A microcomputer program to determine the precision of elimination rate constant and half-life estimates when sampling time is short.

First-order elimination of drugs is often assumed in pharmacokinetics and elimination rate constant is then frequently determined by log-linear regression analysis from plasma concentration measurements. When the time which elapses between the first and the last plasma sample is short compared to the decay half-life, the elimination rate constant may not be determined with satisfactory precision, in particular because of analytical error. Application of basic principles of linear regression analysis allowed us to quantify the theoretical effect of analytical error on the determination of the drug elimination rate constant in that situation. It was highlighted that the precision of that determination could be efficiently improved by measuring samples in replicate, which should be recommended in practice. A user-friendly program was developed which can be used prospectively to optimize sampling strategy, and retrospectively to estimate the precision of parameter estimates. The program works on IBM PC and compatible microcomputers and is available on request.

Rehabilitation after amputation for vascular disease: a follow-up study.

Rehabilitation of one hundred and twenty eight patients with lower limb amputation performed for vascular disease from 1979 to 1987 was assessed. Arteriosclerotic occlusive disease was the most frequent cause of amputation (85.9%). Sixty seven patients (52.3%) were diabetic. Early and late results were analysed. For long-term follow-up evaluation, Univariate method of Kaplan-Meyer product limit was employed. Multifactorial analysis was used to assess factors influencing mortality. On immediate evaluation of rehabilitation with a prosthesis 85.2% of patients were successfully fitted. On long term evaluation 47.8% of below-knee and 22.1% of above-knee amputees were alive and using the prosthesis full time at five years of follow-up (p = 0.0026). Opposite limb preservation at five years was 69.5% for diabetics and 90.2% for non-diabetics, respectively (p = 0.0013). Survival rate at five years was 42.4% for diabetics, and 85.0% for non-diabetics (p = 0.0002). On multifactorial analysis diabetic patients showed a risk of late mortality six times greater than non-diabetics. In conclusion rehabilitation after vascular amputation is feasible in a large number of patients, despite a limited life span. Diabetes represents a major risk factor both for life and for the opposite limb. Knee preservation is an important factor for better rehabilitation.

Theoretical model for both saturable rate and extent of absorption: simulations of cefatrizine data.

A pharmacokinetic model incorporating saturable rate of absorption of the Michaelis-Menten type was recently developed to fit cefatrizine (CFZ) plasma concentrations with time following oral administration of 500-mg capsules to humans. This model (MM) was statistically superior to models incorporating either first-order or zero-order absorption. However, the MM model does not predict the reduction in extent of absorption with dose observed in vivo. In this study, a model is proposed in which a time constraint, delta t, is added to the MM model. This new model (MM-delta t) is tested with data following doses of 250, 500, and 1000 mg of CFZ. When delta t is set to 1.5 hr, the predicted relative changes with dose in bioavailability, F, peak plasma concentration, Cmax, the time at which the peak concentration occurs tmax, and the mean absorption time, MAT, are generally in good agreement with the experimental data. The time interval of 1.5 hr is compatible with passage by a limited region within the small intestine where drug is absorbed by a facilitated transport mechanism. Influence of each absorption model parameter (Vmax, Km, and delta t) on total area under the concentration versus time curve (AUC), F, Cmax, and tmax, is assessed by simulation. The MM-delta t model is able to summarize the nonlinerity observed in both rate and extent of absorption.

Saturable rate of cefatrizine absorption after oral administration to humans.

This study examined the absorption kinetics of cefatrizine, an amino-beta-lactam antibiotic, after oral administration of a single 500-mg dose to 12 healthy volunteers. Plasma concentrations were determined by high performance liquid chromatography. The plots of the percentage of drug unabsorbed and the apparent rate of cefatrizine absorption as a function of time showed, first, a delay and, then, an almost constant rate of absorption with a tendency to move toward first-order kinetics at the end of the process. Three compartmental models incorporating a lag time and first-order elimination kinetics, but differing in their input rate, were used for analysis of the time course of cefatrizine plasma concentrations. The model with first-order absorption kinetics was clearly inadequate. The results were improved with the model for which the rate of absorption is constant, but a model incorporating saturable absorption kinetics of the Michaelis-Menten type improved the fit further. This last model was statistically superior to the constant-rate input model in 6 out of 12 subjects, according to the likelihood-ratio method. Because of the innovative feature of the model incorporating the Michaelis-Menten equation, simulations of the effect of altering the model parameters and the dose administered on the concentration-time profile, were performed. Different hypotheses which might explain why cefatrizine absorption kinetics fits the Michaelis-Menten equation were examined. The observation of saturable absorption kinetics is consistent with a carrier-mediated transport previously reported to occur in the gastrointestinal tract of rats.