Pharmacogenetic screening and therapeutic drugs.

BACKGROUND: Pharmacogenetics is the science of the influence of heredity on pharmacological response. ISSUES: The cost of severe adverse drug reactions in individuals has been estimated in the US alone to be in excess of US$4 billion. It has been argued that in a significant proportion of cases, the efficacy and toxicity profiles of drug therapy would be substantially improved in individuals if characteristics due to genetic variation were taken into account. Methods are now available, which make screening for susceptibility feasible. CONCLUSIONS: There are several therapeutic areas in which screening may give rise to significant improvements in outcome with cost-benefits to both the individual and the community. However, there is currently a lack of data on which cost-benefit analysis can be based. The challenge is to provide this information for new drugs, and for drugs with established therapeutic roles.     

Serotonin-binding proteins in the bovine cerebral cortex: interaction with serotonin and catecholamines.

The soluble serotonin-binding proteins (SBP) present in bovine frontal cortex are very similar to those reported in rat brain. Binding of [3H]serotonin to SBP, present in ammonium sulphate-precipitated proteins from bovine cortex, requires Fe2+ but not Fe3+. In the presence of an optimal concentration of Fe2+ (0.1 mM), bovine SBP behave as a single class of non-cooperative sites for [3H]serotonin binding (Bmax = 120 +/- 12 pmol/mg protein, KD = 0.12 +/- 0.04 microM, n = 3). Binding of [3H]serotonin is decreased by nucleotides and by reagents which modify sulfhydryl groups and reduce disulfide bonds and by metal ion chelators. Serotonin analogs possessing an hydroxyl group on the indole ring and catecholamine analogs possessing an intact catechol moiety are effective competitors (Ki from 0.1 to 0.3 microM). In both cases, the aliphatic amino group does not contribute to the binding, but the affinity is strongly decreased if aromatic hydroxyl groups are methoxylated. Catecholamine-SBP interactions can also be demonstrated directly by binding experiments. Binding of [3H]dopamine is greatly enhanced by Fe2+, Cu2+ and Mn2+, but not by Fe3+. The Fe(2+)-dependent binding component of [3H]dopamine is saturable (Bmax = 279 +/- 64 pmol/mg protein, KD = 0.19 +/- 0.02 microM, n = 3), and possesses the same physicochemical properties as SBP: it elutes immediately after the void volume on a Sephacryl S100 HR (1.6 x 140 cm) gel filtration column (reflecting aggregation) and it migrates with an apparent molecular weight of 57-58 kDa on native polyacrylamide gel electrophoresis. Whereas the serotonin-storing role of SBP in serotonergic neurons has already been well documented, the present data advocate that these proteins may also possess catecholamine-storing properties.     

Phonological features of child African American English.

The production of phonological features of African American English (AAE) was examined for 64 typically developing African American children in the 2nd through the 5th grade. Students read aloud passages written in Standard American English. Sixty of the students read the passages using AAE, and 8 different phonological features were represented in their readings. Phonological features were more frequent than morphosyntactic features. The findings as a whole support use of the taxonomy developed for this investigation in characterizing the phonological features of child AAE.     

Pyridoxine Deficiency and Ethanol-induced Liver Injury

It has been suggested that pyridoxine deficiency may potentiate ethanol-induced liver injury. Our purpose was to clarify the effect of pyridoxine deficiency on ethanol-associated liver injury by comparing liver histology, serum liver enzymes, and the viability of cultured hepatocytes from pyridoxine-deficient and pyridoxine-sufficient rats that had been chronically fed ethanol-enriched diets. Our data fail to substantiate that pyridoxine-deficient animals are more susceptible to the hepatotoxic effects of ethanol than pair-fed pyridoxine-sufficient controls. Furthermore, the addition of pyridoxine to hepatocyte cultures fails to prevent in vitro cytotoxicity of added ethanol. Pyridoxine deficiency may augment ethanol-induced enhancement of hepatic urea synthesis. These data suggest that pyridoxine deficiency may contribute to the abnormal plasma amino acid profiles and nitrogen balance of chronic alcoholics, but that it does not potentiate ethanol-induced liver injury.     

Axonal transport of dopamine D1 receptors in the rat brain

Binding of a specific dopamine D₁ receptor antagonist,¹²⁵I-SCH 23982, was measured in rat brain sections by quantitative autoradiography at various time intervals, following a knife cut through the striatonigral pathway. Twenty-four hours after lesioning, accumulations of D₁ receptor binding sites were found in sagittal sections both rostral and caudal to the lesion site. No other regions studied (caudate-putamen, nucleus accumbens, olfactory tubercle, and substantia nigra pars reticulata) showed any change in D₁ receptor binding 24h after the lesion. In brain sections obtained 10 days after lesioning, only the substantia nigra pars reticulata had a significant decrease in D₁ receptors ipsilateral to the lesion. These findings suggest the possibility of a presence of bidirectional axonal transport of D₁ receptors in rat striatonigral pathway.     

Protein and fat utilization by humans as affected by calcium phosphate, calcium carbonate, and manganese gluconate supplements

The object of this study was to determine the effect of calcium carbonate or calcium phosphate supplements on dietary protein and fat utilization from low and high manganese diets. During the 63-day study, the 14 human adult subjects ate a constant laboratory controlled diet. In separate periods, subjects consumed the basal diet alone or with supplements of calcium carbonate, calcium carbonate plus manganese gluconate, calcium phosphate, or calcium phosphate plus manganese gluconate. Contrast analyses of data indicated that manganese gluconate supplementation of diets, when combined with either calcium phosphate or calcium carbonate, increased fecal losses of fat. When used as single supplements, both calcium phosphate and calcium carbonate depressed fecal fat loss in comparison with values when no supplements were used. Manganese gluconate supplements depressed fecal nitrogen losses calculated as a percentage of dry fecal weight.     

Genetic and environmental influences on cord blood serum IgE and on atopic sensitisation in infancy

It has recently been reported that cord blood serum IgE (CBsIgE) concentrations in a black Third-World cohort were significantly higher than those in a similar cohort of white and coloured newborns, and were not influenced by an atopic family history (aFH). This study reports on the 1-year follow-up of these newborns carried out to determine whether statistical differences in median CBsIgE values at birth could be found between infants in each ethnic group who subsequently developed clinical atopy in the first year of life and those who remained healthy. The infants were seen at 3, 7 and 12 months of age. At each visit a detailed history was taken from the mothers, the infants were examined clinically for the presence of atopic disease and blood was taken for immunological assay (total serum IgE by paper-disc radio-immunosorbent testing, and radio-allergosorbent testing for egg-white, cow's milk and Dermatophygoides pteronyssinus). A combination of clinical and immunological variables was assessed in order to categorise the infants into 'atopic' or 'not atopic' groups at the end of the 1-year follow-up period. The black infants who completed the study had the lowest incidence of aFH (16%), but 64% of them developed atopic disease during infancy. The median CBsIgE values for the black infants who became atopic were lower than, but not statistically different from, those for the group who remained non-atopic (P = 0.57). The white and coloured infants who completed the study had 81.6% and 30.4% incidences of aFH respectively, with 47.4% and 58.7% respectively developing atopic disease during infancy.(ABSTRACT TRUNCATED AT 250 WORDS)