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61.
Adema AD Smid K Losekoot N Honeywell RJ Verheul HM Myhren F Sandvold ML Peters GJ 《Investigational new drugs》2012,30(5):1908-1916
Cytarabine (ara-C) and gemcitabine (dFdC) are commonly used anticancer drugs, which depend on the equilibrative (ENT) and concentrative-nucleoside-transporters to enter the cell. To bypass transport-related drug resistance, lipophilic derivatives elacytarabine (CP-4055), ara-C-5'elaidic-acid-ester, and CP-4126, (CO 1.01) gemcitabine-5'elaidic-acid-ester, were investigated for the entry into the cell, distribution, metabolism and retention. The leukemic CEM-cell-line and its deoxycytidine-kinase deficient variant (CEM/dCK-) were exposed for 30 and 60 min to the radiolabeled drugs; followed by culture in drug-free medium in order to determine drug retention in the cell. The cellular fractions were analyzed with thin-layer-chromatography and HPLC. Elacytarabine and CP-4126 were converted to the parent compounds both inside and outside the cell (35-45%). The ENT-inhibitor dipyridamole did not affect their uptake or retention. Inside the cell Elacytarabine and CP-4126 predominantly localized in the membrane and cytosolic fraction, leading to a long retention after removal of the medium. In contrast, in cells exposed to the parent drugs ara-C and dFdC, intracellular drug concentration increased during exposure but decreased to undetectable levels after drug removal. In the dCK- cell line, no metabolism was observed. The concentrations of ara-CTP and dFdCTP reached a peak at the end of the incubation with the drugs, and decreased after drug removal; peak levels of dFdCTP were 35 times higher than ara-CTP and was retained better. In contrast, after exposure to elacytarabine or CP-4126, ara-CTP and dFdCTP levels continued to increase not only during exposure but also during 120 min after removal of the elacytarabine and CP-4126. Levels of ara-CTP and dFdCTP were higher than after exposure to the parent drugs. In conclusion, the lipophilic derivatives elacytarabine and CP-4126 showed a nucleoside-transporter independent uptake, with long retention of the active nucleotides. These lipophilic nucleoside analogues are new chemical entities suitable for novel clinical applications. 相似文献
62.
Contributions of the Project Competence Longitudinal Study (PCLS) to resilience science and developmental psychopathology are highlighted in this article. Initiated by Norman Garmezy, the PCLS contributed models, measures, and methods, as well as working definitions of concepts like competence, developmental tasks, protective factors, and resilience. Findings from the study corroborated the feasibility of studying adaptation in a normative group of school children, identifying patterns of resilience, competence without major adversity, and maladaptive paths through life. Competence was multidimensional, showing continuity and change over time. Cascading effects across domains indicated that competence and problems spread over time. Thus, adult achievements in developmental tasks were rooted in childhood and adolescence. Young people who showed resilience had much in common with similarly successful peers who experienced less adversity over time, including high-quality relationships with parents and other adults, and good cognitive, as well as social-emotional, skills. Maladaptive youth in the study often faced high adversity with little adaptive capacity (internal or external) and tended to generate stressful experiences. Resilience often emerged in childhood and endured, but there also were late bloomers whose lives turned around in the transition to adulthood. The role of collaboration and mentorship in the PCLS is also discussed. 相似文献
63.
van Heel AJ Montalban-Lopez M Kuipers OP 《Expert opinion on drug metabolism & toxicology》2011,7(6):675-680
Since the commercialization and ubiquitous use of antibiotics in the 20th century, there has been a steady increase in the number of reports on resistant bacteria. In recent years, this situation has become even more dramatic. The relatively slow development of new drugs, especially those with novel modes of action on target bacteria, is not paired with the rapid rate of resistance appearance. Lantibiotics form a group of antimicrobial peptides of bacterial origin with a dual mechanism of action not shared by other therapeutic compounds in use. They have a high potency to inhibit diverse (multidrug resistant) bacteria, combined with a low tendency to generate resistance. These properties make lantibiotics attractive candidates for clinical applications. This paper discusses some of the most recent results obtained in lantibiotic clinical application, paying special attention to the pharmacokinetic and pharmacodynamic properties they display. The objective of this paper is to give insight into the actual clinical applicability of lantibiotics and to point to the unexplored aspects that should be addressed in future research. The authors feel that lantibiotics could increase the number of second line antibiotics for systemic use in the future; however, further research is still needed before this is possible. 相似文献
64.
