bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose‐dependent pharmacokinetics of 1‐(2‐Deoxy‐β‐D‐ ribofuranosyl)‐2,4‐difluoro‐5‐iodobenzene: A potential mimic of 5‐iodo‐2′‐deoxyuridine
Authors: Khalili Panteha , Naimi Ebrahim , Sun Wei Yan , Knaus Edward E. , Wiebe Leonard I. 
Published: December 2003

AbstractThe dose‐range pharmacokinetics of l‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluoro‐5‐iodobenzene (5‐IDFPdR), a C‐aryl nucleoside mimic of IUdR, were studied in male Sprague‐Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from ∼32 ml/min/kg at a dose of 15 mg/kg, to ∼19 ml/min/kg when dosed at 54 mg/kg, and the elimination half‐life increased from 8.4 min to 21.5 min, for the respective doses. While the dose‐normalized area under the concentration‐time curve (AUCnorm) remained practically unchanged (0.132 kg min ml−1) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% (∼0.19 kg min ml−1) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose‐dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half‐life increased from 24.5 min to 176 min, while blood clearance was reduced from ∼37 ml/min/kg to ∼17 ml/min/kg. The urinary recoveries of unchanged 5‐IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5‐IDFPdR (as percent of the dose) was, however, decreased with increasing doses.The overall kinetic profile of 5‐IDFPdR based on these data is suggestive of dose‐dependent pharmacokinetics. Decreased elimination of 5‐IDFPdR with increasing dose, as supported by longer elimination half‐lives at higher doses, is one likely mechanism contributing to the dose‐dependent behaviour of this compound. Saturable non‐renal metabolism might explain the reduced total body clearance of 5‐IDFPdR at higher doses, despite the unchanged or increased urinary clearance.For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5‐IDFPdR, which may be of therapeutic relevance, warrants extended dose‐range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens. Copyright © 2003 John Wiley & Sons, Ltd.
Preclinical evaluation of the pharmacokinetics, brain uptake and metabolism of E121, an antiepileptic enaminone ester, in rats
Authors: Khurana Manoj , Salama Noha N. , Scott Kenneth R. , Nemieboka Noble N. , Bauer Kenneth S. , Eddington Natalie D. 
Published: December 2003

AbstractThe present study describes the brain uptake, pharmacokinetics and metabolism of an anticonvulsant enaminone ester E121, which belongs to a new and active series of compounds with potential in vivo anticonvulsant activity in rodent models, in rats. A single dose of E121 was administered i.p. to male Sprague Dawley rats at 10 mg E121/kg body weight. Cohorts of animals (n=3) were killed at varying times over 0–24 h to collect plasma and brain samples. Urinary excretion of E121 was studied in a separate group of five rats at the same dose. A validated HPLC method was used to quantify E121 and its metabolites in plasma, brain and urine. LC‐MS/MS was used to characterize the metabolites. The plasma and brain Cmax of 11.0±3.0 mg/l and 10.4±1.4 mg/kg, respectively, were observed for E121 at 15 min post dose and they declined in a mono‐exponential fashion. The plasma Cl/F and t1/2 were 0.57 l/h/kg and 0.75 h, respectively. The brain uptake ratio of E121 was 0.9. Mass spectral analysis of urine showed two major metabolites (m/z 280) and one minor metabolite (m/z 236) that were consistent with initial hydrolysis of the compound to the acid followed by further decarboxylation and appears to be the major route of elimination of E121. The rapid and moderate brain uptake of E121 correlates well with its potential anticonvulsant activity (ED50 3.0 mg/kg p.o. in rats). The brain uptake, pharmacokinetic and metabolic profile of E121 supports the need to further evaluate this compound for its potential as an antiepileptic. Copyright © 2003 John Wiley & Sons, Ltd.
Subacute toxicities and toxicokinetics of DA‐8159, a new phosphodiesterase type V inhibitor, after single and 4‐Week repeated oral administration in rats
Authors: Shim Hyun J. , Kim Yu C. , Jang Ji M. , Park Kyung J. , Kim Dong H. , Kang Kyung K. , Ahn Byoung O. , Kwon Jong W. , Kim Won B. , Lee Myung G. 
Published: December 2003

