No abstract

The influence of age, sex, and smoking on theophylline disposition was studied in 38 healthy subjects ranging in age from 26 to 81 yr. There were 8 young (less than 60 yr) and 30 geriatric (greater than 60 yr) subjects, including 28 men (8 smokers) and 10 women (3 smokers). A crossover experimental design was used. A single dose of theophylline elixir (5 mg/kg lean body weight [LBW]) was given as a reference product to all subjects. One week later a sustained-release (SR) theophylline tablet (8 and 6 mg/kg LBW) was given to the young and the geriatric subjects. Serum theophylline concentrations were determined by HPLC. Theophylline elimination (t1/2 beta) is shorter in the geriatric group (6.93 and 8.14 hr); total body theophylline clearance is greater in the geriatric group (44.39 and 32.97 ml/kg/hr), and the apparent volume of distribution is also greater in the geriatric group (26.29 and 22.97 l). Sex and smoking did not influence any of the parameters studied. In 93% of the geriatric subjects, serum theophylline levels of 8 to 20 micrograms/ml were reached at steady state with the SR tablet. Theophylline dose reduction based on an arbitrary age limit is not, therefore, invariably indicated.

Divergent selection for pentobarbital sedation-time response was practiced in mice for 9 generations. At the end of 9 generations of selection, the long-sedation-time line (LST) slept an average of 433 min; the short sedation time line (SST) slept an average of 29 min. The control line (C) slept an average of 71 min. These differences represent an almost 15-fold increase in sedation time for the LST compared to the SST line and a 6-fold increase compared to the C line. The SST line slept about 40% less than the C line after 9 generations of selection (measured in tenth generation progeny). Analysis of selection differentials and realized heritabilities indicated that selection response did not diminish after 9 generations of selection. Realized heritabilities for sedation time ranged from 0.43 to 0.83 for the LST line and from 0.55 to 0.81 for the SST line. Realized heritabilities did not decrease in magnitude due to selection progress, indicating that more progress can still be achieved. Comparing corrected (for environmental factors) to uncorrected heritabilities showed the importance of including a control line in selection experiments. Crossing of lines to study gene action responsible for this trait revealed that this trait was controlled by a number of genes with additive gene action without dominance, overdominance, epistasis, or maternal effects.