Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine

Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t 1/2 = 9.7 h) relative to vincristine (t 1/2 = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd

Prenatal Reflective Functioning and Development of Aggression in Infancy: the Roles of Maternal Intrusiveness and Sensitivity

Maternal reflective functioning (RF) has been associated with quality of parent-child interactions and child development. This study investigated whether prenatal RF predicted the development of infant physical aggression and whether maternal sensitivity and/or intrusiveness mediated or moderated this association. The sample consisted of 96 first-time mothers (M = 22.57 years, SD = 2.13) and their infants (54 % male). Prenatal RF was measured with an interview, maternal behavior was observed during free play at 6 months post-partum, and infant physical aggression was assessed at 6, 12, and 20 months using maternal reports. Multivariate analyses of variance showed that relatively poor prenatal RF was related to relatively high infant physical aggression. These associations were moderated by maternal intrusiveness, with significant differences in physical aggression between RF-groups reportedly only in the absence of intrusiveness. Generally, mothers reported an increase in physical aggression between 6 and 12 months, except when they had both low RF-skills and were relatively less sensitive. It is concluded that prenatal RF is associated with (development of) infant physical aggression, and may be targeted in intervention programs aimed at reducing early physical aggression. Less adequate parenting, however, may counteract the beneficial effects of good RF, or obscure insight into children’s behavioral development

The road to liberalization: Policy design and implementation of Taiwan’s privatization

Policy framework, Performance change, State owned enterprise, H42, K23, L33,

The Effect of the Small Indian Mongoose (Urva auropunctatus), Island Quality and Habitat on the Distribution of Native and Endemic Birds on Small Islands within Fiji

This study investigated the effect of the presence of introduced mongoose, environmental quality and habitat on the distribution of native and endemic birds on 16 small islands within Fiji. In total, 9055 birds representing 45 species were observed within four key habitats (forest, villages, crop land and coastal vegetation) on the 16 islands, half of which had mongoose present. Previous studies attribute bird declines and extirpation anecdotally to the mongoose. The presence of mongoose, environmental quality and habitat type had a measurable influence on observed extant native and endemic bird communities. We conclude that three ground birds; Gallirallus phillipensis, Anas supericiliosa and Porphyrio porhyrio were negatively influenced by the presence of mongoose and that Ptilinopus perousii, Phigys solitarius, Chrysoenas victor, Ducula latrans, Clytorhyrchus vitiensis, Pachycephala pectoralis, Prospeia tabunesis, and Foulehaio carunculata were particularly dependent on good quality forest habitat. Conservation priorities in relation to protecting Fiji’s endemic birds from the effect of mongoose are discussed and preventative measures suggested

PEGylation of a High-Affinity Anti-(+)Methamphetamine Single Chain Antibody Fragment Extends Functional Half-Life by Reducing Clearance

PURPOSE: Methamphetamine (METH) abuse is a worldwide drug problem, yet no FDA-approved pharmacological treatments are available for METH abuse. Therefore, we produced an anti- METH single chain antibody fragment (scFv7F9Cys) as a pharmacological treatment for METH abuse. ScFv’s have a short half-life due to their small size, limiting their clinical use. Thus, we examined the pharmacokinetic effects of conjugating poly(ethylene) glycol (-PEG) to scFv7F9Cys to extend its functional half-life. METHODS: The affinity of scFv7F9Cys and PEG conjugates to METH was determined in vitro via equilibrium dialysis saturation binding. Pharmacokinetic and parameters of scFv7F9Cys and scFv7F9Cys-PEG20K (30 mg/kg i.v. each) and their ability to bind METH in vivo were determined in male Sprague-Dawley rats receiving a subcutaneous infusion of METH (3.2 mg/kg/day). RESULTS: Of three PEGylated conjugates, scFv7F9Cys-PEG20K was determined the most viable therapeutic candidate. PEGylation of scFv7F9Cys did not alter METH binding functionality in vitro, and produced a 27-fold increase in the in vivo half-life of the antibody fragment. Furthermore, total METH serum concentrations increased following scFv7F9Cys or scFv7F9Cys-PEG20K administration, with scFv7F9Cys-PEG20K producing significantly longer changes in METH distribution than scFv7F9Cys. CONCLUSIONS: PEGylation of scFv7F9Cys significantly increase the functional half-life of scFv7F9Cys, suggesting it may be a long-lasting pharmacological treatment option for METH abuse