma drug therapy, Astrocytoma pathology, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Child, Chromatography, High Pressure Liquid, Cyclophosphamide administration & dosage, Dacarbazine administration & dosage, Dactinomycin administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Female, Glioblastoma drug therapy, Glioblastoma pathology, Glioma drug therapy, Glioma pathology, Humans, Medulloblastoma drug therapy, Medulloblastoma pathology, Mice, Mice, Inbred CBA, Mice, Inbred ICR, Mice, SCID, Neoplasms pathology, Neuroblastoma drug therapy, Neuroblastoma pathology, Neuroectodermal Tumors, Primitive drug therapy, Neuroectodermal Tumors, Primitive pathology, Radiation Chimera, Random Allocation, Rhabdoid Tumor drug therapy, Rhabdoid Tumor pathology, Rhabdomyosarcoma, Embryonal drug therapy, Rhabdomyosarcoma, Embryonal pathology, Sesquiterpenes administration & dosage, Sesquiterpenes pharmacokinetics, Tumor Cells, Cultured, Vincristine administration & dosage, Xenograft Model Antitumor Assays, Antineoplastic Agents, Phytogenic therapeutic use, Neoplasms drug therapy, Sesquiterpenes therapeutic use
Abstract

Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. The minimum effective dose of Irofulven causing objective regression (> or =50% volume regression) of advanced tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas). At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of 18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.

Published
2002

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