PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D₁-dopamine receptor antagonists. Both compounds have been labeled with¹¹C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D₁-dopamine receptors. This striatal uptake was displaced by high doses of the selective D₁-antagonist SCH 23390 (2 mg/kg) but not by the 5HT₂-antagonist ketanserin (1.5 mg/kg) or the selective D₂-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [¹¹C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [¹¹C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [¹¹C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [¹¹C]NNC 756 the ratio was about 5. This ratio of 5 for [¹¹C]NNC 756 is the highest obtained so far for PET radioligands for the D₁-dopamine receptor.     

The Compliance Curve for the Flow Limiting Segments of the Airway

Maximum effort flow-static recoil curves were obtained in 5 healthy subjects breathing air, He/O₂, and SF₆/O₂ mixtures. In 4 of them maximum effort flows corresponded to really maximal flows and their curves were transformed into compliance curves for the flow limiting segments of the airway and analyzed from the point of view of a previously presented lung model (Pedersen and Nielsen 1976). The results showed, that viscosity dependent pressure losses from the alveoli to the flow limiting segments were minimal for air and SF₆/O₂, but not for He/O₂. When viscosity dependent pressure losses could be neglected, then expiration of gases of different densities gave almost identical compliance curves for the flow limiting segments. This supported the applicability of the model. The calculated compliance curves for the flow limiting segments were compared with data from the literature, and the findings indicated that flow limitation during expirations with just maximal flows throughout began in the extrapulmonary airways and moved upstream during the expiration.     

ZK 91296, a partial agonist at benzodiazepine receptors

ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl--carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedatiye effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.     

A comparison of spiral computed tomography and latex agglutination D-dimer assay in acute pulmonary embolism using pulmonary arteriography as gold standard

OBJECTIVE: To compare the diagnostic accuracy of contrast medium enhanced spiral computed tomography of the pulmonary arteries (s-CTPA) and a latex agglutination D-dimer assay in patients with suspected acute pulmonary embolism (PE) by using pulmonary arteriography (PA) and clinical follow-up as reference method. DESIGN: Ninety hemodynamically stable patients with symptoms of acute pulmonary embolism were prospectively evaluated with s-CTPA and pulmonary arteriography (PA) within 24 h from admission. Plasma D-dimer levels on admittance were analyzed using a rapid latex agglutination D-dimer assay. The outcome of D-dimer concentrations in plasma below 0.25 and 0.5 mg/l was studied. RESULTS: All PA and s-CTPA investigations were regarded as of acceptable diagnostic quality in a consensus reading. Thirty-three patients had a positive PA (37%). Three patients had false negative and two patients had false positive s-CTPA findings. s-CTPA had 91% sensitivity, 96% specificity, 94% positive predictive value (PPV) and 95% negative predictive value (NPV). The sensitivity and specificity for D-dimer below 0.5 mg/l were 79 and 88%, respectively. The PPV and NPV were 81 and 87%. If a cut-off level of 0.25 mg/l was used the corresponding figures were 91, 65, 63 and 92%. CONCLUSION: s-CTPA has a higher sensitivity and specificity than latex agglutination D-dimer. A cut-off level of 0.25 mg/l can be used as screening method, but s-CTPA must be performed to exclude false positive cases.     

CARBON DIOXIDE ADMINISTRATION FOR CORRECTION OF POSTOPERATIVE HYPOXAEMIA

Twenty-three patients were exposed to inhalation of 2 per cent carbon dioxide in air for 20 minutes after completion of surgery. During the administration period an increase in PaO_a and ventilation was observed, whereas PaCO_a remained unchanged. A comparison with a similar group of 11 untreated patients suggested that this effect is temporary.
The recovery from the effects of anaesthesia appeared to be accelerated by carbon dioxide inhalation.

ZUSAMMENFASSUNG

23 Patienten wurden fur 20 Minuten nach Operationsende einer Konzen-tration von 2% G0₂ im Inhalationsgemisch ausgesetzt. Wahrend dieser Periode wurde ein Anstieg des PaO_s und der Ventilation beobachtet, wahrend das PaCO_a unverandert blieb. Der Vergleich mit einer ahnlichen Gruppe von 11 unbehandelten Patienten zeigte, dass es sich um einen temporSren Effekt handelt.
Die Erholung von den Narkoseauswirkungen schien durch die Kohlen-saureinhalation beschleunigt zu werden.     