Arnoud J.G. Knoops Yolanda van der Graaf Auke P.A. Appelman Lotte Gerritsen Willem P.Th.M. Mali Mirjam I. Geerlings 《Hippocampus》2009,19(11):1115-1122
Visual rating of hippocampal atrophy is often used to differentiate between normal aging and Alzheimer's disease. We investigated whether two visual rating scales of hippocampal atrophy were related to hippocampal volumes, and if visual rating was related to global, cortical and subcortical brain atrophy in persons without dementia. Within the SMART‐MR study, a prospective cohort study among patients with manifest arterial disease, medial temporal lobe atrophy was qualitatively rated in 95 participants without dementia (mean age 62 ± 10 years) using two visual rating scales: the medial temporal lobe (MTA) score was rated on coronal oriented images and the perihippocampal cerebrospinal fluid (HCSF) score was rated on axial oriented images. Hippocampal volume assessed by manual segmentation on a 3‐dimensional FFE T1‐weighted MR image. Automated segmentation was used to quantify volumes of brain tissue and cerebrospinal fluid. Total brain volume, gray matter volume, and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction (BPF), gray matter fraction (GMF) and ventricular fraction (VF). Using ANOVA, crude hippocampal volumes were smaller with increasing MTA and HSCF scores as were hippocampal volumes normalized for intracranial volume (P < 0.05). However, hippocampal volumes normalized for total brain size were not smaller with increasing MTA or HSCF scores (P = 0.33 and P = 0.49). Also, with increasing visual rating scores, BPF was smaller and VF was larger (P < 0.001), and the GMF decreased with increasing HCSF score (P = 0.008). In this nondemented population, visual rating of the medial temporal lobe reflects hippocampal atrophy as well as global and subcortical atrophy. © 2009 Wiley‐Liss, Inc. 相似文献
65.
Marloes L. C. Hagemans Rolinda L. Stigter Carine I. van Capelle Nadine A. M. E. van der Beek Leon P. F. Winkel Laura van Vliet Wim C. J. Hop Arnold J. J. Reuser Auke Beishuizen Ans T. van der Ploeg 《Journal of inherited metabolic disease》2010,33(2):133-139
Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters. 相似文献
66.
Majon Muller Auke P.A. Appelman Yolanda van der Graaf Koen L. Vincken Willem P.Th.M. Mali Mirjam I. Geerlings 《Neurobiology of aging》2011,32(5):885-893
We examined the interaction of brain atrophy and white matter lesions (WML) with cognitive functioning in 605 patients (mean age, 58 ± 10; 76% men) with atherosclerotic disease from the Second Manifestations of ARTerial disease-MR substudy (SMART-MR study). Automated brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and WML on MRI. Total brain, ventricular, and cortical gray matter volume were divided by intracranial volume (ICV). Neuropsychological tests assessing executive functioning and memory performance were performed and composite scores were calculated. We observed that smaller total brain volume, larger ventricular volume, and smaller cortical gray matter volume (all as % of ICV) were associated with worse executive performance and that this association became stronger with presence of brain infarcts or severe WML volume (P-values for interaction <0.05). No interaction between measures of brain volume and cerebrovascular pathology on memory performance was observed. Our findings suggest that patients with cerebrovascular pathology on MRI may be more vulnerable to impairment in executive functioning related to global as well as focal brain atrophy. 相似文献
67.
Jantine D. Jonkman-de Vries J. Jantina Kettenes-van den Bosch Roland E. C. Henrar Auke Bult Jos H. Beijnen 《Investigational new drugs》1996,14(2):181-191
Summary The pharmaceutical development of the investigational cytotoxic drug EO9 included the structural characterization of the bulk drug by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and infrared (IR) spectroscopy, and analytical characterization by high-performance liquid chromatography and ultraviolet/visible spectrophotometry. The presence of impurities in the bulk drug was investigated. The intermediates in the synthesis of EO9 were structurally characterized by NMR spectroscopy and MS, and analytically characterized by HPLC analysis with photodiode array (PDA) detection. All of the intermediates were below their limits of detection in EO9 bulk drug. The amounts of residual organic solvents were determined by gas chromatography. Methanol and ethanol were detected, but the amounts present did not exceed the limits as set in the United States Pharmacopeia XXII. 相似文献
68.
69.
Mary Jo Meadow James Kochevar Auke Tellegen Alan H. Roberts 《Journal of behavioral medicine》1978,1(4):413-426
Studies of autonomic reactivity and of voluntary control of autonomic responses have suggested the importance of individual differences. An inventory of scales was developed to improve the assessment of different dimensions of somatic functioning. In order to enhance their specificity and incremental validity, the scales were constructed to be relatively independent of already known general personality variables such as Stress Reaction (neuroticism), Locus of Control, Hypochondriasis, and Absorption. Three scales, derived from orthogonal factor analyses, were developed and cross-validated: (1) Autonomic Response Frequency, assessing spontaneous fluctuations in autonomic responding; (2) Autonomic Response to Stress, assessing the amount of autonomic arousal perceived by a subject in stress situations; and (3) Somatic Response Control, a self-report measure of capacity to control both autonomic and fine muscle responses. The hypothesis that sympathetic and parasympathetic awareness might define two distinct dimensions was not supported by the data. The new scales will be useful in testing hypotheses of possible relationships among the factors measured and behavioral and psychophysiological indicators of the response to stress.The work reported in this article was supported in part by Rehabilitation Services Administration Grant No. 16-P-56810/5-17 to the University of Minnesota Medical Rehabilitation Research and Training center. 相似文献
70.
Radi M Adema AD Daft JR Cho JH Hoebe EK Alexander LE Peters GJ Chu CK 《Journal of medicinal chemistry》2007,50(9):2249-2253
l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N4-Substituted fatty acid amide prodrugs of 10-16 carbon chain length demonstrated significantly improved antitumor activity over l-1,3-dioxolane-cytidine. These in vitro results suggest that the in vivo therapeutic efficacy of l-1,3-dioxolane-cytidine against solid tumors may be improved with prodrug strategies. 相似文献