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J Meulenbelt

Publications and source records attributed to J Meulenbelt.

At least 19 recordsLinked to original sources
PubMed2001

A population physiologically based pharmacokinetic/pharmacodynamic model for the inhibition of 11-beta-hydroxysteroid dehydrogenase activity by glycyrrhetic acid.

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. Habitual consumption of this compound may lead to hypertension and electrolyte disturbances due to inhibition of 11-beta-hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg glycyrrhetic acid/day for 5 days on 11-beta-hydroxysteroid dehydrogenase activity was studied by measuring the cortisol-cortisone ratio in 24-h urine. A twofold increase in this ratio was observed. It took 4 days for the elevated urinary cortisol-cortisone ratio to return to the baseline ratio after cessation of the treatment. The pharmacokinetics of glycyrrhetic acid were studied after the first and last dose. Using data from a previously performed single-dose study and present multiple-dose treatment, a physiologically based pharmacokinetic model for glycyrrhetic acid was developed. The variability of the pharmacokinetics of glycyrrhetic acid in the population studied could be explained for a considerable part by interindividual differences in gastrointestinal transit of glycyrrhetic acid metabolites. The relationship between glycyrrhetic acid exposure and changes in urinary cortisol-cortisone ratio was described by a pharmacodynamic model, using nonlinear mixed-effect modeling. Literature data on the inhibitory effect of glycyrrhetic acid on 11-beta-hydroxysteroid dehydrogenase activity under various exposure scenarios could be adequately described by the model. Due to the relationship between the pharmacokinetics of glycyrrhetic acid and its inhibitory effect on 11-beta-hydroxysteroid dehydrogenase activity, reflected by a change in the urinary cortisol-cortisone ratio, this ratio might serve as a noninvasive marker to identify individuals at risk for glycyrrhizic acid over-consumption.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling.

Glycyrrhizic acid is currently of clinical interest for treatment of chronic hepatitis. It is also applied as a sweetener in food products and chewing tobacco. In some highly exposed subgroups of the population, serious side effects such as hypertension and electrolyte disturbances have been reported. In order to analyze the health risks of exposure to this compound, the kinetics of glycyrrhizic acid and its active metabolites were evaluated quantitatively. Glycyrrhizic acid and its metabolites are subject to complex kinetic processes, including enterohepatic cycling and presystemic metabolism. In humans, detailed information on these processes is often difficult to obtain. Therefore, a model was developed that describes the systemic and gastrointestinal tract kinetics of glycyrrhizic acid and its active metabolite glycyrrhetic acid in rats. Due to the physiologically based structure of the model, data from earlier in vitro and in vivo studies on absorption, enterohepatic cycling, and presystemic metabolism could be incorporated directly. The model demonstrates that glycyrrhizic acid and metabolites are transported efficiently from plasma to the bile, possibly by the hepatic transfer protein 3-alpha-hydroxysteroid dehydrogenase. Bacterial hydrolysis of the biliary excreted metabolites following reuptake of glycyrrhetic acid causes the observed delay in the terminal plasma clearance of glycyrrhetic acid. These mechanistic findings, derived from analysis of experimental data through physiologically based pharmacokinetic modeling, can eventually be used for a quantitative health risk assessment of human exposure to glycyrrhizic acid containing products.

Animals↗
PubMed2000

A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling.

PURPOSE: To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. METHODS: The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. RESULTS: The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. CONCLUSIONS: Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.

Adult↗
PubMed2000

Hemoperfusion is ineffectual in severe chloroquine poisoning.

OBJECTIVES: To study the toxicokinetics in severe chloroquine poisoning, and to evaluate the efficacy of hemoperfusion. DESIGN: Case report on one observation. SETTING: Medical intensive care unit (ICU) of the University Medical Center Utrecht, The Netherlands. PATIENT HISTORY: A previously healthy, 52-yr-old woman ingested 100 tablets containing 100 mg chloroquine base 1 hr before admission. At admission, she was drowsy, agitated, hypotensive, and in respiratory distress. Shortly thereafter, she was resuscitated from cardiac arrest. After hemodynamic and respiratory stabilization, the patient was transferred to the medical ICU. TOXICOKINETICS EVALUATION: During the course of her stay at the ICU, blood samples were taken for the determination of chloroquine and the metabolite desethylchloroquine concentration. Hemoperfusion was started 3.5 hrs after ingestion of the chloroquine tablets. MEASUREMENTS AND MAIN RESULTS: The following toxicokinetics data during this severe chloroquine poisoning were calculated: apparent volume of the central compartment 181 L, apparent volume of distribution 1137 L, half-life in the distribution phase 6.4 hrs, half-life in the elimination phase 392.8 hrs, and total body clearance 2.01 L/hour. The average extraction ratio during hemoperfusion was 0.07, 0.28, and 0.25, in plasma, erythrocytes and whole blood, respectively. The total amount of chloroquine removed by hemoperfusion was only 480 mg (5.3% of the amount ingested). Simulation of a hemoperfusion session over 5 hrs by using a column with an optimal extraction ratio of 1.0 would have removed 1,816 mg chloroquine, only 18.2% of the amount ingested. This limited contribution of hemoperfusion to the total clearance makes it ineffective. CONCLUSION: Hemoperfusion is not effective in severe chloroquine poisoning, even when started (relatively) early in the course of the intoxication. Toxicokinetic evaluation of a chloroquine poisoning should be based on the evaluation of plasma and whole blood concentrations.