Workplace levels of psychosocial factors as prospective predictors of registered sickness absence

OBJECTIVE: We sought to investigate whether workplace levels of psychosocial work environment factors predict individual sickness absence. METHODS: Data were collected in a prospective study in 52 Danish workplaces in three organizations: municipal care, technical services, and a pharmaceutical company. Psychosocial factors were aggregated as workplace means. We used multilevel Poisson regression models with psychosocial factors as predictors and individual level sickness absence from absence registries as outcome. RESULTS: High workplace levels of decision authority predicted low sickness absence in the technical services (rate ratio = 0.66, 95% confidence interval = 0.51-0.86) and high workplace levels of skill discretion predicted low sickness absence in the pharmaceutical company (rate ratio = 0.74, 95% confidence interval = 0.62-0.88) after control for relevant confounders. Workplaces in municipal care did not differ with respect to the psychosocial factors. CONCLUSIONS: Psychosocial factors at the workplace level may be important predictors of sickness absence.     

Psychosocial work characteristics as predictors for burnout: findings from 3-year follow up of the PUMA Study

OBJECTIVE: The objective of this study was to investigate the impact of psychosocial work characteristics on burnout. METHODS: A total of 1772 participants in different human service sector organizations were eligible for the cross-sectional analyses (baseline) and 952 for the prospective analyses. We measured 14 psychosocial work characteristics and three types of burnout. Linear regression models were used for analyzing associations between psychosocial work characteristics at baseline and burnout at baseline and at 3 years of follow up. RESULTS: Low possibilities for development, high meaning of work, low predictability, high quality of leadership, low role clarity, and high role conflicts predicted burnout at 3 years of follow up after the psychosocial work characteristics were adjusted for each other, potential confounders, and burnout level at baseline. CONCLUSION: Psychosocial work characteristics were prospectively associated with burnout, suggesting that improving the psychosocial work environment may reduce future burnout in human service work.     

Althesin®in Neurosurgical Patients: Effects on Cerebral Hernodynamics and Metabolism

The effect of althesin 0.5 ml/10 kg on arterial blood pressure, intracranial pressure, cerebral blood flow and oxygen uptake was studied on 19 occasions in 16 patients with varied cerebral pathology. Cerebral blood flow (CBF) was measured using the intracarotid 133xenon method and a 35-channel scintillation detector after cannulation of the internal carotid artery, the internal jugular bulb and the lateral cerebral ventricle. Arterial and intracranial pressures were recorded continuously. Blood gas tensions were measured in simultaneously drawn samples from the internal carotid artery and the jugular bulb. Cerebral oxygen uptake was calculated from the product of CBF and arteriovenous oxygen content difference. Control values were obtained with the patients under a basic general anesthesia, consisting of N2O/O2 pancuronium. The effect of a bolus injection of althesin was then studied 1 and 20 min after the injection. A significant reduction in intracranial pressure, cerebral blood flow and metabolism at 1 min was found to have essentially subsided 20 min after the injection. In patients with focal brain damage, regional flow analysis revealed a paradoxical increase in flow after althesin in the areas corresponding to the focus.     

Degree of Sedation Obtained with Various Doses of Diazepam and Nitrazepam

Abstract Using critical flicker fusion (CFF)determination and estimation of drowsiness in eight healthy volunteers the sedative-hypnotic effects of diazepam and nitrazepam were studied. Three dose levels of each drug were used, so that dose-effect curves could be produced. The most reliable results were obtained with the CFF method, and significant dose-effect relations could be demonstrated. The CFF deviation after diazepam initially related well to the concentration in blood serum, but after 4–6 hours the CFF depression vanished rapidly, while the drug concentration remained high. After nitrazepam the signs of drowsiness occurred similarly, while the drug concentration in serum showed on an average a slower rise. The effects began to disappear before the nitrazepam concentration had reached a peak. A rapid tachyphylaxis at the receptor sites seems to be responsible for this incongruity. Nitrazepam exerted significantly stronger sedative effects than diazepam, particularly when the respective serum concentrations were taken into account. This confirms that nitrazepam should be a more efficient sleeping drug, although diazepam also has considerable sedative-hypnotic action.