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Johannes H Proost

Publications and source records attributed to Johannes H Proost.

14 recordsLinked to original sources
PubMed2006

Performance of an iterative two-stage bayesian technique for population pharmacokinetic analysis of rich data sets.

PURPOSE: To test the suitability of an Iterative Two-Stage Bayesian (ITSB) technique for population pharmacokinetic analysis of rich data sets, and to compare ITSB with Standard Two-Stage (STS) analysis and nonlinear Mixed Effect Modeling (MEM). MATERIALS AND METHODS: Data from a clinical study with rapacuronium and data generated by Monte Carlo simulation were analyzed by an ITSB technique described in literature, with some modifications, by STS, and by MEM (using NONMEM). The results were evaluated by comparing the mean error (accuracy) and root mean squared error (precision) of the estimated parameter values, their interindividual standard deviation, correlation coefficients, and residual standard deviation. In addition, the influence of initial estimates, number of subjects, number of measurements, and level of residual error on the performance of ITSB were investigated. RESULTS: ITSB yielded best results, and provided precise and virtually unbiased estimates of the population parameter means, interindividual variability, and residual standard deviation. The accuracy and precision of STS was poor, whereas ITSB performed better than MEM. CONCLUSIONS: ITSB is a suitable technique for population pharmacokinetic analysis of rich data sets, and in the presented data set it is superior to STS and MEM.

Algorithms↗
PubMed2006

Twitch potentiation influences the time course of twitch depression in muscle relaxant studies: a pharmacokinetic-pharmacodynamic explanation.

The time course of twitch depression following neuromuscular blocking agent (NMBA) administration is influenced by the duration of control neuromuscular monitoring (twitch stabilization). The physiological mechanism for this interaction is not known. During twitch stabilization twitch response often increases to a plateau, this is known as twitch potentiation or the staircase phenomenon. Since twitch potentiation contributes to the observed twitch response it may also influence the time course of twitch depression following NMBA administration. Our objective was to estimate the degree that twitch potentiation influences the time course of twitch depression following NMBA administration under conditions typical for muscle relaxation studies. We used previousy described pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation models to simulate twitch data. Simulations consisted of twitch stabilization followed by a NMBA bolus dose and subsequent onset and recovery from muscle relaxation. Twitch data were analyzed for onset and recovery characteristics and the results compared to clinical muscle relaxation studies in existing literature. We found that twitch potentiation likely plays a minor role in shortened onset time and increased duration of twitch depression observed with long periods of twitch stabilization.

Computer Simulation↗
PubMed2006

Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in renal tubular cells: a novel strategy to treat renal fibrosis.

During renal injury, activation of p38 mitogen-activated protein kinase (MAPK) in proximal tubular cells plays an important role in the inflammatory events that eventually lead to renal fibrosis. We hypothesized that local inhibition of p38 within these cells may be an interesting approach for the treatment of renal fibrosis. To effectuate this, we developed a renal-specific conjugate of the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] and the carrier lysozyme. First, we demonstrated that SB202190 inhibited the expression of albumin-induced proinflammatory (monocyte chemoattractant protein-1) and transforming growth factor (TGF)-beta1-induced profibrotic (procollagen-Ialpha1) genes over 50% in renal tubular cells (normal rat kidney-52E). Next, we conjugated SB202190 via a carbamate linkage to lysozyme. However, this conjugate rapidly released the drug upon incubation in serum. Therefore, we applied a new platinum(II)-based linker approach, the so-called universal linkage system (ULS), which forms a coordinative bond with SB202190. The SB202190-ULS-lysozyme remained stable in serum but released the drug in kidney homogenates. SB202190-ULS-lysozyme accumulated efficiently in renal tubular cells and provided a local drug reservoir during a period of 3 days after a single intravenous injection. Treatment with SB202190-ULS-lysozyme inhibited TGF-beta1-induced gene expression for procollagen-Ialpha1 by 64% in HK-2 cells. Lastly, we evaluated the efficacy of a single dose of the conjugate in the unilateral renal ischemia-reperfusion rat model. A reduction of intrarenal p38 phosphorylation and alpha-smooth muscle actin protein expression was observed 4 days after the ischemia-reperfusion injury. In conclusion, we have developed a novel strategy for local delivery of the p38 MAPK inhibitor SB202190, which may be of use in the treatment of renal fibrosis.

