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Because from earlier experiments in rats and a pilot study in humans a no-effect level of glycyrrhizic acid could not be established, a second experiment was performed in healthy volunteers. The experiment was performed in females only, because the effects were most marked in females in the pilot study. Doses of 0, 1, 2 and 4 mg glycyrrhizic acid/kg body weight were administered orally for 8 weeks to 39 healthy female volunteers aged 19-40 years. The experiment lasted 12 weeks including an adaptation and a "wash-out" period. A no-effect level of 2 mg/kg is proposed from the results of this study, from which an acceptable daily intake (ADI) of 0.2 mg/kg body weight can be extrapolated with a safety factor of 10. This means consumption of 12 mg glycyrrhizic acid/day for a person with a body weight of 60 kg. This would be equal to 6 g licorice a day, assuming that licorice contains 0.2% of glycyrrhizic acid. The proposed ADI is below the limit advised by the Dutch Nutrition Council of 200 mg glycyrrhizic acid/day. This reflects the relatively mild acute toxicity of glycyrrhizic acid, which is also emphasised by the "generally recognised as safe" (GRAS) status of glycyrrhizic acid in the USA in 1983. However, the long-term effects of a mild chronic intoxication (causing, for example, a mild hypertension), although not immediately lethal, justify special attention to the amount of glycyrrhizic acid used daily.

Objective: To study the pharmacokinetics of vancoymcin in critically ill patients with acute renal failure treated with continuous venovenous haemofiltration (CVVHF)., Design: Open-label study., Setting: Hospital pharmacy centre and medical intensive care unit of the University Medical Centre Utrecht., Materials and Methods: In a laboratory setting, the sieving coefficient (s) of vancomycin by polyacrilonitrile (PAN) haemofilters of different surface areas was studied. In one patient, the pharmacokinetics of vancomycin were studied following a single dose of vancomycin. Another patient was treated with a vancomycin dosing regimen based on data from the literature, but high trough concentrations made dose reduction necessary after 24 h of withholding therapy. After two doses of 250 mg, serum and ultrafiltrate samples were collected for pharmacokinetic evaluation. INTERVENTIONS++: CVVHF with the following operational characteristics: blood flow 200 ml/min, ultrafiltrate flow 25 ml/min, postdilution, PAN 06 hollow fibre haemofilter., Measurements and Results: The average sieving coefficient in vitro was 0.73 +/- 0.06, 0.86 +/- 0.11, and 0.80 +/- 0.06 for the PAN 03, 06, and 10 haemofilters, respectively. Changes in the sieving coefficient by increasing the ultrafiltration rate were not clinically significant. The first patient was given a single dose of vancomycin, 1000 mg by intravenous infusion. The following pharmacokinetic data were obtained: apparent volume of distribution (Vd) 55.8 l, terminal half-life time (t(1/2 term)) 15.4 h, total clearance (Cl(tot)) 2.5 l/h, CVVHF clearance (CL(CVVHF, form 1)) 1.4 l/h, and body clearance (Cl(body)) 1.1 l/h. The average sieving coefficient during the study period was 0.89 +/- 0.03. In the second patient, the pharmacokinetics of vancomycin were studied following dose reduction: Vd 41.7 l, (1/2 term) 20.3 h, Cl(tot) 1.4 l/h, Cl(CVVHF, form 1) 1.4 l/h, and Cl(body) < 0.1 l/h. The average sieving coefficient during the study period was 0.88 +/- 0. 03. The cumulative amount of vancomycin removed by means of CVVHF during the 12-h study period was 245 mg in patient 1 and 228 mg in patient 2. CONCLUSIONS++: CVVHF with a PAN 06 haemofilter effectively removed vancomycin in two critically ill patients. The amount of vancomycin removed with CVVHF was about 250 mg per 12 h. A clear difference in body clearance in the two patients was observed. Our dosage recommendation for vancomycin in critically ill patients receiving CVVHF is a loading dose of 15-20 mg/kg followed after 24 h by 250 to 500 mg twice daily with close monitoring of the serum and ultrafiltrate vancomycin concentration.

