Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo-fetal development in rats and rabbits.

BACKGROUND: Angiogenesis plays a key role in embryo-fetal development and, based on nonclinical safety data, the majority of vascular endothelial growth factor (VEGF)-targeted antiangiogenic agents used in cancer therapy are not recommended during pregnancy. We investigated the effects of sunitinib (an oral inhibitor of multiple receptor tyrosine kinases [RTKs] including VEGF-receptors) on embryo-fetal development. METHODS: Presumed-pregnant Sprague-Dawley rats and New Zealand White rabbits received repeated daily oral doses of sunitinib (0-30 mg/kg/day), during the major period of organogenesis. Clinical/physical examinations were performed throughout the gestation phase, and blood samples were collected to determine systemic exposure. Necropsy (including uterine examination) was performed on all animals and fetal morphology was examined. RESULTS: The no-observed-adverse-effect level was 1-5 mg/kg/day for maternal toxicity and 3 mg/kg/day for developmental toxicity in rats; 1 and 0.5 mg/kg/day, respectively, in rabbits. Embryo-fetal toxicity included decreases in the number of live fetuses and increases in the numbers of resorptions and post-implantation/complete litter losses; these were observed at doses of > or =5 mg/kg/day in rats and 5 mg/kg/day in rabbits. Malformations included fetal skeletal malformations (generally thoracic/lumbar vertebral alterations) in rats and cleft lip/palate in rabbits. These developmental effects were observed at approximately 5.5- (rats) and approximately 0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/day). CONCLUSIONS: Similar effects have been reported with the prototype monoclonal antibody bevacizumab. As is typically observed for potent inhibitors of RTKs involved in angiogenesis, sunitinib was associated with embryo-fetal developmental toxicity in rats and rabbits at clinically relevant dose levels.

Analysis of repertory grids in clinical practice.

OBJECTIVES: This paper illustrates the use of several different forms of analysis of repertory grid data, using a case study of a client who completed repertory grids at various stages of therapy. METHOD: Participants in a survivors' group completed grids before and after therapy and at 3- and 6-month follow-up. Grids from one of the participants, who had been sexually abused as a child, are presented using different levels of analysis: visual inspection of the raw grid; analysis of dissimilarities between pairs of elements or constructs; hierarchical cluster analysis of elements and constructs both separately and combined; principal components analysis; biplot representation of elements and constructs combined; multidimensional scaling analysis and unfolding analysis. The latter two methods also provide ways of presenting a combined analysis of a number of grids. Computer packages are reviewed, and SYSTAT commands are presented to perform the analyses. RESULTS: The review of methods illustrates how different levels of analysis can usefully back up clients' own accounts of progress through therapy, from detailed analysis of individual ratings in the raw grid, through analyses that pull out structural patterns at the expense of detail, to the broad sweep provided by methods that combine data from a number of grids. CONCLUSIONS: Analysis of repertory grids completed at various stages of therapy can provide useful qualitative information on progress, but can also provide some simple quantitative measures (such as Self-Ideal Self discrepancy as a measure of self esteem) to track progress. Different forms of analysis can be informative, highlighting different aspects of progress, but also allowing checks on adequacy and goodness-of-fit of particular analyses.

Personal constructs, childhood sexual abuse and revictimization.

Within the theoretical framework of Ryle's Procedural Sequence Object Relations Model and Kelly's Personal Construct Theory, this study investigates sex-role polarization of incest survivors and the centrality of abuse within survivors' constructs of men that may contribute to revictimization. Repertory grid methodology was used with 40 female survivors of childhood sexual abuse and 28 non-abused women. Grid measures and psychometric measures were compared between groups of women who had and had not experienced childhood sexual abuse, revictimized and non-revictimized survivors, and survivors who had and had not experienced incestuous abuse. Results showed significant differences between survivors and non-abused women, with survivors having higher levels of depression and perceived distress, lower self-esteem and higher self/ ideal self discrepancy. Hypothesized differences in sex-role polarization were not found. There were few differences between revictimized and non-revictimized survivors, although revictimized survivors rated 'self now' as more powerful than non-revictimized survivors. No differences were found between survivors who had and had not experienced incestuous abuse. In addition to the value of exploring personal constructs, a range of models need to be considered in understanding revictimization and women's construal of men. The implications of using repertory grid methodology for research and clinical work are discussed.

