Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Novel strategies for assessing and managing the risks posed by invasive alien species to global crop production and biodiversity

International actions to combat the threat posed by invasive alien species (IAS) to crops and biodiversity have intensified in recent years. The formulation of 15 guiding principles on IAS by the Convention on Biological Diversity (CBD) stimulated the International Plant Protection Convention (IPPC) to review its role in protecting biodiversity. IPPC standards now demonstrate clearly that the risks posed by any organism that is directly or indirectly injurious to cultivated or uncultivated plants can be assessed and managed under the IPPC. Since the IPPC, unlike the CBD, constitutes an international legal instrument recognised by the World Trade Organization, greater protection from the introduction of IAS is now available. However, phytosanitary measures can only be enacted if they can be justified by risk analysis and we outline some novel strategies to improve the assessment and management of the risks posed by IAS, highlighting some of the key challenges which remain.     

Effects of the level of early productivity on the lifespan of ewes in contrasting flock environments

Selection for high levels of prolificacy has allowed substantial improvements in the production efficiency of New Zealand (NZ) sheep farms, but the consequences on ewe lifetime performance are mostly unknown. In this study, the relationship between the level of prolificacy early in ewes’ productive lives and their probability to survive later (i.e. stayability) was evaluated in two contrasting NZ flock environments. Records were obtained from 6605 ewes from four ram breeder flocks representing either a moderate (n=2) or a highly variable (n=2) nutritional environment. All ewes lambed for the first time at 2 years of age and were mated the following year. The number of lambs born during the first 2 years of productive life (NLB_2–3) was used as a measure of early prolificacy. Effects of NLB_2–3 on stayability to 4, 5, 6, 7 and 8 years old were analysed using logistic regression. Curvilinear effects (logit-transformed) were detected (P<0.05) until stayability to 6 years and to 8 years old in the highly variable and the moderate environment, respectively. The NLB_2–3 that resulted in maximum expected stayability to various ages was 3.9 to 4.2, and 4.5 to 4.7 lambs in the highly variable and in the moderate flock environments, respectively. In addition, ewe stayability was reduced when the proportion of the litter that survived from birth to weaning (i.e. ewe rearing ability) was submaximal during the early productive life. High prolific ewes had a low rearing ability whatever the environment whereas the rearing ability of lowly prolific ewes was apparently more sensitive to the nutritional environment. The poor maternal performance of ewes with low levels of NLB_2–3 led to a premature culling by breeders whereas the high early reproductive effort associated with high levels of NLB_2–3 seemed to be at the cost of ewes’ survival, even in the moderate flock environment. In conclusion, the flock environment influenced the level of early prolificacy beyond which ewe longevity was reduced. It is suggested that further selection for high and early prolificacy in NZ flocks is likely to impair ewes’ lifetime productivity.     

Altered fatty acid composition in regulatory mutants of Streptomyces cinnamonensis

Abstract cDNA-RNA liquid hybridization analysis was used to compare the RNA sequence homology between two members of the Nudaurelia β virus family, Trichoplusia ni virus ( T.ni V) and Dasychira pudibunda virus ( D.p V). Heterologous hybridization experiments demonstrated that these viruses shared little sequence homology. Using oligo(dT) chromatography and oligo(dT)_12–18 as a primer for cDNA synthesis it was shown that neither T.ni V nor D.p V RNA genomes possess a poly(A) tract at the 3' end.     

Quantitative study of natural antioxidant systems for cellular nitrofurantoin toxicity

The toxicity of nitrofurantoin was studied on human WI-38 fibroblasts: this chemical was lethal when added at concentrations higher than 5·10⁻⁵ M in the culture medium. The protection afforded by anitoxidants was then tested: α-tocopherol gave at 10⁻⁴ M a light protection in contrast to ascorbic acid which even became toxic at high concentrations. We also tested catalase, superoxide dismutase and glutathione peroxidase introduced intracellularly by the microinjection technique. On a molecular basis, glutathione peroxidase was 23-times more efficient than catalase and 3000-times more than superoxide dismutase. The results also showed that a similar range of enzyme concentrations was found for the protection against high oxygen pressure. This suggests that, in the case of both oxygen and nitrofurantoin toxicity, the peroxide derivatives are the most toxic intermediates of the free radical attacks.     

The application of a potential-sensitive cyanine dye to rat small intestinal brush border membrane vesicles

The sensitivity of the fluorescent dye, 3,3′-diethylthiadicarbocyanine (DiS-C₂(5)), was too low for the detection of membrane potential changes in rat small intestinal membrane vesicles. Only after adding LaCl₃ or after fractionation of the intestinal membranes by free-flow electrophoresis could the dye be used to monitor electrogenic Na⁺-dependent transport systems. It is concluded that the response of this potential-sensitive dye is influenced by the negative surface charge density of the vesicles.