Electrical shocks commonly cause widespread acute and delayed tissue damage. Cardiac arrhythmias and respiratory arrest are the most life-threatening complications in the acute phase. Prediction of outcome after cardiopulmonary resuscitation is usually based on neurological findings compatible with anoxic encephalopathy. This report describes a case of electrocution followed by cardiopulmonary resuscitation. Although neurological signs on admission pointed towards severe brain injury, the patient fully recovered and was able to resume the level of cognitive functioning prior to the accident.

Resuscitation (CPR) courses stress acquisition of psychomotor skills. The number of mannequins may limit the 'hands-on' time available for each trainee to practise CPR and impede acquisition of skill. This may occur because expensive, sophisticated mannequins are favoured over individual, simple mannequins. In a blind, prospective, controlled study we compared one-rescuer CPR skills of 165 trainees in two cohorts using their own individual light-weight torso mannequins (Actar 911 and Laerdal Little Anne) and a control cohort with four to five trainees sharing a sophisticated mannequin (Laerdal Recording Resusci Anne). No major significant differences (p = 0.18) were found when using the 'Berden scoring system'. Both the Actar 911 and the Little Anne were compatible with the Recording Resusci Anne. Trainees preferred the individual mannequins. We conclude that the results indicate that the use of individual mannequins in conjunction with a sophisticated mannequin neither results in trainees learning incorrect skills nor in significant improvement. Further analysis of the actual training in lay person CPR training courses and evaluation of course didactics to optimize training time appear indicated.

Hospital resolution of mass casualty incidents can have difficulties involving "command and control" and information management, ineffective use of triage classes, and missed diagnostic procedures, leading to lower quality of care. A computer system has been developed to supply continuously updated group and patient data. The system uses barcoded identifiers to represent patients, injuries, facilities, and locations, in order to minimize errors and make exchange of data possible. The system communicates with the permanent hospital information system. This article reports the use of this technology during several experiments and real incidents. Computer registration based on bar codes, despite the greater number of items entered, still showed 25% fewer inaccuracies when compared with handwritten medical charts. Extensive training was shown to be unnecessary. Paramedical personnel judged the automated procedures to be an improvement during the admission of 143 evacuated patients.

A high-performance liquid chromatographic method with ultraviolet (UV) and fluorescence detection was developed for the analysis of one indandione and four hydroxycoumarin anticoagulant rodenticides in human serum. The superwarfarin rodenticides, chlorophacinone, bromadiolone, difenacoum, brodifacoum, and difethialone, can be identified and quantitated simultaneously with this method. After adding a buffer (pH 5.5), the anticoagulants were extracted from serum with chloroform-acetone. The organic phase was separated and evaporated to dryness, and the residue was subjected to chromatographic analysis. The anticoagulants were separated by reversed-phase chromatography and detected by UV absorption at 285 nm and by fluorescence at an excitation wavelength of 265 nm and an emission wavelength of 400 nm. Extraction efficiencies from 55 to 131% were obtained. The within-run precision ranged from 2.0 to 7.1% for UV detection and from 0.0 to 4.8% for fluorescence detection. Between-run precision ranged from 1.3 to 16.0% for UV detection and from 1.8 to 9.0% for fluorescence detection. The anticoagulants can be quantitated at serum concentrations down to 3-12 ng/mL for fluorescence detection and down to 20-75 ng/mL for UV detection. No interferences were observed with the related compounds warfarin and vitamin K1.

Radiocesium may be deposited in the environment as a result of accidents in nuclear installations, for example, as in Chernobyl. Significant internal contamination with radiocesium poses a serious risk to human health, and, therefore, expedient removal is essential to reduce the radiation body burden. In vitro hemodialysis was tested as a potential method to remove radiocesium from a pasteurized plasma solution of bovine or human blood. Clearance values were calculated by a flow independent method. Hemodialysis appears to be a good method to remove radiocesium from blood: within 4 h more than 90% of the administered radiocesium is removed from blood or plasma. Radiocesium in dialysis fluid can be concentrated on Prussian Blue coated columns that were tested previously for hemoperfusion. Radioactive waste disposal problems can be solved by concentration of radiocesium on these columns. In vivo experiments are necessary to confirm these in vitro results.

