[Patient-oriented management of aggression and violence in psychiatry. Description of a training program and first results]. / Patientengerechte Aggressionsbewältigung in der Psychiatrie. Beschreibung eines Seminars und erste Ergebnisse.

Violence, aggression, and patient assaults result in a considerable number of job-related accidents in psychiatry. We describe a patient-oriented training program for managing aggression and violence in psychiatry. Ratings by 335 training participants indicate high to very high acceptance. In addition, ratings in the questionnaire for the study subjects' beliefs about competence and control suggest a statistically significant increase in active behavior and internal locus of control in 31 subjects. No significant changes were observed in the waiting-list control group. Our results suggest that a patient-oriented training program for the management of aggression and violence in psychiatry can have high acceptance and lead to lasting changes in beliefs about competence and control, resulting in an increased internal locus of control.

The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae.

Exposure of Saccharomyces cerevisiae to high osmotic stress evokes a number of adaptive changes that are necessary for its survival. These adaptive responses are mediated via multiple mitogen-activated protein kinase pathways, of which the high-osmolarity glycerol (HOG) pathway has been studied most extensively. Yeast strains that bear the hsp82T22I or hsp82G81S mutant alleles are osmosensitive. Interestingly, the osmosensitive phenotype is not due to inappropriate functioning of the HOG pathway, as Hog1p phosphorylation and downstream responses including glycerol accumulation are not affected. Rather, the hsp82 mutants display features that are characteristic for cell-wall mutants, i.e. resistance to Zymolyase and sensitivity to Calcofluor White. The osmosensitivity of the hsp82T22I or hsp82G81S strains is suppressed by over-expression of the Hsp90 co-chaperone Cdc37p but not by other co-chaperones. Hsp90 is shown to be required for proper adaptation to high osmolarity via a novel signal transduction pathway that operates parallel to the HOG pathway and requires Cdc37p.

Inhibition of ciramadol glucuronidation by benzodiazepines.

Studies on the inhibition of ciramadol glucuronidation by benzodiazepines were performed in vitro and in vivo. Ciramadol glucuronidation was slower (Vmax, 1.56 vs. 5.40 nmol/min/mg of microsomal protein) in human than in dog liver microsomes. Inhibition constants (Ki) for lorazepam and oxazepam were 3 to 4 times higher than that calculated for diazepam. Rates of morphine glucuronidation in human liver microsomes were assessed for comparative purposes and agreed with literature values. Each benzodiazepine appeared to be a competitive inhibitor of ciramadol and morphine UDP-glucuronyltransferase activity. The in vivo disposition of ciramadol was unchanged in dogs pretreated with lorazepam. After diazepam treatment no change in the Vdss of ciramadol occurred, but plasma clearance was significantly reduced, resulting in a prolongation of t1/2. Diazepam caused a significant reduction in the oral clearance of ciramadol, whereas no change occurred in systemic availability. Thus, diazepam may have had a secondary effect on hepatic blood flow (QH) and produced offsetting alterations in both intrinsic clearance (Cl int) and QH. A decrease in the area under the plasma concentration time curves of ciramadol aryl O-glucuronide following iv treatment with diazepam coupled with the in vitro data indicate that the mechanism for the decrease in the clearance of ciramadol is inhibition of its glucuronidation by diazepam. Since glucuronidation plays a major role in the elimination of ciramadol in man and dog, these experiments suggest that the disposition of ciramadol in man would not be affected by coadministration of lorazepam, whereas the potential for a diazepam/ciramadol drug interaction in humans exists.

Gas chromatographic determination of guanabenz in biological fluids by electron-capture detection.

A sensitive gas chromatographic method for the determination of guanabenz[(2,6-dichlorobenzylidene)amino]guanidine in urine and plasma was developed. The method depends upon the acid hydrolysis of guanabenz to 2,6-dichlorobenzaldehyde, which has strong electron capturing properties and is volatile enough to be eluted from a gas chromatographic column. Concentrations as low as 0.1 ng of guana-benz/ml can be determined and recovery of the drug from urine and plasma samples is 81.8+/- 5.5% (SD). No interferences arising from plasma, urine, or reagents were encountered. Examples of the application of the method are given.

Pharmacokinetic disposition of guanabenz in the rhesus monkey.

The pharmacokinetics of guanabenz (E-2,6-dichlorobenzylidene aminoguanidine acetate, Wy-8678) in rhesus monkeys given 14C-labeled and unlabeled drug were investigated. The radioactive dose was well absorbed after intragastric (ig) administration of 1 mg of the labeled drug per kg, as indicated by tissue and urinary recovery of the label. Excretion into urine accounted for 57 +/- 3 (SE)% of the radioactive ig dose. Recovery of radioactivity in urine after iv administration of 0.2 mg/kg was 79 +/- 0.6% of the radioactive dose. Less than 1% of the dose was recovered in urine as unchanged drug after either route of administration. Plasma concentration/time profiles after 1-mg/kg iv and ig doses were fitted by polyexponential equations with a terminal elimination half-life of 12.0 +/- 1.1 hr. A large volume of distribution (VSSD = 10.3 +/- 0.7 liters/kg) indicated extensive extravascular distribution of the drug, which was confirmed by 14C-distribution studies. The systemic clearance was 27.5 +/- 1.4 ml/min/kg with hepatic clearance appearing to be the major determinant in guanabenz elimination. Dose proportionality was evident from a comparison of areas under the plasma concentration-time curves (AUC) of 1- and 5-mg/kg ig doses. The low systemic availability of 0.19-0.31 reflects the extensive presystemic extraction (first-pass effect) of the drug. Similarities in the pharmacokinetics of guanabenz in man and the rhesus monkey indicate that the latter species may serve as a satisfactory model for man in disposition studies.

Relationship of guanabenz concentrations in brain and plasma to antihypertensive effect in the spontaneously hypertensive rat.

The antihypertensive agent guanabenz (E-2,6-dichlorobenzylidene aminoguanidine acetate. Wy-8678) was administered i.v. in single doses of 10, 32 and 100 microgram/kg to groups of spontaneously hypertensive rats. Mean arterial blood pressure and heart rate were monitored continuously. Animals were decapitated at predetermined time intervals and concentrations of the drug in whole brain and plasma were measured by a specific gas chromatographic method. After an initial transient increase in blood pressure, significant dose-dependent maximal decreases in pressure of 15 +/- 8, 46 +/- 20 and 59 +/- 15 mm Hg (mean +/- S.D.) were observed 15 to 30 min after injection of the above respective doses. At the line of the maximal decreases in pressure (T delta max), concentrations of guanabenz in brain were 10 +/- 2, 29 +/- 8 and 89 +/- 21 ng/g and correlated significantly with dose and the magnitude of blood pressure change. The correlation between concentration in brain and change in blood pressure was also significant at subsequent sacrifice times. Concentrations of guanabenz in plasma were below the limit of detection after the 10 microgram/kg dose. At the two higher doses, concentrations in plasma were dose related but did not correlate with decreases in blood pressure. The correlation between concentration in brain and change in blood pressure is in agreement with the predominantly central mechanism of action of guanabenz.