Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study

A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600μgscqd for 14days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n=18), diarrhea (n=14) and nausea (n=10), which were mostly mild or moderate in intensity. Pasireotide 600μgsc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3days of dosing and PK exposures had a moderate accumulation of 20-40% across doses. Pasireotide demonstrated fast absorption (T max,ss: 0.25-0.5h), low clearance (CL/F ss: 8.10-9.03L/h), long effective half-life (T ½,eff: ~12h, on average between 9.7 and 13.1h for 50, 200, and 600μgscqd), and large volume of distribution (V z/F ss: 251-1,091L) at steady state. Dose proportionality was confirmed for C max,ss; other PK parameters (C max, AUC0-24h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600μgscqd. Gallbladder volume increased post-prandially with pasireotide 200 and 600μgscqd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600μgqd, with a linear and time-independent PK profile after sc qd dosing in healthy subject

Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus

Kainate receptors are a class of ionotropic glutamate receptors that have a role in the modulation of glutamate release and synaptic plasticity in the hippocampal formation. Previous studies have implicated corticosteroids in the regulation of these receptors and recent clinical work has shown that polymorphisms in kainate receptor subunit genes are associated with susceptibility to major depression and response to anti-depressant treatment. In the present study we sought to examine the effects of chronic stress and corticosteroid treatments upon the expression of the mRNA of kainate receptor subunits GluR5-7 and KA1-2. Our results show that, after 7 days, adrenalectomy results in increased expression of hippocampal KA1, GluR6 and GluR7 mRNAs, an effect which is reversed by treatment with corticosterone in the case of KA1 and GluR7 and by aldosterone treatment in the case of GluR6. 21 days of chronic restraint stress (CRS) elevated the expression of the KA1 subunit, but had no effect on the expression of the other subunits. Similarly, 21 days of treatment with a moderate dose of corticosterone also increased KA1 mRNA in the dentate gyrus, whereas a high corticosterone dose has no effect. Our results suggest an interaction between hippocampal kainate receptor composition and the hypothalamic-pituitary-adrenal (HPA) axis and show a selective chronic stress induced modulation of the KA1 subunit in the dentate gyrus and CA3 that has implications for stress-induced adaptive structural plasticity

Organic pollutants in sea-surface microlayer and aerosol in thecoastal environment of Leghorn—(Tyrrhenian Sea)

The levels of dissolved and particle-associated n-alkanes, alkylbenzenes, phthalates, PAHs, anionic surfactants and surfactant fluorescent organic matter ŽSFOM. were measured in sea-surface microlayer ŽSML. and sub-surface water ŽSSL. samples collected in the Leghorn marine environment in September and October 1999. Nine stations, located in the Leghorn harbour and at increasing distances from the Port, were sampled three times on the same day. At all the stations, SML concentrations of the selected organic compounds were significantly higher than SSL values and the enrichment factors ŽEFsSML concentrationrSSL concentration. were greater in the particulate phase than in the dissolved phase. SML concentrations varied greatly among the sampling sites, the highest levels Žn-alkanes 3674 mgrl, phthalates 177 mgrl, total PAHs 226 mgrl. being found in the particulate phase in the Leghorn harbour. To improve the knowledge on pollutant exchanges between sea-surface waters and atmosphere, the validity of spray drop adsorption model ŽSDAM. was verified for SFOM, surface-active agents, such as phthalates, and compounds which can interact with SFOM, such as n-alkanes and PAHs. q2001 Elsevier Science B.V. All rights reserved

