Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime--a population study in 25 elderly patients.

OBJECTIVE: To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients. METHODS: Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach. RESULTS: Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data. CONCLUSION: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

Comparisons between antimicrobial pharmacodynamic indices and bacterial killing as described by using the Zhi model.

Various suggestions have been made for empirical pharmacodynamic indices of antibiotic effectiveness, such as areas under the drug concentration-time curve in serum (AUC), AUC > MIC, AUC/MIC, area under the inhibitory curve (AUIC), AUC above MIC, and time above MIC (T > MIC). In addition, bacterial growth and killing models, such as the Zhi model, have been developed. The goal of the present study was to compare the empirical behavior of the Zhi model of bacterial growth and killing with the other empirical pharmacodynamic indices described above by using simulated clinical data analyzed with the USC*PACK PC clinical programs for adaptive control of drug therapy, with one model describing a concentration-dependent antibiotic (tobramycin) and another describing a concentration-independent antibiotic (ticarcillin). The computed relative number of CFU was plotted against each pharmacodynamic index, with each axis parameterized over time. We assumed that a good pharmacodynamic index should present a clear and continuous relationship between the time course of its values and the time course of the bacterial killing as seen with the Zhi model. Preliminary work showed that some pharmacodynamic indices were very similar. A good sensitivity to the change in the values of the MIC was shown for AUC/MIC and also for T > MIC. In addition, the time courses of some other pharmacodynamic indices were very similar. Since AUC/MIC is easily calculated and shows more sensitivity, it appeared to be the best of the indices mentioned above for the concentration-dependent drug, because it incorporated and used the MIC the best. T > MIC appeared to be the best index for a concentration-independent drug. We also propose a new composite index, weighted AUC (WAUC), which appears to be useful for both concentration-dependent and concentration-independent drugs.

Computer-aided prediction of macrolide antibiotic concentrations in human circulating polymorphonuclear leucocytes.

The relative in-vivo intracellular concentration of various macrolides in phagocytes cannot be directly extrapolated from in-vitro experiments that use a fixed and constant extracellular concentration for all compounds, since this fails to consider different rates of intracellular penetration, dosage regimens and pharmacokinetic data. In the proposed model, which takes into account the free plasma concentrations and accumulation characteristics of three antibiotics, roxithromycin, azithromycin and erythromycin, we show that roxithromycin and azithromycin may reach similar concentrations in human polymorphonuclear leucocytes when conditions mimic clinical administration of these drugs, while erythromycin concentrations are lower. This approach may be useful to predict the behaviour of other drugs or other cells, and to assist in the design of rational treatment schemes.

Superiority of home blood pressure measurements over office measurements for testing antihypertensive drugs.