Antimalarials↗
PubMed2000

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration.

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.

Acute Kidney Injury↗
PubMed1999

Bioavailability of carbamazepine from four different products and the occurrence of side effects.

The relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing. Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo, the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However, as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the rate of absorption in single-dose studies with carbamazepine products.

Administration, Oral↗
PubMed1998

Healthy volunteer studies in toxicology.

In the future there will be an increasing need for quantitative human risk assessment in order to develop soundly-based risk level regulations. Human volunteer studies can contribute to gain essential data needed for this risk assessment. Volunteer studies are especially relevant to study the biokinetics and metabolism of a compound. Comparison of these data with those of laboratory animals can increase the accuracy in extrapolation study results from animals to man. Furthermore, the results of volunteer studies can be used to fill in the gaps of knowledge which cannot be solved with in vitro or animal studies in order to develop adequate physiologically-based biokinetic or biodynamic models for human risk assessment.

Animals↗
PubMed1998

[The risks from ingestion of cleaning tablets for dentures and dental prostheses].

OBJECTIVE: To determine the frequency and severity of intoxication caused by cleansing tablets for dental plates or dental prostheses. DESIGN: Questionnaire study. SETTING: National Poisons Control Centre, Bilthoven, the Netherlands. METHOD: In 1996, all 78 physicians who requested information from the Centre about intoxications with cleansing tablets for dental plates or dental prostheses were sent a questionnaire enquiring about the exposure situations and the severity of the effects of the intoxications. RESULTS: Forty-six questionnaires (59%) were returned. Older people (24; 52%) and children (14; 30%) constituted the largest groups of intoxicated. As a rule, accidental ingestion of the tablets was involved. In most cases, one tablet had been swallowed. Local effects, mostly of a mild nature, were reported in 22 patients. Systemic effects were reported in two patients but in these cases the connection with the ingestion was doubtful.

Accidents, Home↗
PubMed1998

Nonaccidental endosulfan intoxication: a case report with toxicokinetic calculations and tissue concentrations.

CASE REPORT: A case of nonaccidental endosulfan intoxication in a previously healthy 43-year-old male patient is reported. On admission, the patient had few symptoms, but refractory seizures began 1 hour after ingestion. The patient died on the fourth day after admission showing clinical signs of cerebral herniation confirmed at autopsy. Blood, urine, and tissue samples were analyzed for alpha-endosulfan, beta-endosulfan, and endosulfan sulfate by capillary gas chromatography with electron capture detection. Concentration versus time data for endosulfan were fitted using the program MW/Pharm, assuming complete bioavailability although it is recognized that the bioavailability of endosulfan after ingestion may have been low and the calculated clearance was primarily due to redistribution. Hemoperfusion was shown to be ineffective.

Adult↗
PubMed1998

Lead toxicokinetics. Development of a biokinetic model to understand and predict the outcome of treatment.

Quite often physicians contact the Dutch Poisons Control Centre for information on patients with increased lead exposure. The most important questions raised by physicians dealing with these patients are how to estimate the lead exposure and the total lead body burden, how to interpret blood lead concentrations and whether the patient needs treatment. In order to answer these questions we need knowledge of the toxicokinetics of lead in the human body. To achieve insight and to make this knowledge accessible to physicians a biokinetic model for lead metabolism in the human body was developed. A four-compartment model with first-order kinetics, based on the concept of Kneip, was used. A biokinetic model uses a mathematical approach to translate the complex biological and kinetic behaviour of lead. In order to develop this biokinetic model two computer programmes were used. At the moment the model is tested with clinical data from patient treated at the medical toxicology outpatient clinic of the Utrecht University Hospital (this department cooperates very closely with the National Poisons Control Centre). Especially with regard to chelation therapy for elevated blood lead levels due to chronic exposure, the model is very helpful in visualising the toxicokinetics of lead in the human body. Toxicokinetic model might help improve knowledge of lead toxicokinetics, leading to well-considered guidelines for treatment of lead intoxications.