AbstractThe subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA‐8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4‐week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA‐8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non‐specific and transient since this were also observed in control rats. In addition, there was no dose‐dependency in these changes. Based on these results, the NOAEL (No‐Observed‐Adverse‐Effect‐Level) for DA‐8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4‐week oral administration, accumulation of DA‐8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose‐normalized area under the plasma concentration–time curve from time zero to the last measured time, 24 h, in plasma (AUC0−24 h) was significantly different among the three doses (the AUC0–24 h based on 20 mg/kg/day was 2.33, 7.00 and 4.19 μg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA‐8164, a metabolite of DA‐8159; the AUC0–24 h of DA‐8164 after dose‐normalized to 20 mg/kg/day of DA‐8159 were 2.74, 5.00 and 1.68 μg h/ml, respectively. Copyright © 2003 John Wiley & Sons, Ltd.
Self‐framing of risky choice
Authors: Wang X. T. 
Published: December 2003

AbstractPrevious research on framing effects has largely focused on how choice information framed by external sources influences the response of a decision maker. This research examined how decision makers framed choice options and how the hedonic tone of self‐framing influenced their risk preference. By using pie charts and a complementary sentence‐completion task in Experiment 1, participants were able to interpret and frame the expected choice outcomes themselves before making a choice between a sure option and a gamble in either a life–death or a monetary problem. Each of these self‐frames (phrases) was then rated by a group of independent judges in terms of its hedonic tone. The hedonic tone of self‐frames was mostly positive and was more positive in the life–death than the monetary context, suggesting a motivational function of self‐framing. However, positive outcomes were still more likely to be framed positively than negative outcomes. In Experiment 2, choice outcomes were depicted with a whole‐pie chart instead of a pie slice in order to emphasize positive and negative outcomes equally. The results showed that the hedonic tone of self‐framing was still largely positive and more positive in the life domain than the monetary domain. However, compared to Experiment 1, the risk preference in the life–death domain was reversed, showing an outcome salience effect: when the pie‐slice chart emphasized only survival outcomes, participants were more risk taking under positive hedonic frames whereas when the whole‐pie chart depicted both survival and mortality outcomes, they became risk averse under positive frames. In sum, self‐framing reflected a positive bias in encoding risk information and affected the risk preference of the decision maker. Like the tone of voice used in communication, the hedonic tone of self‐framing, either positive or negative, can affect risk perception of a choice problem. Copyright © 2003 John Wiley & Sons, Ltd.
Revocable commitments to public goods provision under the real‐time protocol of play
Authors: Goren Harel , Rapoport Amnon , Kurzban Robert 
Published: December 2003

AbstractUsing the real‐time protocol of play—a relatively new experimental mechanism in which the order of play and timing of decisions are determinedendogenously—we investigate voluntary contributions to the provision of pure public goods. We consider the case where the good is binary, players are asymmetric, communication is prohibited, and all‐or‐none contributions to the public good can be withdrawn at any time during the round of play. Our results: (1) support an equilibrium in which contributors maximize the sum of their own payoffs; (2) show considerably higher levels of contribution than under the more commonly used simultaneous protocol of play; and (3) exhibit no decrease in level of contribution across multiple iterations of the stage game. On comparing our results to those of Goren et al. (2003), we conclude that modifying the mechanism so that contributions once made cannot be revoked yields significantly higher levels of contribution over the course of the game. Copyright © 2003 John Wiley & Sons, Ltd.
Intuitive evaluation of likelihood judgment producers: evidence for a confidence heuristic
Authors: Price Paul C. , Stone Eric R. 
Published: December 2003