OBJECTIVE: To compare the effects on office blood pressure and home blood pressure of placebo and active drug administration. DESIGN: After a 2-week wash-out period, patients with mild-to-moderate hypertension entered a 2-week single-blind placebo period and then a 4-week double-blind period. Patients were randomly assigned to be administered either 2 mg trandolapril once daily or its placebo in a 2:1 proportion. Office blood pressure was measured by a physician at the end of each period, using a mercury sphygmomanometer (mean of three consecutive measurements). Home blood pressure was measured during the last week of each period according to standard procedure carefully taught to each patient by the physician. Compliance was checked by using electronic pill boxes. RESULTS: Data for 34 of the 44 patients who entered the study were eligible for analysis. Baseline systolic blood pressure/diastolic blood pressure were significantly (P = 0.0001/P = 0.0001) higher for office blood pressure (161/101 mmHg) than they were for home blood pressure (145/93 mmHg). There was no statistically significant difference between the placebo and active-treatment groups at baseline. During the single-blind period, blood pressures measured at the office and at home did not change significantly. Office blood pressure decreased by 2.7 +/- 10 mmHg for systolic blood pressure and by 0.5 +/- 4 mmHg for diastolic blood pressure whereas home blood pressure increased by 0.8 +/- 6 mmHg for systolic blood pressure and by 0.7 +/- 4 mmHg for diastolic blood pressure. During the double-blind period, office blood pressure fell significantly with trandolapril treatment (systolic by 10.2 +/- 12 mmHg, diastolic by 8.3 +/- 6 mmHg; P = 0.0005/0.0001, versus single-blind placebo period) but this decrease was not significantly different (P = 0.45/0.92) from the fall in members of the placebo group (systolic by 6.9 +/- 9 mmHg, diastolic by 8.0 +/-6 mmHg; P = 0.04/0.002, versus single-blind placebo period). Thus, no antihypertensive effect of trandolapril was demonstrated. The fall lin home blood pressure with trandolapril treatment was significant (systolic by 10.7 +/- 8 mmHg, diastolic by 5.8 +/- 5 mmHg; both P = 0.0001, versus single-blind placebo period) and was significantly greater (P = 0.0004/0.004) than the minimal change observed with placebo (systolic fell by 0.2 +/- 5mmHg, diastolic fell by 0.6 +/- 4 mmHg; P = 0.90/0.62, respectively, versus single-blind placebo period). The evening decrease in home blood pressure was similar to the morning decrease in home blood pressure in members of the trandolapril-treated group. The resulting morning:evening decrease in blood pressure ratio was 0.83 for diastolic blood pressure and 0.95 for systolic blood pressure. For the subgroup of responders, mean of individual ratios was 0.77 +/- 0.43 for diastolic blood pressure and 0.70 +/- 0.39 for systolic blood pressure. CONCLUSION: The placebo effect observed with office blood pressure measurements does not occur with home blood pressure measurements. Expected treatment effect can alter a physician's blood pressure readings. The precision of measurements is greater with home blood pressure (there is a lower SD). Use of home blood pressure measurements increases the power of comparative trials, allowing one either to study fewer subjects or to detect a smaller difference in blood pressure.

Differential effects of a missed dose of trandolapril and enalapril on blood pressure control in hypertensive patients.

A double blind randomised comparison of two angiotensin-converting enzyme (ACE) inhibitors was made in a study in which ambulatory blood pressure was monitored over a steady-state dosage interval and the subsequent 24-h period, the latter being designed to mimic a missed dose of drug. The blood pressure responses on active therapy were compared to an identical recording made at the end of a 3-week placebo run in period. Eighty-eight essential hypertensives were treated with a morning dose of either trandolapril 2 mg or enalapril 20 mg. Mean systolic (SBP) and diastolic blood pressure (DBP) were calculated on each of the following periods: daytime (8:31 a.m.-10:30 p.m.), nighttime (10:31 p.m.-6:30 a.m.), and early morning (6:31 a.m.-8:30 a.m.). Trough/peak was calculated for each group both on active treatment and after a missed dose. Twelve patients were excluded from analysis before opening the randomisation code because of inadequate ambulatory blood pressure monitoring (ABPM) recordings. Demographic data, placebo-period office blood pressure, and ABPM recordings were not significantly different between the two groups. Both trandolapril and enalapril effectively reduced blood pressure over the 24-h period. Twenty four-hour ambulatory SBP and DBP decreased from 148 +/- 14/92 +/- 10 mm Hg to 135 +/- 14/83 +/- 10 mm Hg in the trandolapril group (p < 0.001). The same parameters decreased to a quite similar extent after enalapril, from 143 +/- 13/91 +/- 5 mm Hg to 133 +/- 15/83 +/- 8 mm Hg (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Placental penetration of cefpirome (HR 810): study of fetal concentrations after in vitro infusions of human placenta at term]. / Pénétration placentaire du cefpirome (HR 810): étude des concentrations foetales après perfusion in vitro de placenta humaine à terme.

