Biomedical subjects

M O Karlsson

Publications and source records attributed to M O Karlsson.

At least 19 recordsLinked to original sources

PubMed1999

Lactational exposure and neonatal kinetics of methylmercury and inorganic mercury in mice.

The concentration of mercury in milk and the distribution pattern in the sucking pup was followed over time after administration of a single iv injection of 0.5 mg/kg body wt of 203Hg-labeled methylmercuric chloride or mercuric chloride to lactating mice on Day 10 of lactation. Mercury concentrations in milk of the dams and in whole body, blood, plasma, GI-tract, liver, kidneys, and brain of the offspring were followed up to 11 days after dosing (until lactational Day 21). Following the inorganic mercury dose to the dams, most of the mercury in milk was delivered to the pups during the first 24 h, but the maximum mercury concentration in plasma and tissues of pups was not reached until 7 days after dosing, indicating a prolonged absorption of inorganic mercury in the sucking pup. Pups of dams given methylmercury were exposed to a much lower and constant mercury concentration in milk. The estimated accumulated mercury dose via milk per pup of dams given methylmercury was less than half of that estimated after the inorganic mercury dose. When the accumulated dose via milk from methylmercury-exposed dams was compared to the amount of mercury in pup's carcass (whole body minus GI-tract including content), it was revealed that almost all mercury delivered via milk was absorbed, and that the suckling pups had a very low elimination of mercury until lactational Day 17. Lactational exposure following a maternal methylmercury or inorganic mercury dose resulted in almost similar mercury concentrations in liver, kidneys, and plasma of the suckling, but higher concentrations in brain (as most 14 times) and also twice as high mercury body burden in the methylmercury group. Thus, differences in kinetics indicate that lactational exposure of methylmercury is a greater hazard for the breast-fed infant than inorganic mercury.

Animals↗

PubMed1999

Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM.

The building of population pharmacokinetic/pharmacodynamic (PK/PD) models is a time consuming and complicated task. This is partly due the lack of specialized tools for the visualization and exploration requirements of this type of analysis. In this paper we present Xpose, a model building aid for population PK/PD analysis using NONMEM, which simplifies the task of producing documentation, data set checkout plots, goodness of fit plots and graphical model comparison. It also facilitates covariate model building by the use of stepwise generalized additive modeling (GAM), bootstrap of the GAM analyses and tree based modeling. The plots and analyses are presented in the form of a text based menu system and the only thing the user has to do is to make NONMEM produce one or more table files named in a specific way.

Computer Simulation↗

PubMed1999

Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.

5-alpha Reductase Inhibitors↗

PubMed1999

The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination.

AIMS: To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules. METHODS: In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined. RESULTS: The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%). CONCLUSIONS: G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.

Adult↗

PubMed1999

Interchangeability and predictive performance of empirical tolerance models.

Models of tolerance are commonly derived on empirical grounds, because of lack of knowledge about the mechanism of tolerance or because of the difficulty of appropriately simplifying complex physiological processes. The present study was performed to evaluate the interchangeability of tolerance models used in the literature and to address some determinants for selection of an appropriate design and data analysis strategy. Seven models were chosen (noncompetitive antagonist model, partial agonist model, reverse agonist model, direct moderator model, indirect moderator model, pool model and adaptive pool model) along with their corresponding parameter estimates, representing a wide range of empirical models. The performance of the models on various data sets was evaluated. Data were simulated from each original model and were further analysed by the other models. The effect-time course of each and every data set could be described well by at least 2 different empirical tolerance models, but no model could describe all the data sets adequately. However, all models could adequately describe at least 2 different data sets. This indicates that, without additional knowledge or assumptions, it is unlikely that reliable mechanistic information can be deduced from the mere fact that 1 (or more) of these models can describe the data. Generally, data expressing only limited tolerance can be described by a wide variety of models, whereas few models will be appropriate for data characterised by extensive tolerance. The models that gave an adequate description of a data set were selected for further study that investigated their predictive capacity based on the parameters previously determined. Predictions were made for 4 different administration schemes. The selected models gave similar predictions for the extended designs of 3 data sets for which the original study designs characterised tolerance well. For the other 4 data sets, the selected models gave disparate predictions, although the models described the original data set well. Thus, the predictive capability of a model was linked to the original study design, whereas the correlation between predictive performance and the type of model was weak or absent. Based on the results, factors of importance for the design and evaluation of studies of tolerance were identified and discussed.