AbstractThis research tests the hypothesis of Yates et al. (1996) that people prefer judgment producers who make extreme confidence judgments. In each of three experiments, college students evaluated two fictional financial advisors who judged the likelihood that each of several stocks would increase in value. One of the advisors (the moderate advisor) was reasonably well calibrated and the other (the extreme advisor) was overconfident. In all three experiments, participants tended to prefer the extreme advisor. Experiments 2 and 3 showed that the advisors' confidence influenced participants' perception of their knowledge, and Experiment 3 showed that it influenced their perception of the number of categorically correct judgments they made. Both of these variables were, in turn, related to participants' preferences. Experiment 3 also suggested that need for cognition and right‐wing authoritarianism are positively related to preference for the extreme advisor. A quantitative model is presented, which captures the basic pattern of results. This model includes the assumption that people use a confidence heuristic; they assume that a more confident advisor makes more categorically correct judgments and is more knowledgeable. Copyright © 2004 John Wiley & Sons, Ltd.
Impact of mood, framing, and need for cognition on decision makers' recall and confidence
Authors: Kuvaas Bård , Kaufmann Geir 
Published: December 2003

AbstractThis study examined the impact of mood, information framing, and need for cognition on participants' amount of recall and level of confidence in a simulated business‐decision‐making setting. No main effect was obtained for either positive or negative mood. However, in support of the congruity–incongruity hypothesis, participants who received mood‐congruent framing information (positive mood/positive framing and negative mood/negative framing) showed significantly better recall and were significantly less overconfident than those who received mood‐incongruent framing information (positive mood/negative framing and negative mood/positive framing). Yet, congruity–incongruity effects were moderated by decision makers' need for cognition and were obtained only among participants' with a lower cognitive processing requirement. Copyright © 2004 John Wiley & Sons, Ltd.
Biology of insulin‐like growth factors in development
Authors: Dupont Joëlle , Holzenberger Martin 
Published: December 2003

AbstractInsulin‐like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type–specific and developmental stage–specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth‐stimulating insulin‐like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF‐dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan. Birth Defects Research (Part C) 69:257–271, 2003. © 2003 Wiley‐Liss, Inc.
TGF‐β signaling in human skeletal and patterning disorders
Authors: Serra Rosa , Chang Chenbei 
Published: December 2003

AbstractMembers of the transforming growth factor beta (TGF‐β) family of multifunctional peptides are involved in almost every aspect of development. Model systems, ranging from genetically tractable invertebrates to genetically engineered mice, have been used to determine the mechanisms of TGF‐β signaling in normal development and in pathological situations. Furthermore, mutations in genes for the ligands, receptors, extracellular modulators, and intracellular signaling molecules have been associated with several human disorders. The most common are those associated with the development and maintenance of the skeletal system and axial patterning. This review focuses on the mechanisms of TGF‐β signaling with special emphasis on the molecules involved in human disorders of patterning and skeletal development. Birth Defects Research (Part C) 69:333–351, 2003. © 2003 Wiley‐Liss, Inc.
From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis
Authors: Harry Lorraine E. , Paleolog Ewa M. 
Published: December 2003

AbstractFormation of new blood vessels, which is fundamental in embryonic development, occurs through a combination of angiogenesis and vasculogenesis. Angiogenesis also plays a vital role postnatally, especially in reparative processes such as wound and fracture healing. Some of these events, especially in fracture healing, recapitulate processes observed in developmental angiogenesis. However, dysregulated angiogenesis is well documented to underlie a number of pathological disorders, including rheumatoid arthritis (RA). The vascular endothelial growth factor (VEGF)/VEGF receptor system is the best characterized regulator of angiogenesis. VEGF is expressed in a range of cells in response to soluble mediators (such as cytokines and growth factors), cell‐bound stimuli (such as CD40 ligand), and environmental factors (such as hypoxia). As a consequence, this molecule is vital in the modulation of physiological and pathological angiogenesis. This review will focus in particular on the role played by VEGF in embryogenesis and skeletal growth, in fracture healing (in which increased angiogenesis is likely to be beneficial in promoting union), and in RA (in which excessive angiogenesis is thought to play a significant role in disease pathogenesis). In the not‐too‐distant future, targeting VEGF may prove to be of benefit in the treatment of diseases associated with excessive or aberrant angiogenesis, such as malignancies and RA. Birth Defects Research (Part C) 69:363–374, 2003. © 2003 Wiley‐Liss, Inc.
Roles of FGF receptors in mammalian development and congenital diseases
Authors: Coumoul Xavier , Deng Chu‐Xia 
Published: December 2003