The conduct of a two-generation reproductive toxicity study via dermal exposure in the Sprague-Dawley rat--a case study with KBR 3023 (a prospective insect repellent).

KBR 3023, 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)-piperidine, a prospective insect repellent being developed by the Bayer Corporation, was evaluated for reproductive toxicity in the Sprague-Dawley rat. As the intended human use of the test compound is topical, the test system was also exposed to the compound via the dermal route. Specifically, the adult rats (P generation) were fitted with Elizabethan collars, to reduce the likelihood of oral ingestion, and dermally administered either 0, 50, 100, or 200 mg KBR 3023/kg body weight throughout the study (5 d/week) beginning at the onset of the 10-week premating period and continuing through the mating, gestation, and lactation phases. Clinical signs and changes in body weight and food consumption were assessed throughout the study. All adults and neonates underwent a gross necropsy examination. Tissues retained for microscopic examination from all adult animals included the kidney, liver, pituitary, reproductive organs, and samples of skin from the shaved dose site. In addition to the parameters noted above, the animals were evaluated for the effect of the test compound on estrous cycling, mating, fertility, gestation length, litter size, pup sex ratio, and pup viability. There were no test compound-related clinical signs or effects on body weight or food consumption observed in either the adults or the pups during any phase of the study. There were no compound-related effects on any reproductive or litter parameters. Dermal findings at the dose site (acanthosis and hyperkeratosis) were noted in both generations. Other than the dermal findings, no compound-related necropsy findings were seen in either the adults or the pups. No compound-related histopathologic findings were noted in the reproductive tissues of either the males or females. Based on these results, KBR 3023, administered as described in this study at dose levels as high as 200 mg/kg body weight (the physical limit of dermal application for this compound), did not demonstrate any reproductive toxicity.

Comparative organophosphate-induced effects observed in adult and neonatal Sprague-Dawley rats during the conduct of multigeneration toxicity studies.

Five organophosphates: tribufos, oxydemeton-methyl, fenamiphos, coumaphos, and trichlorfon were evaluated for their potential to produce reproductive and neonatal toxicity following continuous dietary exposure during multigenerational reproduction toxicity studies in the Sprague-Dawley rat. Dietary concentrations were selected to demonstrate parental effects in the high dose and provide for a no-adverse effect level at the low dose. There were no clinical signs observed in the adults or neonates during either generation. Significant effects on body weight and food consumption, when observed, were typically observed only with the highest dietary concentration and were greater in the second generation. Reproductive effects, including decreased fertility and mating indices, were only observed with test compounds and at dietary concentrations demonstrating effects on body weight and/or food consumption. Similarly, pup body weight was also affected by those test compounds that produced significant maternal effects during lactation. Significant inhibition of parental cholinesterase activities (plasma, erythrocyte, and brain) was similarly observed in both generations with all test compounds, with at least the highest concentrations. In general, females demonstrated greater enzyme inhibition than the males. For example, mean PChe inhibition considering both generations and all test compounds was 74% for the females, whereas inhibition was 51% in the males. Effects on cholinesterase activities in the neonates (Lactation Day 4) were, for most test compounds, below 10% at the highest dietary concentration. However, by Lactation Day 21, inhibition of enzyme activity (considering all test compounds at the highest concentration and all enzymes) was approximately 30%. The increase in inhibition is attributed to the consumption of the treated feed during the latter stages of lactation. Considering the relative maternal (termination) and neonatal (Lactation Day 4) cholinesterase effects at the highest dietary concentration, it was observed that the effects in the neonate were, for all organophosphates tested, significantly less than those observed in the dam.