9 results on '"Leggas, Markos"'
Search Results
2. Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.
- Author
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Tsakalozou, Eleftheria, Adane, Eyob, Liang, Yali, Arnold, Susanne, and Leggas, Markos
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CANCER treatment ,SMALL cell lung cancer ,CAMPTOTHECIN ,TUMORS ,XENOGRAFTS ,CLINICAL trials ,PHARMACOKINETICS ,PATIENTS - Abstract
Purpose: Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7- t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment. Methods: After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days. Results: Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial. Conclusions: We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation. [ABSTRACT FROM AUTHOR]
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- 2014
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3. Validated LC–MS/MS method for simultaneous determination of SIM and its acid form in human plasma and cell lysate: Pharmacokinetic application.
- Author
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Ahmed, Tamer A., Horn, Jamie, Hayslip, John, and Leggas, Markos
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SIMVASTATIN ,BLOOD plasma ,PHARMACOKINETICS ,CANCER patients ,IONIZATION (Atomic physics) ,HYPERLIPIDEMIA ,AMMONIUM acetate - Abstract
Abstract: Simvastatin (SIM) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC–MS/MS method was developed to measure SIM and its acid form (SIMA) in plasma and peripheral blood mononuclear cells (PBMCs) obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75:25 (% v/v) acetonitrile:ammonium acetate (0.1M, pH 5.0) mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5–500ng/mL for SIM and 5–500ng/mL for SIMA in plasma and 2.5–250ng/mL for SIM and 5–250ng/mL for SIMA in cell lysate. Recovery was >58% for SIM and >75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
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4. Pharmacokinetic Modeling to Assess Factors Affecting the Oral Bioavailability of the Lactone and Carboxylate Forms of the Lipophilic Camptothecin Analogue AR-67 in Rats.
- Author
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Adane, Eyob, Liu, Zhiwei, Xiang, Tian-Xiang, Anderson, Bradley, and Leggas, Markos
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PHARMACOKINETICS ,DRUG bioavailability ,ORAL drug administration ,LACTONES ,CARBOXYLATES ,DRUG lipophilicity ,CAMPTOTHECIN ,LABORATORY rats - Abstract
Purpose: Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats. Methods: Plasma pharmacokinetic (PK) studies were conducted following administration of AR-67 lactone or carboxylate doses alone or after pre-dosing with inhibitors of the efflux transporters P-gp and Bcrp. A population PK model that simultaneously fitted to oral and intravenous data was used to estimate the bioavailability (F) and clearance of AR-67. Results: An inverse Gaussian function was used as the oral input into the model and provided the best fits. Covariate analysis showed that the bioavailability of the lactone, but not its clearance, was dose dependent. Consistent with this observation, the bioavailability of AR-67 increased when animals were pretreated orally with GF120918 or Zosuquidar. Conclusion: Absorption of AR-67 is likely affected by solubility of its lactone form and interaction with efflux pumps in the gut. AR-67 appears to be absorbed as the lactone form, most likely due to gastric pH favoring its formation and predominance. F increased at higher doses suggesting saturation of efflux mechanisms. [ABSTRACT FROM AUTHOR]
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- 2012
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5. Factors Affecting the In Vivo Lactone Stability and Systemic Clearance of the Lipophilic Camptothecin Analogue AR-67.
- Author
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Adane, Eyob D., Zhiwei Liu, Tian-Xiang Xiang, Anderson, Bradley D., and Leggas, Markos
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LACTONES ,CAMPTOTHECIN ,RIFAMPIN ,PHARMACOKINETICS ,GENETIC polymorphisms - Abstract
The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3
rd generation camptothecin analogue. Pharmacokinetic studies were conducted in rats given intravenous boluses of AR-67 lactone or carboxylate with or without pharmacologic inhibitor pretreatment (GF120918 or rifampin). Pharmacokinetic modeling was used to estimate clearances, while simulations assessed the impact of clearance changes on overall AR-67 exposure. Our modeling showed that carboxylate clearance was 3.5-fold higher than that of the lactone. GF120918 decreased lactone clearance only, but rifampin decreased both lactone and carboxylate clearances. Simulations showed that decreasing carboxylate clearance, which controls the overall drug disposition, leads to significant increase in AR-67 exposure. The apparent in vivo blood stability of AR-67 is partly dependent on the increased carboxylate clearance. This may have clinical implications for populations with single nucleotide polymorphisms that impair the function of uptake transporter genes (e.g., SLCO1B1), which are potentially responsible for AR-67 carboxylate clearance. [ABSTRACT FROM AUTHOR]- Published
- 2010
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6. Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: Lessons learned of the EPR effect and image-guided drug delivery.