Animals↗

PubMed1999

Mechanism-based modeling of rebound tachycardia after chronic l-propranolol infusion in spontaneous hypertensive rats.

The aims of the study were to characterize the rate and extent of the rebound effect after abrupt cessation of a chronic exposure of l-propranolol in spontaneous hypertensive rats, using exercise-induced tachycardia as a pharmacodynamic endpoint. Thirty-two spontaneous hypertensive rats were randomized to receive either placebo or 4 or 8 mg/kg/day s.c. infusion of l-propranolol for 11 days using osmotic minipumps. The heart rate was measured after standardized physical exercise before and during drug exposure and over 12 days after cessation, using a computerized tail-cuff method. Blood samples were collected after each effect measurement during the infusion. A similar reduction in exercise tachycardia was registered for the two doses. No apparent tolerance development was found, but both doses showed a clear rebound effect of similar extent and intensity. The maximal rebound effect was observed on the second day after cessation and was found to have a duration of about 6 days. A mechanism-based model was developed to describe the rate and extent of changes in beta-adrenoceptor up- and down-regulation with increased sensitivity of the transducer complex. The half-life of disappearance of up-regulated beta-adrenoceptors was estimated to be 2.0 days (1.0-3.9 days). The effect-versus-time data was analyzed by nonlinear mixed-effect modeling with the program NONMEM. A dose-dependent reduction in the growth of body weight was observed during drug treatment, which was reversible. A dose- and time-dependent increase in the alpha(1)-acid glycoprotein concentration was also observed.

Adrenergic beta-Antagonists↗

PubMed1998

Kinetics of methylmercury and inorganic mercury in lactating and nonlactating mice.

The elimination of mercury was followed for 9 days (Days 10-19 of lactation) in milk and/or 21 days in blood and plasma of lactating and nonlactating mice administered a single iv injection of either 203Hg-labeled methylmercuric chloride or 203Hg-labeled mercuric chloride (0.5 mg Hg/kg body wt). Demethylation of methylmercury to inorganic mercury was taken into consideration by analyzing the data with a combined pharmacokinetic model based on the assumption of constant blood plasma ratios for methylmercury and inorganic mercury. A three-compartment model fitted the blood and plasma concentrations vs time profiles for both compounds. Plasma clearance and volume of distribution at steady state for methylmercury were 95. 3 ml/h/kg and 18,500 ml/kg, respectively, in lactating mice, and significantly higher than in nonlactating mice with values of 47.1 ml/h/kg and 9400 ml/kg, respectively. The terminal half-lives of methylmercury in plasma were similar, 170 h in lactating and 158 h in nonlactating mice. No differences were observed between the pharmacokinetic parameters in lactating and nonlactating mice administered inorganic mercury. The lactational transfer of mercury was more efficient following administration of inorganic mercury than after administration of methylmercury, with a five times higher peak concentration in milk, higher milk:plasma concentration ratios, and 8% of the administered dose excreted in milk compared with 4% for methylmercury. Mercury concentrations in milk following an iv dose of inorganic mercury decreased with a terminal half-life of 107 h, whereas after administration of methylmercury, the concentration of total mercury in milk remained at an almost constant level during the whole period of investigation. There was a nonlinear relationship between mercury in milk and plasma following inorganic mercury administration. It is suggested that inorganic mercury enters the mammary gland by a carrier-mediated transport system, which is saturated at high plasma levels of inorganic mercury. The present study shows that physiological changes during lactation alter the pharmacokinetics for methylmercury in mice but not for inorganic mercury.

Animals↗

PubMed1998

Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone.

OBJECTIVE: To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone. METHODS: Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. RESULTS: A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. CONCLUSIONS: A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.

Aged↗

PubMed1998

Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements.

