Apparent kinetic parameters Vmax and KM have been measured for the oxidative N-demethylation of twelve para-substituted N, N-dimethylanilines catalysed by rat liver microsomes. Vmax was enhanced by pretreatment of the rats with phenobarbital, whereas pretreatment with beta-naphthoflavone gave no appreciable enhancement. In the case of phenobarbital pretreatment the kinetic parameters could be expressed in terms of lipophilic and electronic effect of the substituents. Kinetic parameters from control and beta-naphthoflavone microsomes gave no statistically meaningful correlation.
The kinetics of fenfluramine isomers were studied in the rat following oral doses of racemic fenfluramine. The data, analyzed using an analogue computer, indicate that the d-fenfluramine is metabolised and excreted at a slower rate than the 1-isomer, resulting in higher plasma and brain concentrations. The kinetic parameters of both isomers were dose-dependent. The rates of disappearance decreased as the dose was raised. The increase in brain area under the curves (AUC) was much greater than the increase of the dose. These findings suggested the rat has a limited capacity for disposition of fenfluramine.
The chemotherapeutic effects of different doses of adriamycin in (C3H × 020)F1 mice bearing mammary carcinoma have been investigated and a model of the growth of neoplastic cells under the influence of treatment is described. An estimate of cell kill and of the fraction of cells surviving after treatment is given by the efficacy constant K, which is a function of the dose level of the drug. The therapeutic value of each treatment is, however, also related to the degree of toxicity which in our model is expressed by the probability of death for each dose level.
Walker 256 carcinoma was transplanted subcutaneously to 6-week-old male CD-COBS rats. Percutaneous diameters of the growing tumoral mass were measured daily. Groups of 4–10 animals selected at random were killed at established intervals, and tumoral tissue was isolated and weighed. Tumor weight was correlated with its percutaneous diameters. The overall growth of Walker 256 carcinoma was simulated by several mathematical models: linear approach, Gompertz equation, and a new model based on changes in blood supply to growing tumoral tissue were considered.
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