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Hollis, Christin P., Weiss, Heidi L., Leggas, Markos, Evers, B. Mark, Gemeinhart, Richard A., and Li, Tonglei
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PACLITAXEL , *NANOCRYSTALS , *DRUG delivery systems , *ANTINEOPLASTIC agents , *PHARMACOKINETICS , *CRYSTALLIZATION , *LABORATORY mice - Abstract
Abstract: Paclitaxel (PTX) nanocrystals (200nm) were produced by crystallization from a solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of a survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48h by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for theranostics, in tracking drug distribution and pharmacokinetics. [Copyright &y& Elsevier]
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- 2013
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7. Stable RNA nanoparticles as potential new generation drugs for cancer therapy.
- Author
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Shu, Yi, Pi, Fengmei, Sharma, Ashwani, Rajabi, Mehdi, Haque, Farzin, Shu, Dan, Leggas, Markos, Evers, B. Mark, and Guo, Peixuan
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NANOPARTICLES , *CANCER treatment , *CANCER chemotherapy , *NUCLEOTIDE sequence , *DRUG development , *NANOTECHNOLOGY , *RNA - Abstract
Abstract: Human genome sequencing revealed that only ~1.5% of the DNA sequence coded for proteins. More and more evidence has uncovered that a substantial part of the 98.5% so‐called “junk” DNAs actually code for noncoding RNAs. Two milestones, chemical drugs and protein drugs, have already appeared in the history of drug development, and it is expected that the third milestone in drug development will be RNA drugs or drugs that target RNA. This review focuses on the development of RNA therapeutics for potential cancer treatment by applying RNA nanotechnology. A therapeutic RNA nanoparticle is unique in that its scaffold, ligand, and therapeutic component can all be composed of RNA. The special physicochemical properties lend to the delivery of siRNA, miRNA, ribozymes, or riboswitches; imaging using fluogenenic RNA; and targeting using RNA aptamers. With recent advances in solving the chemical, enzymatic, and thermodynamic stability issues, RNA nanoparticles have been found to be advantageous for in vivo applications due to their uniform nano-scale size, precise stoichiometry, polyvalent nature, low immunogenicity, low toxicity, and target specificity. In vivo animal studies have revealed that RNA nanoparticles can specifically target tumors with favorable pharmacokinetic and pharmacodynamic parameters without unwanted accumulation in normal organs. This review summarizes the key studies that have led to the detailed understanding of RNA nanoparticle formation as well as chemical and thermodynamic stability issue. The methods for RNA nanoparticle construction, and the current challenges in the clinical application of RNA nanotechnology, such as endosome trapping and production costs, are also discussed. [Copyright &y& Elsevier]
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- 2014
- Full Text
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8. Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma
- Author
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Horn, Jamie, Jordan, Sherri L., Song, Lin, Roberts, Michael J., Anderson, Bradley D., and Leggas, Markos
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LACTONES , *PRODRUGS , *AMINOBUTYRIC acid , *PHARMACOKINETICS , *CHROMATOGRAPHIC analysis - Abstract
Abstract: A method for the quantitation of DB-67 ((20S)-10-hydroxy-7-tert-butyldimethylsilylcamptothecin) lactone and carboxylate in mouse plasma has been developed, validated, and applied in pharmacokinetic studies. The analytes were separated by reversed-phase chromatography with fluorescence detection. Validation demonstrated the selectivity and specificity for the carboxylate and lactone, with linearity between 1–300ng/mL and 2.5–300ng/mL for the carboxylate and lactone, respectively (accuracy 90–110% of theory and coefficient of variation ≤5.7%). Carboxylate to lactone conversion was <4% using this method. The assay was found to be suitable for the analysis of DB-67 lactone and carboxylate in pharmacokinetic studies following intravenous administration of DB-67 or its δ-aminobutyric acid ester derivative. [Copyright &y& Elsevier]
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- 2006
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9. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
- Author
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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
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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
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