AbstractFour fibroblast growth factor receptors (FGFR1–4) constitute a family of transmembrane tyrosine kinases that serve as high affinity receptors for at least 22 FGF ligands. Gene targeting in mice has yielded valuable insights into the functions of this important gene family in multiple biological processes. These include mesoderm induction and patterning; cell growth, migration, and differentiation; organ formation and maintenance; neuronal differentiation and survival; wound healing; and malignant transformation. Furthermore, discoveries that mutations in three of the four receptors result in more than a dozen human congenital diseases highlight the importance of these genes in skeletal development. In this review, we will discuss recent progress on the roles of FGF receptors in mammalian development and congenital diseases, with an emphasis on signal transduction pathways. Birth Defects Research (Part C) 69:286–304, 2003. Published 2003 Wiley‐Liss, Inc.
Wnts and wing: Wnt signaling in vertebrate limb development and musculoskeletal morphogenesis
Authors: Yang Yingzi 
Published: December 2003

AbstractIn the past twenty years, secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development from hydra to human. In the developing vertebrate limb, Wnt signaling is required for limb bud initiation, early limb patterning (which is governed by several well‐characterized signaling centers), and, finally, late limb morphogenesis events. Wnt ligands are unique, in that they can activate several different receptor‐mediated signal transduction pathways. The most extensively studied Wnt pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β‐catenin in regulating a diverse array of biological processes. Recently, more attention has been given to the noncanonical Wnt pathway, which is β‐catenin–independent. The noncanonical Wnt pathway signals through activating Ca2+ flux, JNK activation, and both small and heterotrimeric G proteins, to induce changes in gene expression, cell adhesion, migration, and polarity. Abnormal Wnt signaling leads to developmental defects and human diseases affecting either tissue development or homeostasis. Further understanding of the biological function and signaling mechanism of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. This review provides a critical perspective on how Wnt signaling regulates different developmental processes. As Wnt signaling in tumor formation has been reviewed extensively elsewhere, this part is not included in the review of the clinical significance of Wnt signaling. Birth Defects Research (Part C) 69:305–317, 2003. Published 2003 Wiley‐Liss, Inc.
Nodal signaling and vertebrate germ layer formation
Authors: Weng Wei , Stemple Derek L. 
Published: December 2003

AbstractThe understanding of germ layer formation in vertebrates began with classical experimental embryology. Early in the 20th century, Spemann and Mangold (1924) identified a region of the early embryo capable of inducing an entire embryonic axis. Termed the dorsal organizer, the tissue and the activity have been shown to exist in all vertebrates examined. In mice, for example, the activity resides in a region of the gastrula embryo known as the node. Experiments by the Dutch embryologist Nieuwkoop (1967a, 1967b, 1973, 1977) showed that a signal derived from the vegetal half of the amphibian embryo is responsible for the formation of mesoderm. Nieuwkoop's results allowed the development of in vitro assays that led, in the late 1980s and early 1990s, to the identification of growth factors essential for germ layer formation. Through more recent genetic investigations in mice and zebrafish, we now know that one class of secreted growth factor, called Nodal because of its localized expression in the mouse node, is essential for formation of mesoderm and endoderm and for the morphological rearrangements that occur during gastrulation. Birth Defects Research (Part C) 69:325–332, 2003. © 2003 Wiley‐Liss, Inc.
PTHrP, PTH, and the PTH/PTHrP receptor in endochondral bone development
Authors: Schipani Ernestina , Provot Sylvain 
Published: December 2003

AbstractEndochondral bone development is a fascinating story of proliferation, maturation, and death. An understanding of this process at the molecular level is emerging. In particular, significant advances have been made in understanding the role of parathyroid‐hormone‐related peptide (PTHrP), parathyroid hormone (PTH), and the PTH/PTHrP receptor in endochondral bone development. Mutations of the PTH/PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP, PTH, and the PTH/PTHrP receptor genes, respectively, have demonstrated the critical role of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes, and their replacement by bone cells. A future area of investigation will be the identification of downstream effectors of PTH, PTHrP, and PTH/PTHrP receptor activities. Furthermore, it will be of critical importance to study how these proteins cooperate and integrate with other molecules that are essential for growth plate development. Birth Defects Research (Part C) 69:352–362, 2003. © 2003 Wiley‐Liss, Inc.