Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg^–1, and the steady-state volume of distribution (V_ss) was 2.16 1·kg^–1. The distribution (t_1/2) and elimination (t_1/2) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min^–1·kg^–1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CV_intra) as it was between patients (CV_inter). The steady-state trough plasma concentration (C_min obs) ranged from 4.8 to 30 mg·1^–1 (mean 16.0 mg·1^–1 and median 14.3 mg·1^–1). Peak concentrations (C_max obs) ranged from 8.35 to 45 mg·1^–1 (25.4 mg·1^–1, and median 23.3 mg·1^–1). The values of V1 and V_ss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg^–1. The mean V_ss was 2.68 1·kg^–1, with a CV_intra of 12.6 to 56% and a CV_inter of 13.2%. A shorter distribution half-life t_1/2 was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t_1/2 and the mean residence time became longer due to a decrease in clearance. For t_1/2 the mean value was 16.3 h. The mean MRT was 21.9 h, CV_intra 9.19 to 48.5%, and the CV_inter 35.3%. The mean clearance was 2.16 ml·min^–1·kg^–1, CV_intra 7.28 to 25.5%, and the CV_inter 20.4%. This value is 50% lower than after a single dose.Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.     

Bildanalyse bei der Mehrschicht-Spiral-CT der Lunge mit MPR- und MIP-Rekonstruktionen

PURPOSE: To test, whether axial, coronal and sagittal MIP and MPR reconstructions of diagnostic quality can be obtained from 1-mm collimation MSCT data of the chest for the evaluation of thoracic anatomy and pathology. MATERIALS AND METHODS: 1-mm collimation MSCT scans were obtained with a pitch of 6 in an acrylic phantom and in 20 patients. Axial images were reconstructed with 0.6-mm increment. Multiplanar reformations (MPRs) and sliding thin-slab maximum intensity projections (STS-MIPs) were reconstructed in axial, coronal and sagittal planes. Images were printed in lung windows and evaluated by three readers by using a standardized evaluation scheme. RESULTS: Overall, both methods allowed good visualization of anatomic structures. MIP was superior for visualization of the pulmonary arteries (p < 0.05) while central and peripheral bronchi and the lung parenchyma were better depicted on multiplanar reconstructions. A confident diagnosis of thoracic pathology was feasible using both modalities, however MIPs appeared less usefull for evaluation of gross parenchymal abnormalities, such as pneumonic infiltrates or fibrotic changes. No significant difference in the degree of motion artifacts were detected between both modalities. CONCLUSION: MSCT data sets are ideally suited for generating MPR and MIP reconstructions. While MIPs are superior for the evaluation of thoracic vessels, MPR is advantageous for visualizing central and peripheral bronchi and the pulmonary parenchyma.     

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli: a 15O-PET study

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.     

A photothrombotic ring stroke model in rats with or without late spontaneous reperfusion in the region at risk

This study aimed at developing a dual setup of the photothrombotic ring stroke model with or without late spontaneous reperfusion in the region at risk and to explore the morphological consequences. The exposed crania of adult male Wistar rats were subjected to a ring-shaped laser-irradiation beam (o.d. 5.0 mm, 0.35 mm thick) for 2 min simultaneously with intravenous erythrosin B (17 mg/kg) infusion. Transcardial carbon-black perfusion revealed that a laser intensity of 0.90 W/cm(2) resulted in late, that is, starting at 72 h, spontaneous reperfusion, whereas the lowest laser intensity that produced lack of reperfusion at 7 days post-irradiation was 1.84 W/cm(2). Laser-Doppler flowmetry showed prompt cortical cerebral blood flow (cCBF) reduction both in the ring lesion and region at risk (12% and 25% of control values) after high-intensity irradiation; these reduced flow values were more rapid and pronounced than in the low-intensity irradiation setup as previously shown. The high- compared with low-intensity irradiation setup produced more frequent occurrence of thrombi in the ring-lesion region and a larger ischemic cortical lesion with a more rapid pace of ischemic cellular changes in the ring-lesion region and the region at risk. The region at risk transformed into pannecrosis in the high-intensity, but recovered morphologically in the low-intensity irradiation setup. This dual photothrombotic setup with or without spontaneous reperfusion enables the study of events related to ischemic cell survival or death in an anatomically predefined region at risk.     