Animals↗
PubMed2005

Prediction of the pharmacokinetics of succinylated human serum albumin in man from in vivo disposition data in animals and in vitro liver slice incubations.

Suc-HSA is a potent HIV-inhibitor with possible application in man. To facilitate the assessment of dosing regimens for future phase I clinical studies, we predicted the pharmacokinetic properties of Suc-HSA in man. Slices prepared from rat, monkey and human liver were incubated with succinylated albumin, and the maximum uptake rate V(m) and Michaelis-Menten constant K(m) were calculated. The pharmacokinetics after multiple doses of Suc-HSA were studied in rats. The pharmacokinetic parameters of Suc-HSA in man were predicted from the results and data from literature, using pharmacokinetic modeling and interspecies scaling techniques, and potential intravenous dose regimens for HIV treatment in man were calculated. On the basis of in vitro uptake studies in rat, monkey and human liver slices and in vivo disposition data in monkey (data from earlier study) and rat, we predicted the following parameters for liver uptake in humans: V(m) 82.5 microg h(-1) kg(-1) and K(m) 0.228 microg ml(-1). The predicted steady-state concentration after daily intravenous bolus doses of 1 mg kg(-1) is between 4 and 30 microg ml(-1), i.e. well above the IC50 of about 0.4 microg ml(-1). Additional loading doses of 8 mg kg(-1) in total are needed to reach steady-state within a few days.

Animals↗
PubMed2005

Volume of the effect compartment in simulations of neuromuscular block.

BACKGROUND: The study examines the role of the volume of the effect compartment in simulations of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants. METHODS: The molar amount of the postsynaptic receptors at the motor end plates in muscle was assumed constant; the apparent receptor concentration in the effect compartment is the ratio of this amount and the volume arbitrarily assigned to the effect compartment. The muscle relaxants were postulated to diffuse between the central and the effect compartment and to bind to the postsynaptic receptors. NMB was calculated from the free concentration of the muscle relaxant in the effect compartment. RESULTS: The simulations suggest that the time profiles of NMB and the derived pharmacokinetic and pharmacodynamic variables are dependent on the apparent receptor concentration in the effect compartment. For small, but not for large, volumes, times to peak submaximal NMB are projected to depend on the magnitude of NMB and on the binding affinities. CONCLUSION: An experimental design to estimate the volume of the effect compartment is suggested.

Animals↗
PubMed2005

Renal-selective delivery and angiotensin-converting enzyme inhibition by subcutaneously administered captopril-lysozyme.

In previous studies, we have demonstrated that the low molecular weight protein lysozyme can be used as a renal-selective drug carrier for delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril. Typically, such macromolecular drug-targeting preparations are administered intravenously. In the present study, we investigated the fate of captopril-lysozyme following subcutaneous administration, a convenient route for long-term treatment. The absorption from the subcutaneous injection site and renal uptake of lysozyme were determined by gamma scintigraphy in rats. Bioavailability, renal accumulation, and stability of the captopril-lysozyme conjugate were evaluated by high performance liquid chromatography analysis and by ACE activity measurements. Lysozyme was absorbed gradually and completely from the subcutaneous injection site within 24 h and accumulated specifically in kidneys. After subcutaneous injection of the captopril-lysozyme conjugate, higher renal captopril levels and lower captopril-lysozyme levels in urine indicated the improved renal accumulation in comparison with intravenous administration of the conjugate, as well as its stability at the injection site. After both treatments, captopril-lysozyme conjugate effectuated renal ACE inhibition, whereas plasma ACE was not inhibited. In conclusion, our results demonstrate that we can use the subcutaneous route to administer drug delivery preparations like the captopril-lysozyme conjugate.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Improving pharmacokinetic-pharmacodynamic models of muscle relaxants using potentiation modelling.

