Feinstrukturanalyse von Immundefizienzviren (HIV, SIV, EIAV) Schlussbericht

The project, consisting of several topics and performed in a number of (inter-)-national cooperations, aimed at gaining structure-function related information on HIV. To collect key data on the infectious virion. In HIV clone HXB3 strain suspensions the ratio of infectious/noninfectious particles was followed during ageing at 37 C. The spontaneous loss of gp 120 knobs was correlated with loss of viral infectivity (half life 30 h). The virion contains 5 x 10"-"1"7 g, i.e. about 1200 molecules p24/virion. To investigate the action of HIV-PR inhibitors on virus production and morphogenesis. In vitro results showed suppression of virus infectivity at concentrations of 1 nmol and below. One reason for inhibition was identified as an arrest in budding and malformation of immature virions, i.e. a late stage in HIV production. To analyse the fine structure of HIV in detail: a novel structural constituent, the Core-Envelope-Link, was described. CEL appears to be essential for functional maturation of HIV and thus might offer another opportunity for antiviral therapy. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(47,31) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Sendai virosomes revisited: Reconstitution with exogenous lipids leads to potent vehicles for gene transfer

A reliable new procedure is described for the reconstitution of Sendai viral envelopes suitable for gene transfer. Both fusion and hemagglutinin- neuraminidase glycoproteins were extracted from purified Sendai virus and reconstituted together with DNA in the presence of cholesterol:sphingomyelin:phosphatidylcholine:phosphatidylethanolamine (Chol:SM:PC:PE) in a molar ratio of 3.5:3.5:2:1. Before reconstitution, the DNA to be transferred was condensed by pretreatment with polylysine. Exogenous lipid addition and the DNA-condensation step were essential for maximal size as well as for fusogenic activitY of the resulting virosomes, the analysis of which revealed (1) the absence of any genomic material originating from Sendai virus, (2) the presence of fusogenic spikes in a functional orientation, (3) the encapsulation of reporter genes, and (4) high-transfer activitY for plasmids carrying the green fluorescent protein (GFP) gene and double-stranded nucleotides into different mammalian cells. Transfer rates were up to 10-fold higher than those obtained with different cationic lipids. Gene delivery by means of our lipid-enriched Sendai virosomes extends the known gene transfer strategies, including those based on Sendai virus previously published

Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

Personalised Therapeutic

Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

Personalised Therapeutic

Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Clinical Oncolog

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range K14 to 33%) at t=4 without morning dose (P=0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment