The effects of age and gender on the single dose pharmacokinetics of avitriptan administered to healthy volunteers

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150-mg capsule after a 10-hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N-desmethyl avitriptan (ND048), O-desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP). Urine samples were analyzed for only avitriptan and MPP. Avitriptan was well tolerated in all four groups. The drug was rapidly absorbed with a median time to maximum plasma concentration (tmax) between 0.5 and 1.5 hours. No significant gender-related differences were found in the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC0-infinity) of avitriptan. Renal clearance of avitriptan was significantly smaller in young women compared with young men, but this is clinically not relevant because only 2% to 3% of the total dose is excreted unchanged. Compared with the young volunteers, mean Cmax was approximately 50% higher in the elderly but there was no difference in the AUC0-infinity between the 2 age groups. Plasma concentrations of ND048, OD048, and MPP were each 50 to 100 fold lower than those of avitriptan. Hence some age- and gender-related differences found in the pharmacokinetics of avitriptan metabolites are probably not relevant in the assessment of overall safety and efficacy of avitriptan. Based on the pharmacokinetics and tolerability, no age or gender-related dose adjustment is necessary for avitriptan.     

Effects of prenatal cocaine exposure on embryonic expression of sonic hedgehog

PURPOSE: To estimate the impact of visual impairment in older Australians on the use of community support services. METHODS: In the Blue Mountains Eye Study, 3654 people aged 49 or older were examined- 82.4% of eligible residents in an area west of Sydney, Australia. Presenting and best-corrected visual acuities were measured using a LogMAR chart. Subjects were categorized as having visual impairment if their better eye read 40 or fewer letters (20/40 or worse). Interview data included marital and other socioeconomic status measures, living status (alone or with spouse or other person), use of community support services, reliance on regular help from nonspouse family members or friends, and perceived ability to go out alone. RESULTS: After adjusting for age, gender, education, living status, walking disability, and health-related factors, for each one-line (five-letter) decrease in best-corrected visual acuity, there was a corresponding increase in reliance on community support services (odds ratio [OR], 1.17; 95% confidence interval, [CI] 1.07-1.28) or combined community and family support (OR 1.22; 95% CI, 1.12-1.32). Visually impaired persons were three times as likely to use regular support services provided by the municipality (OR 3.1; 95% CI, 1.8-5.1). A similar increased reliance on regular help from community, nonspouse family members, or friends was found. Visually impaired persons were also much more likely to state that they thought they were unable to go out alone (OR 6.2; 95% CI, 2.6-14.3). The findings were similar when presenting visual acuity was used to define visual impairment or after subjects with walking disabilities were excluded. Visual impairment seemed to have a greater effect on use of community support services in women than in men. CONCLUSIONS: After adjustment was made for confounding factors, visual impairment was found to affect significantly and negatively the independence of elderly people, particularly older women. Presenting visual acuity closely approximated best-corrected visual acuity in its impact on the use of community support services.     

Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro as a possible mechanism for oral submucous fibrosis

Oral submucous fibrosis (OSF), a chronic oral mucosal condition commonly found in south Asians, is a disorder characterized by a quantitative as well as a qualitative alteration of collagen deposition within the subepithelial layer of the oral mucosa. Since degradation of collagen by fibroblast phagocytosis is an important pathway for physiological remodelling of soft connective tissues, we have investigated phagocytosis of collagen- and fibronectin-coated latex beads by fibroblast cultures with an in vitro model system. Coated fluorescent latex beads were incubated with human oral mucosa fibroblasts and the fluorescence associated with internalized beads was measured by flow cytometry. Cells from normal tissues that had been incubated with beads for 16 h contained a mean of 75% collagen phagocytic cells and 70% fibronectin phagocytic cells; however, about 15% and 10% of phagocytic cells individually contained more than twice the mean number of beads per cell. In contrast, cells from OSF tissues exhibited a 40% reduction of the proportions of collagen phagocytic cells (mean=35%) and a 48% decrease of the proportions of fibronectin phagocytic cells (mean=22%), none of the cells having a high number of beads as compared to normal fibroblasts. OSF lesions appear to contain fibroblasts with marked deficiencies in collagen and fibronectin phagocytosis. To investigate if inhibition of phagocytosis could be demonstrated in vitro, normal fibroblast cultures were incubated with areca nut alkaloids (arecoline, arecaidine). The cultures had a dose-dependent reduction in the proportions of phagocytic cells. On the other hand, corticosteroid used in the treatment of OSF exhibited a dose-dependent enhancement in the proportion of phagocytic cells. Therefore, our hypothesis for OSF, although oversimplified, is that betel nut alkaloids (arecoline, arecaidine) inhibit fibroblast phagocytosis and this provides a mechanism for the development of OSF. The benefit of a local intralesional injection of corticosteroid is also possibly, at least in part, through an enhancement of fibroblast collagen phagocytosis.     

One protein, two enzymes

Two enzymes, designated, E-2 and E-2', catalyze different oxidation reactions of an aci-reductone intermediate in the methionine salvage pathway. E-2 and E-2', overproduced in Escherichia coli from the same gene, have the same protein component. E-2 and E-2' are separable on an anion exchange column or a hydrophobic column. Their distinct catalytic and chromatographic properties result from binding different metals. The apo-enzyme, obtained after metal is removed from either enzyme, is catalytically inactive. Addition of Ni2+ or Co2+ to the apo-protein yields E-2 activity. E-2' activity is obtained when Fe2+ is added. Production in intact E. coli of E-2 and E-2' depends on the availability of the corresponding metals. These observations suggest that the metal component dictates reaction specificity.     

Paradigms in obstetric nursing]

Recent finding suggest that many fetuses have to adapt to a limited supply of nutrients and in doing so they permanently change their physiology and metabolism. These 'programmed' changes may be the origins of a number of diseases in life, including coronary heart disease and the related disorders stroke, diabetes and hypertension.