Prediction of hospitalizations by schizophrenia patients' assessment of treatment: an expanded study

This study examines whether schizophrenia patients' global assessment of treatment predicts outcome in community care. Eighty-five patients rated the extent to which their treatment was right for them. The outcome measure was assessed by means of a hospitalization index reflecting the duration of full and partial hospitalization within a follow-up period of 24 months. Patients who dropped out (n = 21) assessed their treatment more negatively than those who remained in the care system during follow-up. Patients with no hospitalization (n = 25) expressed a more negative assessment than patients who were hospitalized in the follow-up period at least once (n = 39). In this latter subgroup, however, patients with a more negative assessment had a longer duration of hospitalization during follow-up, and patients' assessment of treatment was the best single predictor of outcome (r = -0.50, P < 0.01). In a multiple regression analysis, patients' assessment of treatment, the number of previous hospitalizations and the hospitalization index in the two years prior to the interview, together, explained approximately half of the variance of outcome (adjusted R2 = 0.46). The findings underline the relevance of asking patients whether treatment is right for them, although the relationship between patients' assessment of treatment and long-term outcome seems more complex than previous studies suggested.     

Opposite links of positive and negative symptomatology with memory errors in schizophrenia

We wished to confirm and extend a previous correlational study of our group, suggesting that positive symptoms in schizophrenia were linked to an increase in certain types of memory errors, and negative symptoms to a decrease in other types of errors. A post-hoc analysis was conducted in 33 schizophrenic patients and 40 normal control subjects on memory errors collected in a free recall task and two types of recognition tasks. The memory errors were intrusions and list errors in free recall, and decision bias towards false alarms in recognition, all assumed to reflect a source-monitoring failure. In a first analysis, the patient sample was split along the median for positive symptoms as rated by the Scale for the Assessment of Positive Symptoms (SAPS). In a second analysis, it was split along the median for negative symptoms as rated by the Scale for the Assessment of Negative Symptoms (SANS). Patients with high ratings of positive symptoms made more memory errors (intrusions, list errors, false alarms) than those with low ratings, supporting the hypothesis of a link between positive symptomatology and source-monitoring failure. On the other hand, patients with high ratings of negative symptoms made fewer of these errors than the other patients. Fewer errors were specifically associated with more affective flattening, alogia and anhedonia, whereas avolition was entirely unrelated to them.     

The blood enzymatic antioxidative potential in bronchial asthma patients

This study aims at assessing the ability of asthma patients to defend themselves against the noxious effects of oxidative stress, known being the inflammatory nature of this disorder. As the anti-radical defence ability of the body is reflected by the antioxidative potential of blood and tissues, our study was based on the determination of the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and CAT/SOD and GPx/SOD ratios in the blood. Except for SOD, the activity of which was lower in asthma patients by -34.08%, CAT and GPx had values increased by +32.18%, respectively, with a resulting increase of CAT/SOD and GPx/SOD ratios. Our data, demonstrating a change in per-oxidants/antioxidants balance in favour of the first ones, seem to suggest that in the treatment of bronchial asthma the association of some compounds with antioxidants effects would be beneficial.     

Lung cancer risk in male workers occupationally exposed to diesel motor emissions in Germany.