Repeated motor nerve stimulation performed during neuromuscular monitoring enhances the evoked mechanical response of the corresponding muscle resulting in an increased twitch response. This is known as twitch potentiation or the staircase phenomenon. For neuromuscular modelling research twitch stabilisation techniques are often used to reduce the visible effect of potentiation, but such techniques are not always effective. Our objective was to model pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation and to estimate neuromuscular block (NMB) in the presence of twitch potentiation. We combined a standard PK-PD model with a model describing the degree of twitch potentiation. The combined model was used to predict mechanomyographic twitch measurements and estimate NMB and twitch potentiation during muscle relaxation monitoring. Model parameters and prediction accuracy were compared to the standard PK-PD model with and without linear baseline correction. The PK-PD-potentiation model allows NMB to be estimated in the presence of twitch potentiation. It also accurately predicts data from twitch stabilisation, which is ignored with the standard PK-PD model. Compared to the standard PK-PD model, estimated PD parameters ec50 and gamma were found to be higher using the PK-PD-potentiation model. Compared to linear baseline correction, estimated PD parameters ke0 and ec50 were found to be higher. A PK-PD-potentiation model can estimate the degree of twitch potentiation and the degree of NMB during neuromuscular monitoring. This model leads to different PD parameter estimations than the standard PK-PD model however the differences are small enough to be unlikely to cause great concern among researchers.

Algorithms↗
PubMed2005

Evaluation of a closed-loop muscle relaxation control system.

Automatic muscle relaxation control may reduce anesthesiologists' workload freeing them for other patient care requirements. In this report we describe a muscle relaxation controller designed for routine clinical application using rocuronium and the train-of-four count. A muscle relaxation monitor (TOF Watch SX) was connected to a laptop computer running a controller algorithm program that communicates with a syringe pump to form a closed-loop muscle relaxation system. The control algorithm uses proportional-integral and lookup table components and is designed to avoid the usability restrictions of existing controllers. The controller is optimized using an objective method to avoid the uncertainties of ''hand-crafted'' controller algorithms. Controller target was train-of-four count 1 or 2 and controller performance was evaluated in 15 patients. During 39 hours of closed-loop control, 96.1% of all twitches recorded were in the target range. Average rocuronium infusion rate was 0.36 mg.kg(-1).h(-1) (sd 0.18 mg.kg(-1).h(-1)). We show that the controller remains useful even in the presence of disturbances that can arise in routine clinical conditions. The muscle relaxation controller maintained the target train-of-four count values and may serve as a basis for the design of hardware and user interfaces for closed-loop muscle relaxation control in clinical conditions.

Aged↗
PubMed2003

A pharmacokinetic-pharmacodynamic model for neuromuscular blocking agents to predict train-of-four twitches.

The train-of-four (TOF) stimulation pattern consists of 4 stimuli (T1, T2, T3, and T4) at 2 Hz, and is used in daily anesthesiological practice to determine the degree of relaxation caused by muscle relaxants. At a surgical levels of relaxation the degree of relaxation can be estimated by counting the number of "measurable" or "visible" muscular reactions to the 4 stimuli in the TOF stimulation pattern (TOF count). During recovery relaxation can be estimated by calculating the TOF ratio (T4/T1). Bartkowski and Epstein described a pharmacokinetic-pharmacodynamic (PK-PD) model to predict TOF ratio by modifying and extending the PK-PD model as described by Sheiner to use a hypothetical distributed effect compartment described by a median equilibration rate constant and a dispersion parameter. We extended the Bartkowski and Epstein PK-PD model to simulate all four TOF twitches by including EC50 terms for T2 and T3. We fit this model to data from the pig and compared the results to fitted models using separate PD models for each TOF twitch (extended Sheiner model). The extended Bartkowski and Epstein model fit the twitch height data from all four TOF twitches better than the extended Sheiner model and has fewer parameters.

Anesthesia↗
PubMed2003

Pharmacokinetic-pharmacodynamic modeling of rocuronium in case of a decreased number of acetylcholine receptors: a study in myasthenic pigs.