A case of severe mercuric chloride poisoning with clinical signs of mucosal damage of the gastrointestinal tract and anuric renal failure, is presented. The initial whole blood mercury concentration was 14,300 micrograms l-1. This concentration is supposed to be associated with fatal outcome due to multiple organ failure. Because of anuric renal failure, haemodialysis was necessary. Kidney function returned to normal within 10 days. Haemodialysis proved to be ineffective with regard to total mercury elimination. Treatment with DMPS was started because of very severe poisoning, anuric renal failure and optimistic reports on the "new" chelating agent 2,3-dimercapto-1 propanesulphonic acid (DMPS) in mercury poisoning. DMPS was administered by parenteral route initially and was continued thereafter by oral route, until whole blood and urine mercury concentrations had decreased below a level considered as toxic. Except for a temporary pruritic erythema of the skin, no side effects of DMPS treatment were observed. The clinical course was mild, despite continuing high whole blood mercury concentrations. Recovery was uneventful and complete. DMPS treatment, administered by intravenous and oral route, was shown to be an effective alternative for BAL in life-threatening mercuric chloride intoxication. The pharmacokinetic data presented in this case report suggest that non-renal mercury clearance may considerably exceed renal mercury clearance.

Systemic methyl bromide (CH3Br) poisoning with signs and symptoms of varying severity developed in nine greenhouse workers after acute inhalational exposure on two consecutive days. Measurements of CH3Br, carried out at the site within hours after the accident, suggest that exposure on the second day may have been in excess of 200 ppm (800 mg/m3) CH3Br. All workers were admitted for observation. Seven of them were discharged after an uneventful overnight observation and residual symptoms, if any, subsided within three weeks of the accident. Two patients needed intensive care for several weeks because of severe reactive myoclonus and tonic-clonic generalised convulsions. These conditions were unresponsive to repeated doses of diazepam, clonazepam, and diphenylhydantoin but could be suppressed effectively by induction of a thiopental coma that had to be continued for three weeks. In some of the patients prior subchronic exposure to CH3Br, as shown by their occupational histories and high serum bromide (Br-) concentrations, is likely to have been a factor contributing to the severity of their symptoms. A direct association between serum Br- concentrations and the severity of neurological symptoms, however, seemed to be absent. An on site investigation into the circumstances leading to the accident showed the presence of an empty and out of use drainage system that covered both sections of the greenhouse. This was probably the most important factor contributing to the rapid and inadvertent spread of CH3Br.

Healthy volunteers who participated in an experiment were asked to complete a questionnaire about their experiences. Special attention was paid to their motives and the informed consent procedure. The motives of healthy volunteers for participating in a study differed according to age. Young volunteers mostly participated because of the financial compensation, while older volunteers mainly participated to get a medical check-up, which was part of the selection procedure, or because of the benefit that other people might obtain from the results of the experiment. In most experiments the volunteers were content with the information given about the experiment, which was provided orally and in a hand-out. The information procedure was crucial for the experiment, because optimum information was of the utmost importance in keeping the volunteers motivated during the experiment. Another conclusion was that the researcher should not be afraid that too much information was given. Adequate information was also important in recruiting new volunteers, because they mostly become interested because of information obtained from their predecessors. A personal approach towards the volunteers during the experiment was appreciated by them and was an important help in keeping the volunteers motivated during the experiment.