BACKGROUND: Although in several epidemiological studies exposure to diesel motor emissions (DME) shows an elevated lung cancer risk, it is still controversial whether DME is a human carcinogen. METHODS: In a pooled analysis of two case-control studies on lung cancer in Germany a total of 3498 male cases with histologically or cytologically ascertained lung cancer and 3541 male population controls were included. Information about lifelong occupational and smoking history was obtained by questionnaire. Drivers of lorries, buses, taxies, diesel locomotives and forklift trucks, bulldozers, graders, excavators, and tractors, were considered as exposed to DME and their cumulative exposure was estimated. All odds ratios were adjusted for smoking and asbestos exposure. RESULTS: The evaluation of lung cancer risk for all jobs with DME-exposure combined showed an odds ratio of OR=1.43 (95%-CI: 1.23-1.67). Most pronounced was the increase in lung cancer risk in heavy equipment operators (OR=2. 31 95%-CI: 1.44-3.70). The risk of tractor drivers increased with length of employment and reached statistical significance for exposures longer than 30 years (OR=6.81, 95%-CI: 1.17-39.51). The group of professional drivers (e.g., trucks, buses, and taxies), showed an increased risk only in West Germany (OR=1.44, 95%-CI: 1. 18-1.76), but not in East Germany (OR=0.83, 95%-CI: 0.60-1.14). DME-exposure in other traffic related jobs (e.g., diesel engine locomotive drivers, switchmen, forklift operators) was associated with an odds ratio of OR=1.53 (95%-CI: 1.04-2.24). CONCLUSIONS: The study provides further evidence that occupational exposure to diesel motor emissions is associated with an increased lung cancer risk.     

Incidence of myocardial infarction in the Danish MONICA population 1982-1991.

BACKGROUND: Cardiovascular mortality has been declining in Denmark over the past 20 years. Trends in incidence of myocardial infarction (MI) over the period 1982-1991 are described within the framework of the World Health Organization MONICA Project. METHODS: The DAN-MONICA heart register included all cases of MI in 25-74-year-old men and women living in 11 municipalities around Glostrup County Hospital evolving over a period of 10 years. They were identified retrospectively based mainly on relevant ICD diagnoses in death certificates and hospital discharge reports. Cases meeting WHO-MONICA criteria for definite or possible MI, recurrent as well as first-ever MI, were registered. Subsequent tracing of cases through national registers on deaths and hospitalizations by means of the patient's civil registration number ensured the completeness of the registration. RESULTS: A total of 6025 cases of MI occurred in the period, 4532 among men and 1493 among women. A total of 2923 men and 1047 women had a first-ever MI in the period. The age-standardized rates show a definite decline over the registration period for men and a less distinct decline for women. CONCLUSIONS: The DAN-MONICA heart register meets the requirements for completeness and uniformity throughout the registration period. Causes and magnitude of bias are well described. Even when possible sources of bias are taken into account, the incidence of MI decreased significantly over the 10-year-period 1982-1991 by an average of 5.0% per year for men and 3.5% per year for women.     

Pathological excretion patterns of urinary proteins in renal cell cancer patients exposed to trichloroethylene

A study was carried out to investigate urinary protein excretion patterns by means of SDS-polyacrylamide-gel-electrophoresis (SDS-PAGE) in renal cell cancer patients who had previously been exposed to high levels of trichloroethylene. Thirty-eight out of 41 (93%) renal cell cancer patients investigated had former extensive trichloroethylene exposure, but only 23 out of 50 (46%) renal cell cancer patients without a history of occupational exposure to trichloroethylene revealed urinary protein patterns indicative of toxic effects on the tubular system. One hundred controls without histories of overt renal disease and not occupationally exposed to trichloroethylene were examined in the same way; only 11 (11%) of them displayed protein excretion patterns indicative of damage to the renal tubule. These results are supported by alpha 1-microglobulin excretion data. The following conclusions are drawn: (1) Substantially more cases of tubular damage are found amongst renal cell carcinoma patients having been exposed to substantial levels of trichloroethylene over many years as compared with renal cell carcinoma patients not exposed to trichloroethylene. (2) The results support the view that chronic tubular damage is a precondition for the nephrocarcinogenic effect of trichloroethylene. (3) The findings indicate that urine protein patterns, on the basis of the SDS-PAGE methodology, represent a 'biological effect parameter' for the medical surveillance of persons occupationally exposed to trichloroethylene.