OBJECTIVES: To develop a model for 24-hour ambulatory blood pressure measurements (ABPM) that can be applied in a pharmacokinetic-pharmacodynamic model. METHODS: Four different data sets were prepared from 2 studies to accommodate different modeling strategies. In study A, a double-blind placebo-controlled study in 47 patients, 24-hour ABPM profiles (74 to 99 measurements per profile) were obtained during the placebo run-in phase and after 3, 5, and 11 weeks during the treatment. Three to 5 plasma samples were taken. Cosine and polynomial models were evaluated to describe the circadian rhythm in blood pressure based on 3 data sets (1: only run-in data; 2: only placebo data; 3: all data). In study B, a double-blind placebo-controlled study in 94 patients, two 24-hour ABPM profiles per patient (during placebo run-in and after 8 weeks) were recorded and randomly reduced to 15 measurements per profile to evaluate the robustness of the baseline model. RESULTS: The mean moxonidine clearance was 35 L/h, and the volume of distribution was 132 L. The final baseline model consisted of 2 cosine terms with fixed-effect parameters for rhythm-adjusted 24-hour mean blood pressure, amplitude, phase, and period; random-effect parameters for interindividual variability in rhythm-adjusted 24-hour mean, amplitude, and clock time; and interoccasion variability in rhythm-adjusted 24-hour mean and clock time. The final baseline model was combined with an Emax model for the drug effect. An effect compartment was used (kco = 0.198 h-1). The maximum decrease in diastolic blood pressure (Emax) was 16.7%, and EC50 was 0.945 microgram/L. CONCLUSION: The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.

Aged↗

PubMed1998

A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.

OBJECTIVE: To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor. METHODS: Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program. RESULTS: The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2. CONCLUSIONS: A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.

5-alpha Reductase Inhibitors↗

PubMed1998

A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosuppression.

BACKGROUND: Hematologic toxicity after cancer chemotherapy and other drug effects that occur late compared to the exposure are usually modeled with use of some summary exposure variable such as the area under the concentration-time curve (AUC model) or the time of exposure above a threshold concentration (threshold model). An underlying assumption for both of these models is that the drug exerts a direct effect while present in the body and that it is the time integral of this direct effect that is related to the ultimate observed effect, either linearly (AUC model) or by a step function (threshold model). We propose a more general model that allows this relationship to be characterized by a nonlinear continuous function. METHODS: Data on survival fraction of neutrophiles and time course of leukopenia from 92 courses of paclitaxel therapy in 21 patients with breast or ovarian cancer was related to paclitaxel concentration-time profiles with the AUC, threshold, and general models. The properties of the general model were also investigated with use of simulations. RESULTS: For both pharmacodynamic end points, the general model described the data significantly better than the AUC or threshold models. CONCLUSION: The general model is an extension to the present way of relating concentration-time profiles to late-effect measures, and it may provide an improved description of the concentration-response relationship and more accurate predictions of the ultimate effect when doses and schedules are varied. It can explain complex relationships between concentration-time profiles and the observed effect, and predictions from it lack some of the counterintuitive properties that the AUC or threshold model have when extrapolations are made.

Antineoplastic Agents, Phytogenic↗

PubMed1998

Early systolic mitral leaflet "loitering" during acute ischemic mitral regurgitation.