BACKGROUND: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. METHODS: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. RESULTS: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 3,769) and the residual SD (3.2 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 micro m (ranging from 0.17 to 0.59 micro m) compared to 2.71 micro m (ranging from 2.42 to 4.43 micro m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. CONCLUSION: Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.

Algorithms↗
PubMed2002

Targeting of RGD-modified proteins to tumor vasculature: a pharmacokinetic and cellular distribution study.

Angiogenesis-associated integrin alpha(v)beta(3) represents an attractive target for therapeutic intervention because it becomes highly upregulated on angiogenic endothelium and plays an important role in the survival of endothelial cells. Cyclic RGD peptides were prior shown to have a high affinity for alpha(v)beta(3) and can induce apoptosis of endothelial cells. In our laboratory, monocyclic RGD peptides (cRGDfK) were chemically coupled to a protein backbone. Previous results demonstrated that the resulting RGDpep-HuMab conjugate bound with increased avidity to alpha(v)beta(3)/alpha(v)beta(5) on endothelial cells. In our present study, RGDpep-HuMab was injected intravenously and intraperitoneally in B16.F10 tumor-bearing mice to determine its pharmacokinetics and organ distribution. In the tumor, the RGDpep-HuMab conjugate specifically localized at the endothelium as was demonstrated by immunohistochemistry. The control RADpep-HuMab conjugate was not detected in the tumor. Besides tumor localization RGDpep-HuMab was found in liver and spleen associated with macrophages. This uptake by macrophages is probably responsible for the more rapid clearance of RGDpep-HuMab from the circulation than HuMab and RADpep-HuMab. The half-life of RGDpep-HuMab (90 min) was still considerably longer than that of free RGD peptides (<10 min). This prolonged circulation time may be favorable for drug targeting strategies because the target cells are exposed to the conjugate for a longer time period. Taken together these results indicate that RGD-modified proteins are suitable carriers to deliver therapeutic agents into tumor or inflammation induced angiogenic endothelial cells.

Animals↗
PubMed2002

Pharmacokinetic/pharmacodynamic modeling of rocuronium in myasthenic patients is improved by taking into account the number of unbound acetylcholine receptors.

UNLABELLED: Patients with myasthenia gravis are more sensitive than healthy patients to nondepolarizing neuromuscular blocking drugs. We performed a pharmacokinetic/pharmacodynamic modeling study of rocuronium in eight myasthenic patients and eight matched control patients. Patients were anesthetized with propofol and sufentanil and a mixture of nitrous oxide/oxygen. Mechanomyographical monitoring of the adductor pollicis was applied. Rocuronium was infused at a rate of 25 micro g. kg(-1). min(-1) in myasthenic patients and 116.7 micro g. kg(-1). min(-1) in control patients and was terminated at 70% neuromuscular block. Arterial blood samples were drawn during onset and offset of the block and for 4 h after the administration of rocuronium. Plasma concentrations were determined by high-performance liquid chromatography. Pharmacokinetic/pharmacodynamic modeling was performed by using the Sheiner model and the unbound receptor model (URM), which takes into account the number of unbound acetylcholine receptors. The effective concentration at 50% effect and the steepness of the concentration-effect relationship were significantly decreased in myasthenic patients. Both the URM and the Sheiner model provided an adequate fit in myasthenic patients. The acetylcholine receptor concentration was significantly decreased in myasthenic patients. The URM explains the observed differences in time course and potency, whereas the Sheiner model does not. IMPLICATIONS: We performed a pharmacokinetic/pharmacodynamic modeling study in myasthenic patients and control patients. The unbound receptor model, which takes into account the number of unbound acetylcholine receptors in the biophase, was introduced and compared with the model proposed by Sheiner.

Adolescent↗
PubMed2002

An isolated, antegrade, perfused, peroneal nerve anterior tibialis muscle model in the rat: a novel model developed to study the factors governing the time course of action of neuromuscular blocking agents.

BACKGROUND: A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors. METHODS: The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated. RESULTS: The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants. CONCLUSION: The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.

Androstanols↗