1. A total of 0, 4 and 9 mg kg-1 body weight sodium bromide was administered orally to 45 healthy female volunteers. 2. The experiment lasted for six menstrual cycles: only during the first three cycles was bromide administered; 3. At the start, at the end of the administration period and at the end of the experiment a physical examination and haematological and routine clinical chemistry tests were performed. Except for nausea in relation to the intake of bromide, no adverse effects were observed. 4. The bromide concentration in plasma rose to 3.22 +/- 0.93 mmol kg-1 in the 4 mg kg-1 group and to 7.99 +/- 1.89 in the 9 mg kg-1 group by the end of the administration period. 5. Before and at the end of the experiment the thyroid hormones (T4, FT4, TBG, T3 and TSH) were analysed. No significant differences were observed between the groups. 6. Before, after three menstrual cycles and at the end of the experiment an EEG with a Visual Evoked Response was recorded. At the 4 and 9 mg kg-1 dose level in the alpha 1-band and the beta-bands significant changes were found (P < 0.1 and P < 0.05, respectively). The Visual Evoked Response showed no significant differences between the three groups. 7. From this experiment and previous experiments a no-effect level in humans for sodium bromide of 4 mg kg-1 body weight is proposed.

Prussian blue salts are used in clinical practice as an antidote for the treatment of humans contaminated with radioactive cesium. A decomposition product of these Prussian blue salts may be the highly toxic cyanide. A method to simulate gastrointestinal cyanide-release was applied to four different Prussian blue salts: K3Fe[Fe(CN)6], Fe4[Fe(CN)6]3, NH4Fe[Fe(CN)6] (pur. and unpur.). Cyanide-release was higher in artificial gastric juice than in water and artificial intestinal juice. Under all conditions cyanide-release from Fe4[Fe(CN)6]3 was the lowest. Since Fe4[Fe(CN)6]3 also binds more cesium, it appears to be the most suitable Prussian blue salt for use as an antidote after radiocesium contamination in humans.

The in vitro binding characteristics of radioactive 137Cs to two forms of Prussian blue [colloidally (soluble) K3Fe[Fe(CN)6] and insoluble Fe4[Fe(CN)6]3] and to activated charcoal and sodium polystyrene sulfonate (Resonium-A) were investigated by constructing Langmuir isotherms at pH = 1.0, 6.5 and 7.5 at 37 degrees C. At the three pHs investigated, 137Cs binding to activated charcoal and sodium polystyrene sulfonate was negligible. Binding of 137Cs to insoluble Prussian blue exceeded that for the soluble form and was pH dependent for both formulations. Maximum binding capacities were 87 mg/g (pH = 1.0), 194 mg/g (pH = 6.5) and 238 mg/g (pH = 7.5) for the insoluble form and 48 (pH = 1.0), 73 (pH = 6.5) and 78 (pH = 7.5) for the soluble form. As activated charcoal did not bind 137Cs, charcoal hemoperfusion is of no value. This has been confirmed by an in vitro experiment, using a Gambro Adsorbs 300 C cartridge.

The effects of histamine administered in samples of fish to eight healthy volunteers (4 females and 4 males), aged 21-30 years, were studied. The subjects were given 0, 45 and 90 mg of histamine that had been metabolized from histidine by photobacteria in the fish and 90 mg of histamine added to fresh fish, for breakfast. The subjects were observed during 6 h after breakfast. Special attention was paid to clinical symptoms, blood pressure and ECG. The pH of the gastric contents was recorded continuously from 5 min before to 6 h after the meal. Blood samples to measure the histamine concentration were taken at intervals during 24 h after breakfast. Two of the subjects showed effects (facial flushing, headache) that could be attributed to the ingestion of histamine. No significant changes were observed in the blood pressure and ECG. The pH of the gastric fluids did not decrease significantly. The histamine concentration in plasma correlated closely with the histamine dose ingested (p < 0.001, r = 0.996). The Cmax of the dose of 90 mg did not differ statistically significant from the Cmax of the dose of 90 mg histamine added to unspoiled fish.

Between December 1988 and March 1989 twelve patients in the Utrecht University Hospital developed an infection with a methicillin-resistant Staphylococcus aureus (MRSA). Twenty other patients and 39 personnel members became colonized with the same MRSA strain. In spite of early isolation measures, progression of this epidemic was probably caused by the extreme degree of contagiousness of the first patient, who had a drug-induced allergic skin eruption. It seems likely that spread occurred via personnel and via a computer tomographic scanner. To contain the epidemic it was necessary to institute a special isolation ward with dedicated personnel. Although several MRSA strains have been introduced in the University Hospital since 1986, the strain we describe here is the only one which spread epidemically.