BACKGROUND: The mechanism by which incomplete mitral leaflet coaptation develops during ischemic mitral regurgitation is debated, with recent studies suggesting that incomplete mitral leaflet coaptation may be due to apically displaced papillary muscle tips. Yet quantitative in vivo three-dimensional mitral leaflet motion during ischemic mitral regurgitation has never been described. METHODS: Radiopaque markers (sutured around the mitral anulus, to the central free mitral leaflet edges, and to both papillary muscle tips and bases) were imaged with the use of biplane videofluoroscopy in six closed-chest, sedated sheep before (control) and during induction of acute ischemic mitral regurgitation. Leaflet coaptation was defined as the minimum distance measured between edge markers during control conditions. RESULTS: During control, leaflet coaptation occurred 23 +/- 7 msec (mean +/- standard error of the mean) after end-diastole, when left ventricular pressure was 27 +/- 6 mm Hg. During ischemic mitral regurgitation, coaptation was delayed to 115 +/- 19 msec after end-diastole (p < or = 0.01 vs control [n = 4]) when left ventricular pressure was 88 +/- 4 mm Hg. At end-diastole during ischemic mitral regurgitation, the mitral anulus area was 14% +/- 2% larger than control (7.4 +/- 0.3 cm2 vs 6.5 +/- 0.2 cm2, p < or = 0.005) as the result of the lengthening of muscular annular regions (76.0 +/- 2.5 mm vs 70.5 +/- 1.4 mm, p < or = 0.01). Mitral anulus shape (ratio of two diameters) at end-diastole was more circular during ischemic mitral regurgitation (0.79 +/- 0.01 vs 0.71 +/- 0.02, p < 0.01). At end-diastole during ischemic mitral regurgitation, the posterior papillary muscle tip was displaced 1.5 +/- 0.5 mm laterally and 2.0 +/- 0.6 mm posteriorly (p < or = 0.02 vs control), but there was no apical displacement of either papillary muscle tip. CONCLUSIONS: Incomplete mitral leaflet coaptation during acute ischemic mitral regurgitation occurred early in systole, not at end-systole, and was due to "loitering" of the leaflets associated with posterior mitral anulus enlargement and circularization, as well as some posterolateral, but not apical, posterior papillary muscle tip displacement. These data suggest that early systolic mitral anulus dilatation and shape change and altered posterior papillary muscle motion are the primary mechanisms by which incomplete mitral leaflet coaptation occurs during acute ischemic mitral regurgitation.

Acute Disease↗

PubMed1998

Morphine-3-glucuronide has a minor effect on morphine antinociception. Pharmacodynamic modeling.

The objective of this study was to quantify the influence of morphine-3-glucuronide (M3G) on the morphine antinociceptive effect (ANE) and respiratory effects in the rat. Three groups of rats were pretreated with either saline or M3G at two different rates. Morphine infusion of 10 mg/h/kg (group A) or 20 mg/h/kg (group B) was administered to each pretreatment group for 3 h. The ANE was measured by the electrical stimulation vocalization method, and blood gas parameters (pCO2, pO2, and pH) were assessed. Independent of pretreatment all groups displayed a concurrent increase in the ANE. The maximal effect diverged between pretreatments. Acute tolerance was observed, but no rebound effect was detected. To characterize the ANE, an effect compartment model and an indirect response model were selected, both capable of describing the observed features. In both models incorporation of M3G led to a better explanation of the data. On the basis of the parameters obtained in the fits, naturally occurring M3G would reduce the antinociceptive effect during a morphine infusion (plasma concentration 15 microM) by 15-20%. The exposure of M3G did not significantly change the respiratory response following the morphine treatment.

Analgesics, Opioid↗

PubMed1998

Automated covariate model building within NONMEM.

PURPOSE: One important task in population pharmacokinetic/pharmacodynamic model building is to identify the relationships between the parameters and demographic factors (covariates). The purpose of this study is to present an automated procedure that accomplishes this. The benefits of the proposed procedure over other commonly used methods are (i) the covariate model is built for all parameters simultaneously, (ii) the covariate model is built within the population modeling program (NONMEM) giving familiar meaning to the significance levels used, (iii) it can appropriately handle covariates that varies over time and (iv) it is not dependent on the quality of the posterior Bayes estimates of the individual parameter values. For situations in which the computer run-times are a limiting factor, a linearization of the non-linear mixed effects model is proposed and evaluated. METHODS: The covariate model is built in a stepwise fashion in which both linear and non-linear relationships between the parameters and covariates are considered. The linearization is basically a linear mixed effects model in which the population predictions and their derivatives with respect to the parameters are fixed from a model without covariates. The stepwise procedure as well as the linearization was evaluated using simulations in which the covariates were taken from a real data set. RESULTS: The covariate models identified agreed well with what could be expected based on the covariates that were actually supported in each of the simulated data sets. The predictive performance of the linearized model was close to that of the non-linearized model. CONCLUSIONS: The proposed procedure identifies covariate models that are close to the model supported by the data set as well as being useful in the prediction of new data. The linearized model performs nearly as well as the non-linearized model.