Cefpirome (CPO) is a new parenteral cephalosporin with a wide antibacterial spectrum. In order to explore the possibility of using CPO in late pregnancy, we studied its placental transfer in vitro in a model of human placenta infusion. Mother-to-foetus in vitro transfer of CPO is high, similar to that of amoxicillin, with a placental clearance index of 0.20. A pharmacokinetic simulation based upon this result and data from literature suggests that CPO concentrations in foetal blood and amniotic fluid should be appropriate for the treatment of severe materno-foetal infections in late pregnancy. These preliminary results need to be confirmed by in vivo pharmacokinetic and clinical studies before recommending the use of CPO in late pregnancy.

Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers.

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t1/2 beta) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl tablets have an adequate in vivo dissolution profile.

Pooling plasmas for a rapid answer in pharmacokinetic studies: application to a bioequivalence study of hydrocortisone tablets.

Two methods of plasma pooling in pharmacokinetic studies are described. The first method allows the estimation of the average plasma profile of all subjects receiving a given dose or formulation, with at most as many assays as there are time points. The second method allows to estimate the individual AUCs of all subjects with only a single assay for each drug administration. These techniques were successfully employed to predict the final results of a bioequivalence study of two formulations of hydrocortisone 10 mg tablets. Plasma pooling methods can provide early partial information on the results of pharmacokinetic studies. They can be most useful in bioequivalence studies, where early estimates of the average curves and individual AUCs can lead to a decision not to proceed with all the assays, if bioequivalence appears unlikely. The pooling methods may also have useful potential applications in Phase I ascending dose-tolerance studies and in the field of pharmacokinetic studies in small animals. Further studies are necessary to test these methods in order to gain more information on their reliability in the decision-making process in these fields as well as in bioequivalence studies.

Transient inhibition of RU 486 antiglucocorticoid action by dexamethasone.

RU 486 antagonizes both progesterone and glucocorticoids at the receptor level. To study the duration of RU 486 antiglucocorticoid activity on corticotropic function and to establish the means of overcoming it with dexamethasone, plasma corticolipotropic hormones and cortisol were measured in 10 healthy male patients during the 3 days after intake, at 2200 h, of a single 400-mg dose of RU 486, alone or combined with a single dexamethasone dose (1, 2, or 4 mg) given at 2400 h. On the first day after RU 486 alone, ACTH, lipotropin, and cortisol plasma levels were significantly higher than basal values. The 1-mg dose of dexamethasone totally abolished the stimulatory effect of RU 486, and higher doses of dexamethasone (2 and 4 mg) further depressed hormone levels. During the succeeding days, antiglucocorticoid activity of RU 486 alone was still present 34 h after administration, while on the third day all hormone levels returned to normal. After the combined administration, the RU 486 effect reappeared as early as the first day with the 1-mg dose of dexamethasone, while it was delayed until the third day with the higher doses. These results showed that a single 400-mg dose of RU 486 induced a response that lasted at least 34 h. Thus, a dose-dependent competition between RU 486 and dexamethasone was demonstrated. However, the suppressive effect of dexamethasone was only transient, after which the antiglucocorticoid activity of RU 486 reappeared.

[Premedication using intrarectal midazolam. Study of effective dosage in pediatric anesthesia]. / Prémédication par le midazolam intrarectal. Recherche de la dose efficace en anesthésie pédiatrique.

The object of this study was to determine the optimal dose of midazolam given per rectum which would produce sedation adequate for inducing inhalational anaesthesia in paediatric practice. Five doses were studied: 0.15, 0.25, 0.30, 0.35 and 0.40 mg X kg-1. The criteria used to appreciate the effectiveness of the sedation at 30 min were the change in the child's behaviour, with a scale of 6 levels, and the acceptance of the mask and anaesthetic vapours. There was a significant correlation between the dose administered and the degree of sedation, as well as between the dose administered and the lack of reaction to the mask. Significantly better results were found with the higher doses of 0.35 and 0.40 mg X kg-1, when compared with the children who had received 0.15 and 0.25 mg X kg-1. Only in the groups who received 0.35 and 0.40 mg X kg-1 were the degrees of sedation and acceptance of induction considered as adequate. The dose of 0.35 mg X kg-1 seemed to be the best dose for adequately premedicating a child.