A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs.

In vitro dose-response curves for anticancer agents are useful for predicting the clinical response to chemotherapy, and models to capture the time-dependency of dose-response curves are necessary for potential clinical extrapolation. Usually, the modified Hill model is used (see Levasseur et al., Cancer Res., 58: 5749-5761, 1998), although this model is neither mechanistic nor predictive for understanding how drug and tumor cell characteristics affect the shape of the dose-response curve. A new exponential kill (EK) model is proposed to predict the shape of dose-response curves based on the cell cycle phase specificity of a drug, the cell cycle time, the duration and concentration of drug exposure at the site of action, and a scaling factor for the level of drug resistance. Explicit analytical equations are presented for predicting the ICx (the concentration required to reduce cell growth by x%), the maximum cell kill achievable at high doses after a given duration of drug exposure, and the slope of the survival fraction versus log (concentration) plot at the ICx. Numerical solutions illustrate that there may be an optimal, finite duration of drug exposure that maximizes cell kill for a given area under the concentration versus time curve, and an analytical equation is given to calculate when such an optimal, finite duration exists. The EK model generates sigmoidal dose-response curves, like those seen empirically and previously described by the Hill model, which eventually plateau with increasing drug concentration at levels that depend on the cell cycle specificity of the drug, the cell cycle time, and the duration of exposure to the drug. This study includes no original data. Instead, empirical results in the literature are used to test the model. Because data by Levasseur et al. (1998) was fit to the Hill model assuming the plateau in the effect versus concentration curve to be independent of exposure duration, a full test of the model is not possible using their published data. Some tests of the EK model were possible, however, showing that EK model predictions yield good fits to in vitro data published in that and in another study. In addition, combining the EK model with a pharmacokinetic model resulted in predictions that were consistent with results of clinical studies comparing etoposide given in different schedules. Further tests of the model are necessary.

Consumer pressure, seed versus safe-site limitation, and plant population dynamics.

Plants often suffer reductions in fecundity due to insect herbivory. Whether this loss of seeds has population-level consequences is much debated and often unknown. For many plants, particularly those with long-lived seedbanks, it is frequently asserted that herbivores have minimal impacts on plant abundance because safe-site availability rather than absolute seed number determines the magnitude of future plant recruitment and hence population abundance. However, empirical tests of this assertion are generally lacking and the interplay between herbivory, spatio-temporal variability in seed- or safe-site-limited recruitment, and seedbank dynamics is likely to be complex. Here we use a stochastic simulation model to explore how changes in the spatial and temporal frequency of seed-limited recruitment, the strength of density-dependent seedling survival, and longevity of seeds in the soil influence the population response to herbivory. Model output reveals several surprising results. First, given a seedbank, herbivores can have substantial effects on mean population abundance even if recruitment is primarily safe-site-limited in either time or space. Second, increasing seedbank longevity increases the population effects of herbivory, because annual reductions in seed input due to herbivory are accumulated in the seedbank. Third, population impacts of herbivory are robust even in the face of moderately strong density-dependent seedling mortality. These results imply that the conditions under which herbivores influence plant population dynamics may be more widespread than heretofore expected. Experiments are now needed to test these predictions.

When can a clonal organism escape senescence?

Some clonal organisms may live for thousands of years and show no signs of senescence, while others consistently die after finite life spans. Using two models, we examined how stage-specific life-history rates of a clone's modules determine whether a genetic individual escapes senescence by replacing old modules with new ones. When the rates of clonal or sexual reproduction and survival of individual modules decline with age, clones are more likely to experience senescence. In addition, the models predict that there is a greater tendency to find senescence in terms of a decline in the rate of sexual reproduction with clone age than in terms of an increase in the probability of clone mortality, unless rates of sexual reproduction increase dramatically with module stage. Using a matrix model modified to represent the clonal lifestyle, we show how a trade-off between sexual and clonal reproduction could result in selection for or against clonal senescence. We also show that, in contrast to unitary organisms, the strength of selection on life-history traits can increase with the age of a clone even in a growing population, countering the evolution of senescence.

Development of a protocol for assessing time-weighted-average exposures of young children to power-frequency magnetic fields.

