[Suicidality in German-speaking school psychiatry : Thematization in textbooks from 1803 until the present]. / Suizidalität in der deutschsprachigen Schulpsychiatrie : Thematisierung in Lehrbüchern von 1803 bis heute.

BACKGROUND: This chronology gives an overview about continuities and changes in the perception of suicidality in German-speaking school psychiatry over the past 200+ years. QUESTIONS: This study was guided by the following questions: has suicidality been perceived as regularly being connected to certain mental illnesses? Which other possible causes have been discussed by psychiatrists from the nineteenth century to the beginning of the twenty-first century? What approaches have major psychiatrists adopted towards suicidal patients and threatened suicide? What treatment and preventive strategies have been suggested? METHODOLOGY: First, we compiled a list of the, in our view, most influential textbooks on psychiatry of German-speaking school psychiatry from 1803 until the present. These textbooks were then skim-read for relevant passages on suicidality. The material gained was elicited, classified and analyzed in relation to the questions at hand. Futhermore, an attempt was made to arrive at contextual estimations. RESULTS: Several authors named a certain set of psychiatric illnesses that are assumed to involve or increase the risk of suicide. These illnesses include depression, schizophrenia and also physical illnesses. In nineteenth century textbooks heredity, anatomical anomalies and nationality were discussed as potential influencing factors. In contrast, more recent books discuss models of how suicidal behavior emerges and often refer to the Werther effect. With respect to therapy there is a trend towards therapeutic discussions and modern psychopharmacotherapy. DISCUSSION: Over time, there have been continuities and changes in psychiatrists' approach to suicidality not only as far as clinical aspects are concerned but also the general approach to and management of suicidal patients.

In vitro to in vivo comparison of the substrate characteristics of sorafenib tosylate toward P-glycoprotein.

Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(-/-) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(-/-) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(-/-) mice were 1.3- to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(-/-) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase.

BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.

Endotoxin-reduced milk oligosaccharide fractions suitable for cell biological studies.

Endotoxins (ET) are able to activate leukocytes and other cell types and thus affect cell adhesion studies with regard to biological functions of human milk oligosaccharides (HMO). In our HMO preparations we detected ET in concentrations of 1.1 to 32.7 ng/mg. However, as we found in previous tests, an ET concentration of less than 100 pg/ml was necessary in order to avoid effects on the expression of CD11b and CD62L on human neutrophil granulocytes. Therefore, we used affinity chromatography with a detoxifying gel (polymixin B) which reduces the ET concentration of 414.9 +/- 121.5 (mean +/- SEM) and 47.9 +/- 5.9 pg/mg for the acidic and the neutral HMO, respectively. As only about 50 - 100 microg HMO per ml test solution are usually used in biological assays, the residual ET concentration does not interfere with cellular functions. We conclude that despite structural similarities between ET as lipopolysaccharides and complex HMO, a one step purification of HMO preparations was sufficient to get HMO material that can be used in cell culture systems.

Investigations of the in vitro transport of human milk oligosaccharides by a Caco-2 monolayer using a novel high performance liquid chromatography-mass spectrometry technique.

Complex lactose-derived oligosaccharides belong to the main components of human milk and are believed to exert multiple functions in the breast-fed infant. Therefore, we investigated the transepithelial transport of human milk oligosaccharides over Caco-2 monolayers. Main human milk oligosaccharides (HMOs) in the apical, basolateral, or intracellular compartment were separated by high performance liquid chromatography using a Hypercarb(TM) column and analyzed on line by mass spectrometry. This method allowed the identification and quantification of these components in intra- and extracellular fractions without prior purification. Using this technique we were able to show that acidic and neutral HMOs cross the epithelial barrier. The transepithelial flux of neutral, but not acidic, oligosaccharides was temperature-sensitive and partly inhibited by brefeldin A and bafilomycin A. Furthermore, net flux from the apical to the basolateral compartment was only observed for the neutral components. Similarly, apical cellular uptake was only found for neutral components but not for acidic oligosaccharides. Intracellular concentrations of neutral HMOs were significantly increased by inhibitors of transcytosis such as brefeldin A, N-ethylmaleimide, or bafilomycin A. The cellular uptake was saturable, and an apparent K(m) for lacto-N-fucopentaose I of 1.7 +/- 0.1 mmol/liter and for lacto-N-tetraose of 1.8 +/- 0.4 mmol/liter was determined. Furthermore, the uptake of lacto-N-fucopentaose I could be inhibited by the addition of the stereoisomer lacto-N-fucopentaose II but not by lacto-N-tetraose. These findings suggest that neutral HMOs are transported across the intestinal epithelium by receptor-mediated transcytosis as well as via paracellular pathways, whereas translocation of acidic HMOs solely represents paracellular flux.

Human milk oligosaccharides are minimally digested in vitro.

In examining the functional aspects of human milk oligosaccharides (HMO), it is not known whether they are digested during the passage through the infant's gastrointestinal tract. HMO were prepared from individual milk samples (n = 6) and separated into neutral and acidic compounds by chromatography. These oligosaccharide fractions were studied for their digestibility by human salivary amylase, porcine pancreatic amylase and brush border membrane vesicles (BBMV) isolated from porcine small intestine; we also examined the effect of low pH on these structures. The characterization of HMO and their digestion products was performed by high-pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) as well as TLC. It was shown that neither salivary amylase nor pancreatic amylase cleaved HMO. Only after a 2-h incubation with BBMV were slight modifications of the HMO observed. HPAEC-PAD analysis revealed two new components within the neutral oligosaccharide fractions; these were characterized by mass spectrometric analysis as lacto-N:-triose and galactose. Only lacto-N:-triose was present within digestion assays of oligosaccharides, which did not contain fucosyl or N:-acetylneuraminic acid residues. These results suggest that <5% of the HMO are digested in the intestinal tract. Hence, HMO may play a role as prebiotics or as factors influencing the local immune system of the intestine in breast-fed infants.