Two patients exposed to high concentrations of toluene in air (greater than 7000 mg/m3) were found at the bottom of a small swimming pool under construction. Their symptoms were stupefaction, paresis, and amnesia. Patient A had been exposed for three hours and patient B for two hours. Ninety minutes after the exposure, the toluene blood concentration in patient A was 4.1 mg/l and in patient B 2.2 mg/l. Urinary ortho-cresol secretion was shown to be a good index of exposure to toluene. After high level exposure, urinary meta-cresol excretion may also be used to monitor toluene exposure.

The reproducibility and diagnostic value of local bone to soft tissue uptake ratio of 99mTc(Sn)-MDP as a bone tracer was examined in a prospective study in 35 patients who were under investigation and/or treatment for postmenopausal osteoporosis. The ratio of tracer uptake in the second lumbar vertebra (L2) and both femoral shafts was calculated from the number of counts in suitable regions of interest. Results obtained with settings and calculations in the routine practice were compared to the results obtained by revision of all raw data in one run by one person. The results were compared to the serum alkaline phosphatase activity (AP) and to local bone mineral mass as determined by dual photon absorptiometry (DPA). In 15 patients serial measurements during fluoride therapy were also compared to serum osteocalcin values and to bone histomorphometric data. The precision error of the calculation of uptake ratios from raw counts (including selection of region of interest) was 13.9% for the femoral shaft and 14.7% for L2. The mean difference between left and right femoral shaft in individuals was not significant and its variance was small P greater than 0.1). There was a weak but significant linear correlation between local uptake ratio in the spine and AP in the total material (r = 0.328 P less than 0.01). However, changes in local uptake ratio during therapy with fluoride in 15 patients were too small to be of any value and did not correlate with changes in alkaline phosphatase or osteocalcin or trabecular surface covered with osteoblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Urine was collected from 289 inhabitants of a cadmium-polluted quarter of Stadskanaal. The excretion of cadmium, protein, beta-2-microglobulin and glucose were determined. After being divided according to sex and to smoking habits, the results of the inhabitants were compared with those of 293 controls. In inhabitants as well as controls, cadmium excretion was age-dependent. Cadmium excretion in females increased faster with age than in males. In male-smoker controls, cadmium excretion was significantly higher (p less than 0.001) than in male-non-smoker controls. In male-non-smoker inhabitants, cadmium excretion (p = 0.05), protein excretion (p less than 0.01) and glucose excretion (p less than 0.01) were significantly higher than in corresponding controls. In male-smoker inhabitants, protein excretion (p less than 0.01) and glucose excretion (0.01 less than p less than 0.05) were significantly higher than in corresponding controls. In female-non-smoker inhabitants glucose excretion was significantly higher (0.01 less than p less than 0.05) than in corresponding controls. For some categories, living in the polluted area was associated with an increased cadmium excretion in urine and a slight difference in renal function, possibly related to a difference in cadmium body burden. It was concluded that, considering the actual values of each parameter, the observed differences were not relevant in terms of potential health hazards.

The uptake of two different preparations of(99m)Technetium-methylene diphosphonate in fetal rat calvaria is compared. The localization of(99m)Tc after administration of(99m)Tc(Sn)-MDP and(99m)Tc-MDP showed equal distribution in autoradiography.

In the days after the nuclear reactor accident at Chernobyl (USSR) in April 1986, the Dutch Poison Control Center had to answer questions concerning possible health effects caused by (over)exposure to ionizing radiation. These questions were similar to questions asked regarding exposure to toxic agents after chemical accidents. It is obvious that the experience and practical approach of a Poison Control Center in handling toxicological problems can be used in problems concerning ionizing radiation.

