Purpose: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer. Experimental Design: HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib. Results: The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group. Conclusions: These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.

Presidential Studies QuarterlyVolume 37, Issue 1 p. 176-178 Presidential Temples: How Memorials and Libraries Shape Public Memory – By Benjamin Hufbauer Michael E. Long, Michael E. Long Pasco-Hernando Community College, FloridaSearch for more papers by this author Michael E. Long, Michael E. Long Pasco-Hernando Community College, FloridaSearch for more papers by this author First published: 06 February 2007 https://doi.org/10.1111/j.1741-5705.2007.02591_8.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume37, Issue1March 2007Pages 176-178 RelatedInformation

Previous articleNext article No AccessThe Battle for the Black Ballot: Smith v. Allwright and the Defeat of the Texas All-White Primary – By Charles L. Zelden The Battle for the Black Ballot: Smith v. Allwright and the Defeat of the Texas All-White Primary. By Charles L. Zelden. (University Press of Kansas, 2004.)Michael E. LongMichael E. Long1Pasco-Hernando Community College Search for more articles by this author PDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by The Journal of Politics Volume 69, Number 1February 2007 Sponsored by the Southern Political Science Association Article DOIhttps://doi.org/10.1111/j.1468-2508.2007.00529.x Views: 69Total views on this site Copyright © 2007, Southern Political Science AssociationPDF download Crossref reports no articles citing this article.

Proc Amer Assoc Cancer Res, Volume 47, 2006 3090 ZD6474 (ZACTIMA™; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine) is a selective and potent inhibitor of VEGFR, EGFR and RET signaling that is currently undergoing Phase III evaluation for the treatment of cancer. Preclinical pharmacokinetic studies are an important means of assessing whether ZD6474 exposure in animal models simulates that achieved in patients. In the studies presented here, plasma and tissue pharmacokinetics were determined in MCF-7 tumor-bearing nude mice following single oral doses of ZD6474 (10, 25 and 50 mg/kg). Plasma pharmacokinetics of ZD6474 were linear, with AUC and Cmax increasing proportionally with dose. Tissue pharmacokinetics showed that ZD6474 was extensively distributed to tissues in a dose-dependent manner, with liver and lung concentrations of 212 μg/g (∼450 μM) and 161 μg/g (∼340 μM), respectively, at 4 hours post-dosing at 50 mg/kg. In the tumor, Cmax ranged from 27-71 μg/g across the three doses. Analysis of feces for putative metabolites by LC/MS/MS, by reference to a ZD6474 analytical standard, showed that N-desmethyl-ZD6474 was the most prominent metabolite, but this still accounted for less than 2% of the total amount of ZD6474 present. Analysis of plasma and liver for metabolites identified in feces showed the presence of the N-desmethyl-ZD6474 at concentrations less than 1% of ZD6474. Using standard pharmacokinetic calculations, the single-dose data appeared to accurately predict steady-state plasma and tissue drug concentrations following multiple dosing. A comparison of ZD6474 pharmacokinetics in mouse and man allows for the calculation of mouse dosing that simulates exposure in man at clinically relevant doses. Daily doses in mice that reflect the steady-state AUC, Cmax or Cmin in man at the 300 mg/day dose have been calculated as 16.2, 15.0 and 43.8 mg/kg, respectively. This pharmacokinetic study in tumor-bearing nude mice will allow combination studies of ZD6474 with radiation and/or chemotherapy to be performed in mice using doses that simulate the exposure to ZD6474 achieved in man. ZACTIMA is a trademark of the AstraZeneca group of companies

Paclitaxel (Taxol) is an effective agent against a broad range of human cancers. Studies on the metabolism and disposition of paclitaxel have shown that it is primarily eliminated via hepatic metabolism by P450 enzymes (2C8 and 3A4) to essentially inactive metabolites, and that biliary and gut transport by P-glycoprotein (PGP) as well as urinary elimination of the parent compound play relatively minor roles. Recent studies in vitro have shown that paclitaxel treatment increases the level of CYP2C8 and CYP3A4 in human hepatocytes as well as PGP in colon tumor cells. The data suggest that previous paclitaxel exposure may influence metabolism and elimination of subsequent doses. Further, since weekly paclitaxel dose schedules are becoming more common as opposed to the original every 21-day dosing, the likelihood of enzyme induction from previous doses impacting that from subsequent doses is increased.

PURPOSE:Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study. EXPERIMENTAL DESIGN:This study evaluated the toxicity and pharmacokinetics of combining exisulind (150-250 mg) given orally twice daily and docetaxel (30-36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle. RESULTS:Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed. CONCLUSIONS:The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.