Mathematical Computing↗

PubMed1998

Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients.

Deriving a population pharmacokinetic model from real data is always associated with numerous assumptions. Violations of these assumptions, especially if undetected, may lead to inappropriate conclusions being made from the analysis. Routinely, only a few of the assumptions are explicitly stated and justified in the reporting of a population model. Here, we attempt to be exhaustive in the presentation of the assumptions made in the course of an analysis of moxonidine pharmacokinetics. The different ways that assumptions were justified, through experience, graphical examination, or additional modeling, are outlined. Models for relaxing assumptions regarding the covariate and statistical submodels, not previously reported in the area of population pharmacokinetic modeling, are also described.

Adult↗

PubMed1998

The population pharmacokinetics of recombinant- and urinary-human follicle stimulating hormone in women.

AIMS: To characterize the pharmacokinetics of recombinant-human follicle stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvolution techniques. METHODS: Sparse data were available from 62 female patients who received u-hFSH intramuscularly (i.m.) and 60 female patients who received r-hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF-ET) procedure. The dose of u-hFSH and r-hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u-hFSH/r-hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r-hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash-out. The volunteers then received multiple r-hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u-hFSH, 150 IU, given by the i.v. and i.m. routes. RESULTS: Analysis of the intensively sampled r-hFSH and u-hFSH data sets found that disposition could be described using a two-compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 and 18 h, respectively. The different bioavailabilities (F) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r-hFSH and u-hFSH data. The population estimates of apparent clearance (CL/F) were 0.71 and 0.33 l h(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 l h(-1) at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r-hFSH and u-hFSH were essentially the same, 26% and 25%, respectively. CONCLUSIONS: The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.

Absorption↗

PubMed1998

Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria.

AIMS: To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. METHODS: Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg(-1) day(-1) in 23 paediatric (aged 2-12 years) and 31 adult (aged 16-45 years) Vietnamese patients with uncomplicated falciparum malaria. The population model was developed using NONMEM, incorporating interoccasion variability and accounting for a systematic change in artemisinin pharmacokinetics with time, modelled as a change in oral bioavailability. RESULTS: Clinical efficacy, in terms of parasite clearance and fever subsidence times, was comparable between children and adults. A one-compartment model with separate pharmacokinetic estimates for children and adults was found best to describe the disposition of artemisinin after oral administration. The population estimates for artemisinin clearance and distribution volume, respectively, were 432 1 h(-1) and 16001 for adults and 14.41 h(-1) kg(-1) and 37.91 kg(-1) for children, with an intersubject variability (collectively for both age groups) of 45% and 104%, respectively. The oral bioavailability was estimated to decrease from Day 1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults. CONCLUSIONS: Artemisinin pharmacokinetic data was successfully derived in both paediatric and adult patients using 2-3 capillary blood samples taken in conjunction with parasitaemia monitoring. This study's findings advocated the dosing of artemisinin to children according to bodyweight and to adults according to a standard dose.

Administration, Oral↗

PubMed1998

Mitral valve opening in the ovine heart.

To study the three-dimensional size, shape, and motion of the mitral leaflets and annulus, we surgically attached radiopaque markers to sites on the mitral annulus and leaflets in seven sheep. After 8 days of recovery, the animals were sedated, and three-dimensional marker positions were measured by computer analysis of biplane videofluorograms (60/s). We found that the oval mitral annulus became most elliptical in middiastole. Both leaflets began to descend into the left ventricle (LV) during the rapid fall of LV pressure (LVP), before leaflet edge separation. The anterior leaflet exhibited a compound curvature in systole and maintained this shape during opening. The central cusp of the posterior leaflet was curved slightly concave to the LV during opening. Markers at the border of the "rough zone" were separated by 10 mm during systole. We conclude that coaptation occurs very near the leaflet edges, that the annulus and leaflets move toward their open positions during the rapid fall of LVP, and that leaflet edge separation, the last event in the opening sequence, occurs near the time of minimum LVP.

Animals↗