an analytical cross-sectional study

HINTERGRUND und ZIELSETZUNG: Die Hepatitis B und C gehören weltweit zu den häufigsten Infektionskrankheiten. Sie sind wesentliche Risikofaktoren für die Entwicklung einer Leberzirrhose bzw. eines hepatozellulären Karzinoms. Die Prävalenz in Deutschland wird für beide Entitäten bei jeweils ca. 0,5% angegeben bzw. geschätzt. Die frühe Erkennung und Therapie einer Hepatitis B und C senkt als Maßnahme der Sekundärprävention die Mortalität. Deshalb wird ein Screening, insbesondere von Risikogruppen, mittels serologischer Tests empfohlen. Zielsetzung dieser Arbeit war zum einen die Prüfung der tatsächlichen Prävalenz von Hepatitis B und C bei Patienten einer Berliner Rettungsstelle und zum anderen die Evaluation eines Fragebogens, der spezifische Risikofaktoren abfragt. METHODIK: Bei Patienten der interdisziplinären Rettungsstelle der Charité am Campus Benjamin Franklin wurden nach Aufklärung und schriftlicher Zustimmung serologische Tests auf Hepatitis B und C durchgeführt (HBsAg, Anti-HBc, HCV-AK). Im Falle eines reaktiven Anti-HBc Ergebnisses wurde Anti-HBsAg bestimmt. Ein reaktives HCV- AK-Ergebnis galt erst nach einem positiven Bestätigungstest (Immunoblot) als reaktiv. Personen mit reaktivem HBsAg- oder HCV-AK-Ergebnis wurden nachverfolgt und weiter untersucht. Zusätzlich wurde ein von den Studienteilnehmern ausgefüllter standardisierter Fragebogen mit 14 Fragen zu mit Hepatitis-assoziierten Faktoren ausgewertet. ERGEBNISSE: 1942 Personen zwischen 18 und 97 Jahren nahmen an der Untersuchung teil. Nach Alterskorrektur wurden folgende Seroprävalenzen festgestellt: HBsAg: 0,4% (95% CI: 0,1-0,7%), Anti-HBc: 8,3% (95% CI: 7,1-9,5%), HCV-AK: 0,9% (95% CI: 0,5-1,3%). Bei allen 5 Personen mit reaktivem HBsAg-Befund, die nachverfolgt werden konnten, lag eine chronische Hepatitis vor – bei 60% (3/5) bestand eine sofortige Behandlungsindikation. Von den 17 Personen mit bestätigt reaktivem HCV-AK-Ergebnis lag bei 55% (9/17) eine chronische Infektion vor. Bei 5 der 6 Personen mit aktuellem HCV-RNA-Nachweis in der PCR war die Infektion bereits bekannt - eine Behandlungsindikation ergab sich in keinem Fall. Bei der Auswertung des Fragebogens zeigte sich die Angabe der Herkunft aus Hochprävalenzgebieten statistisch hochsignifikant mit einem reaktivem HBsAg- Ergebnis assoziiert (OR 20,62; 95% CI: 4,14-102,80). Bezüglich des HCV-AK- Status ergab sich eine statistisch signifikante Assoziation mit der Frage nach parenteralen Risikofaktoren (OR: 3,65; 95% CI: 1,35-9,85) SCHLUSSFOLGERUNG: Die hier erhobenen Prävalenzen von chronischer und durchgemachter Hepatitis B und C decken sich mit den Daten größerer Bevölkerungsstichproben. Das Vorliegen einer chronischen Hepatitis B war – anders als bei der chronischen Hepatitis C - in den meisten Fällen bislang nicht bekannt. Eine Herkunft aus Ländern mit erhöhter Prävalenz für HBV-Infektionen ist der stärkste Risikofaktor für das Vorliegen einer chronischen Hepatitis B. Gesundheitspolitische Maßnahmen zur Prävention und Identifikation (Screening) von Hepatitis B und deren Folgen sollten diese Bevölkerungsgruppe besonders berücksichtigen. Für die HCV-Infektion wurden parenterale Risikofaktoren durch den Fragebogen als wichtigster Risikofaktor im untersuchten Kollektiv bestätigt. Die meisten Fälle mit HCV-Infektionen waren den Betroffenen bekannt. Damit scheint das unbekannte Infektionsrisiko für die Bevölkerung eher gering zu sein. Der hier eingesetzte Fragebogen zu Risikofaktoren einer Virushepatitis ist als Vorselektionskriterium zur Detektion von chronischen und somit behandlungsbedürftigen Virushepatitiden bei zu geringer Spezifität/Trennschärfe der Fragen nicht geeignet.BACKGROUND and AIM of the study: Hepatitis B and C belong to the most common infectious diseases in the world. They often result in cirrhosis of the liver and hepatocellular carcinoma. The prevalence of both entities in Germany is estimated to be around 0,5%. Early detection and treatment as a measure of secondary prevention lowers mortality. Therefore screening by serological testing, especially of risk groups, is recommended. In this work we investigated the actual prevalence of Hepatitis B and C in an emergency department in Berlin and evaluated a questionnaire focusing on specific risk factors. METHODS: Patients attending the Charité Department of Emergency Medicine at the Campus Benjamin Franklin in Berlin were tested for hepatitis B and C after informed written consent (HBsAg, anti-HBc, HCV-antibodies). If the anti-HBc-test was reactive, anti-HBsAg was tested. HCV-antibody tests had to be confirmed by a positive control test (immunoblot). Those with reactive HBsAg- or HCV-antibody-results were followed up and examined further. In addition a standardized questionnaire containing 14 items which are connected to viral hepatitis was answered by the participants and analyzed. RESULTS: 1942 peoples aged 18-97 years were tested. The following seroprevalences were detected (after age-adjustment): HBsAg: 0,4% (95% CI: 0,1-0,7%), anti-HBc: 8,3% (95% CI: 7,1-9,5%), HCV-antibody: 0,9% (95% CI: 0,5-1,3%). All 5 persons with reactive HBsAg-results who could be followed up had chronic hepatitis. In 60% (3/5) of the cases there was indication for immediate treatment. Out of 17 patients with confirmed reactive HCV-antibody-results 55% (9/17) had a chronic infection. In 5 of 6 cases with current HCV-RNA-verification by PCR the infection was already known - there was no indication for treatment. Analyzing the questionnaire, origin from high-prevalence-countries was statistically significantly associated with reactive HBsAg-results (OR 20,62; 95% CI: 4,14-102,80). As far as HCV-antibody results are concerned, parenteral risk factors showed a statistically significant association (OR: 3,65; 95% CI: 1,35-9,85). CONCLUSIONS: The prevalence of chronic viral hepatitis or contact with hepatitis B or C in the past matches the existing data from population- based-surveys. Chronic hepatitis B was – in contrast to hepatitis C - unknown in most of the cases. Migration background from high-prevalence-countries is the most important risk factor for chronic hepatitis B in the studied population. Public health measures in Germany for the prevention and screening for hepatitis B should therefore especially include this part of the population. For HCV-infection parenteral risk factors were confirmed being the main risk for HCV-infection in the study population. According to the results of this survey with mostly known HCV-infections the unknown risk of infection for the general population seems to be rather low. The questionnaire used in this survey about risk factors of viral hepatitis is not useful as preselecting-criteria for detecting chronic viral hepatitis requiring treatment because of insufficient specificity/discriminatory power

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Evaluation of biomarkers for pharmacological activity

In recent years the cost of drug development has increased the demands on efficiency in the selection of suitable drug candidates. Biomarkers for efficacy and safety could be a plausible strategy to improve this selection process. In the present work, we focus on the study and evaluation of different physiological variables as biomarkers for pharmacological activity. We proposed three different approaches using multivariate and univariate techniques. We note that even though one could argue that the multivariate procedure is more powerful than the other alternatives, the univariate methods also offer a great flexibility to answer interesting scientific questions. The three approaches were used to analyze a crossover study involving an opioid antagonist.status: publishe