Absorption↗
PubMed1997

[A painful encounter with the weever (Echiichtis vipera)].

The National Poisons Information Centre of the National Institute of Public Health and the Environment in the Netherlands in the past 2 years received dozens of requests for information about intoxication due to stings of the weever, Echiichtis vipera. The venomous apparatus of the weever consists of gill cover spines and 5 to 8 dorsal fin spines. The fish buries itself in the sandy or muddy bottom of the sea to wait for prey. The mixture of toxins that enters the skin upon contact with the spines causes a heavy local reaction, characterized mostly by pain, which untreated persists for 24 hours. An erythematous oedema may develop locally, spread over the entire extremity and persist for days. Systemic reactions are rare. Since the toxin mixture is heat labile, treatment is essentially simple: clean the wound and immerse the affected limb as soon as possible in warm water (45 degrees C) for 30 to 90 minutes. This makes the pain disappear.

Animals↗
PubMed1997

Effect of nitrite on blood pressure in anaesthetized and free-moving rats.

The effect of nitrite on blood pressure and heart rate was studied in anaesthetized (non-telemetric method) and free-moving rats (biotelemetry system). In anaesthetized rats, NaNO2 (10-1000 mumol/kg), infused over 5 min, induced a dose-related decrease in blood pressure. The maximal decrease in mean arterial blood pressure (MAP), caused by 1000 mumol/kg NaNO2 and measured 15 min after infusion was 55.9 +/- 3.2% (n = 3). After NaNO2 infusion, in the plasma, rapid conversion of nitrite into nitrate was observed. However, sodium nitrate (NaNO3, 100 mumol/kg) did not decrease blood pressure and there was no conversion of nitrate into nitrite. Free-moving rats received KNO2 which was added to drinking water (36 mmol/litre) for a period of 3 days. KNO2 decreased the MAP and increased the heart rate during the rat's activity phase at night but not during their resting phase in the day. An equal concentration of potassium (KCl, 36 mmol/litre added to drinking water) for 3 days did not decrease blood pressure. It is concluded that nitrite decreases blood pressure in rats, which probably induces, by renin-angiotensin system activation, hypertrophy of the adrenal zona glomerulosa.

Anesthesia, General↗
PubMed1997

Acute work-related poisoning by pesticides in The Netherlands; a one year follow-up study.

The National Poisons Control Centre of the National Institute of Public Health and the Environment in the Netherlands conducted a prospective study on acute poisoning arising from exposure to pesticides in agricultural workers. The study was performed to determine the extent and severity of acute pesticide poisoning in the Netherlands and the working conditions that lead to these poisonings. All cases of potential acute occupational intoxication by pesticides in which the Poisons Control Centre was consulted in 1991 were thoroughly studied by an occupational hygienist and a specialist in internal medicine. With the consent of the patients and their physicians, the patients' medical condition and the working conditions leading to exposure were investigated on the spot. After the exclusion of 73 patients (27 non-occupational exposures, 7 occupational exposures in non-agricultural workers, 1 accident occurred abroad, 32 patients with illnesses unrelated to pesticides and 6 who could not be traced for follow-up), 54 cases of possible acute work-related pesticide poisoning remained for study. In 37 of the 54 events there was a direct relation between exposure to pesticides and acute health problems. In one patient doubt remained about the origin of the complaints and in 16 of the 54 cases pesticide poisoning was highly unlikely and the complaints could be attributed to other diseases. In the 37 remaining cases symptoms consisted of skin and/or eye lesions (23 cases) and systemic health effects (14 cases). Exposure to the soil disinfectant 1,3-dichloropropene resulted in severe skin damage. Direct contact of pesticides with the eyes invariability resulted in local irritation. Severe systemic poisonings occurred after exposure to organophosphate and carbamate insecticides and the soil disinfectant methyl bromide. Investigations at the site of the exposure revealed 43 cases of clear exposure to pesticides, in which, except for two cases, 1 worker per incident was involved. In 67% of the cases exposures took not place during pesticide dissemination, but during preparatory activities (35%), repair of application equipment (14%) and during re-entry (14%). In 79% of the cases splashing of pesticides or spray drift led to the exposure. In most accidents (74%) imperfect technical design or technical defects were important risk factors for exposure. Although most workers were aware of the risk of using pesticides, they were still careless in taking adequate protective measures. Especially during preparatory and reparations activities the wearing of protective clothing has to be emphasized.

Adolescent↗