A study was carried out in 1990 to guide the development of a protocol for assessing residential exposures of children to time-weighted-average (TWA) power-frequency magnetic fields. The principal goal of this dosimetry study was to determine whether area (i.e., spot and/or 24 h) measurements of power-frequency magnetic fields in the residences and in the schools and daycare centers of 29 children (4 months through 8 years of age) could be used to predict their measured personal 24-h exposures. TWA personal exposures, measured with AMEX-3D meters worn by subjects, were approximately log-normally distributed with both residential and nonresidential geometric means of 0.10 microT (1.0 mG). Between-subjects variability in residential personal exposure levels (geometric standard deviation of 2.4) was substantially greater than that observed for nonresidential personal exposure levels (1.4). The correlation between log-transformed residential and total personal exposure levels was 0.97. Time-weighted averages of the magnetic fields measured in children's bedrooms, family rooms, living rooms, and kitchens were highly correlated with residential personal exposure levels (r = 0.90). In general, magnetic field levels measured in schools and daycare centers attended by subjects were smaller and less variable than measured residential fields and were only weakly correlated with measured nonresidential personal exposures. The final measurement protocol, which will be used in a large US study examining the relationship between childhood leukemia and exposure to magnetic fields, contains the following elements: normal- and low-power spot magnetic field measurements in bedrooms occupied by subjects during the 5 years prior to the date of diagnosis for cases or the corresponding date for controls; spot measurements under normal and low power-usage conditions at the centers of the kitchen and the family room; 24-h magnetic-field recordings near subjects' beds; and wire coding using the Wertheimer-Leeper method.

Stabilities of dobutamine, dopamine, nitroglycerin and sodium nitroprusside in disposable plastic syringes.

The solutions of dobutamine hydrochloride (5 mg/ml), dopamine hydrochloride (4 mg/ml), nitroglycerin (1 mg/ml) and sodium nitroprusside (1 mg/ml) in dextrose 5% injection were stable for 24 h when stored at 25 degrees C in 60-ml plastic syringes. For sodium nitroprusside, the syringes must be wrapped with aluminium foil (provided by the manufacturer), otherwise the loss in potency is very high (22%). There was no change in the pH values of dobutamine and dopamine solutions as well as sodium nitroprusside solutions in the prewrapped syringes. However, the pH value of nitroglycerin solutions decreased to 4.3 from 4.6 and that of sodium nitroprusside solutions in unwrapped syringes from 4.2 to 3.5; these solutions had discoloured. The chromatogram also showed new peaks from the products of decomposition. The physical appearances of the other solutions did not change.

Chemical stabilities of isoetharine hydrochloride, metaproterenol sulphate and terbutaline sulphate after mixing with normal saline for respiratory therapy.

The chemical stabilities of isoetharine hydrochloride inhalation solution, metaproterenol sulphate inhalation solution and terbutaline sulphate injection, after diluting 1 in 10 with sodium chloride 0.9% injection were studied. On storing the solutions in amber-coloured syringes, they were stable for at least 120 days at 5 degrees C. At 25 degrees C they were also stable for 120 days except that isoetharine solution discoloured and lost 7.8% of its potency after 90 days of storage. There was a new peak in the chromatogram from the decomposition product. All other solutions remained clear for 120 days at both temperatures. The initial and final pH values were similar except that after 120 days at both temperatures. The initial and final pH values were similar except that after 120 days at 25 degrees C, the pH value of terbutaline solution had increased from 4.9 to 5.4.

Chemical stability of thiopental sodium injection in disposable plastic syringes.

The chemical stability of thiopental sodium injection (2.5%) when stored at 25 degrees and 5 degrees in disposable plastic syringes of two manufacturers (Monoject and Becton Dickenson and Co.) has been studied using the USP-NF method. The injection appeared to be stable for five days at 25 degrees and 45 days at 5 degrees with a loss in potency of less than 7%. The thiopental sodium did not adsorb on the syringes. The pH values and the physical appearance did not change. An additional peak was obtained in the chromatogram from both the freshly prepared and the assay solution probably due to an impurity in the powder.