A sensitive method is described for the simultaneous determination of glycyrrhizin and glycyrrhetic acid in human plasma. Quantitation is by high-performance liquid chromatography using ion-pair chromatography on a reversed-phase column. Variable-wavelength ultraviolet detection is employed. For the extraction of both compounds from plasma, a new solid-phase ion-pair extraction procedure using octadecylsilane columns was developed. Because of the strong forces involved in the protein binding of glycyrrhizin, quantitative extraction of this compound from plasma was possible only after an alkaline pH shift. A considerable improvement in selectivity and sensitivity was obtained by automated column switching involving on-line preseparation of the solid-phase extract on a short precolumn and chromatographic analysis of a heart-cut from the precolumn eluate. The limit of detection of both glycyrrhizin and glycyrrhetic acid was 0.1 mg/l in 0.5 ml of plasma. From a preliminary study in human volunteers, it was concluded that glycyrrhetic acid rather than glycyrrhizin is preferred in a study in human volunteers to assess the zero effect level of glycyrrhizin.

To prepare sections of undecalcified bone suitable both for autoradiography with short-lived radionuclides such as 99m-technetium (t 1/2 = 6 hr) and for normal histology, rapid processing is necessary. By modifying the routine technique of embedding in plastic, sections can be obtained within 6 hours. The most important modification concerns the temperature used for the different steps in the process. The procedure has been used to localize 99mTc labeled methylene diphosphonate for skeletal scintigraphy.

The localization of 99mTc(Sn)-MDP in bone tissue was compared with 99mTc-MDP by means of microautoradiography of undecalcified bone sections. Sections of good histological quality were obtained by a rapid embedding method in methylmethacrylate. No differences were found in the localization of these radiopharmaceuticals in fetal rat calvariae after incubation in vitro or in rat femora after administration in vivo. In the incubation experiment, hydrolyzed 99mTc was formed. The uptake was high in areas of new bone formation. No uptake was seen in cells or in resorbing areas. In compact bone 99mTc(Sn)-MDP was predominantly taken up in the vicinity of blood vessels.

The HSA-binding of 99mTc incubated as 99mTc(113Sn)-MDP depends in vitro on the presence of competing anions normally present in plasma and on the MDP and Tc concentration, but is independent of the Sn concentration. The HSA-binding of 113Sn depends on the MDP and Sn concentration; not on the Tc concentration. 99mTc(Sn)-MDP binds to HSA as a unit. The binding of 99mTc(Sn)-MDP to plasma proteins in vivo is much lower as calculated from in vitro experiments because of competition between 99mTc(Sn)-MDP and endogenous anions for the same binding-sites.

The labeling of methylene diphosphonate with 99mTc is possible after reduction of pertechnetate by means of controlled potential electrolysis. This results in a [99mTc]MDP complex which differs slightly from 99mTc(Sn)-MDP in paper and gel chromatography. The scintigraphic images of both preparations are comparable in quality. Biodistribution in rats shows a higher bone uptake for the 99mTc(Sn)-MDP complex, whereas [99mTc]MDP shows a higher uptake in the gastric wall.

In The Netherlands accidental intoxications in children due to benzodiazepines are regularly encountered. In 1987 of 1630 requests for information at the National Poison Control Centre about probable benzodiazepine intoxications 144 (8.8%) concerned children 0-12 years of age. The symptoms of this type of intoxication are non-specific and if the physician does not think of benzodiazepine intoxication extensive diagnostic procedures may be performed. If children show symptoms e.g. unconsciousness, ataxia and hypotonia, the physician should always think of benzodiazepine intoxication and try to confirm or to exclude this possibility by toxicological analysis. We discuss ways and means of the diagnosis and how to avoid pitfalls on the way.

In an incubation experiment the Human Serum Albumin (HSA) binding of 99mTc-MDP (electrolytically labeled) and 99mTc(Sn)-MDP is established. During the incubation some pertechnetate is formed and in the case of 99mTc(Sn)-MDP also some hydrolyzed 99mTc. The HSA binding of 99mTc-MDP is less than the HSA binding of 99mTc(Sn)-MDP as established with gel chromatography, TCA-precipitation, ammonium sulfate precipitation and ultrafiltration. TCA-precipitation seems to be an insufficient method for determining the protein binding of 99mTc(Sn)-MDP. The urinary excretion in rats shows only one 99mTc-compound in both cases. The bone seeking properties of the urine-excreted 99mTc-compound were confirmed in another rat.