Presidential Studies QuarterlyVolume 34, Issue 2 p. 465-467 Dispatches from Lincoln's White House: The Anonymous Civil War Journalism of Presidential Secretary William O. Stoddard Michael E. Long, Michael E. Long Pasco-Hernando Community CollegeSearch for more papers by this author Michael E. Long, Michael E. Long Pasco-Hernando Community CollegeSearch for more papers by this author First published: 14 May 2004 https://doi.org/10.1111/j.0360-4918.2004.056_5.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume34, Issue2June 2004Pages 465-467 RelatedInformation

Purpose. Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60-100 mg/m(2) by infusion every 3 weeks. Now weekly low-dose (30-36 mg/m(2)) regimens are being evaluated in phase I trials. Such low-dose studies require a more sensitive, specific and rapid assay of docetaxel in biological fluids for the determination of pharmacokinetic parameters. Because docetaxel is primarily metabolized by CYP3A4 and is highly protein-bound in the plasma, there is potential for drug-drug interactions and high interpatient variability in pharmacokinetics. Therefore, pharmacokinetic studies are an important component to understanding the therapeutic variability of docetaxel-containing chemotherapeutic regimens. Methods. To this end, we developed an analytical assay for docetaxel based upon tandem LCMS and paclitaxel as an internal standard. The sensitivity of the new assay allowed us to monitor plasma levels of docetaxel out to 48 h after the end of the infusion in patients enrolled in a phase I trial of exisulind (orally, twice daily) receiving weekly docetaxel doses of 30 or 36 mg/m(2) where plasma docetaxel levels are below the lower limit of quantitation for traditional HPLC/UV-based assays at later time-points.Results. The inclusion of the 48-h time-point had significant effects on the calculated pharmacokinetic parameters when using either a three-compartment or non-compartmental analysis. The terminal half-life was significantly increased when the 48-h time-point was included in the pharmacokinetic analysis, and the use of model parameters derived with the inclusion of the 48-h time-point were able to more accurately predict plasma levels at later times. Conclusions. The results reflect the importance of accurate and sensitive analytical methods for the determination of pharmacokinetic parameters and the effect of this later time-point on docetaxel pharmacokinetic modeling. Further, with the increased use of weekly docetaxel in combination with other agents, the inclusion of these later sampling time-points and sensitive methods for drug level determinations are important components in the description of pharmacokinetic drug interactions.

The studies described herein were designed to determine whether doxorubicin (DOX) pharmacokinetics (PKs) could be described by a physiologically based PK model that incorporated macromolecule-specific binding and organ-specific metabolism and excretion. Model parameters were determined experimentally, or were gathered from the literature, in a species-specific manner, and were incorporated into a physiologically based description of DOX blood and tissue distribution for mice, dogs, and humans. The resulting model simulation data were compared with experimentally determined data using PK parameters calculated using compartmental or noncompartmental analysis to assess the predictability of the models. The resulting physiologically based PK model that was developed could accurately predict blood and tissue PKs of DOX in mice. When this model was interspecies extrapolated to predict DOX levels in dogs and humans undergoing treatment for cancer, predictions in dog plasma or human serum were also consistent with the actual clinical data. This model has potential utility for predicting the magnitude of PK interactions of DOX with other drugs, and for predicting changes in DOX PKs in any number of clinical situations.

The purpose of the studies presented here is to determine if alterations in doxorubicin (DOX) pharmacokinetics that seem to occur following multiple-dosing are due to changes in DOX elimination via P-glycoprotein (PGP) mediated transport in the liver, kidney and gut. A pharmacokinetic study in female Balb/c mice was carried out with blood and tissue DOX levels measured in animals following a single DOX treatment (6 mg/kg), and in animals following a second DOX treatment after receiving a DOX treatment a week earlier. The pharmacokinetics of DOX in blood and tissues was altered by earlier exposure to DOX, as the animals that were treated once a week for 2 weeks showed an increased rate of DOX elimination from blood and tissues following the second treatment. Immunoblot analysis of PGP expression in liver and kidney from naïve and DOX-treated mice showed an approximately 1.2-fold elevation of PGP protein in these tissues in response to DOX exposure. Immunohistochemical staining of liver and small intestine sections for PGP showed 1.6-fold and 1.9-fold increases, respectively, in the DOX-treated tissues. These results have implications both in multiple-dosing regimens, as well as multiple-drug regimens, where DOX is used in combination with other drugs that are substrates for PGP-mediated efflux. Increases in PGP expression in both hepatic and extrahepatic tissues can lead to changes in the pharmacokinetics of DOX, as well as other drugs that are transported by PGP.