Gerfried Zeichen — Aus Anlass seiner Emeritierung

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Complete elimination of the hepatobiliary mr contrast agent Gd-EOB-DTPA in hepatic dysfunction: An experimental study using transport-deficient,mutant rats

Mutant Wistar rats (TR^– rats) are characterized by a defect in the canalicular transport system for organic anions in the hepatocytes. Anionic hepatobiliary contrast agents for X-ray and MR imaging usually depend on this transport system for biliary secretion. The current study investigated in rats whether Gd-EOB-DTPA, a hepatocyte-directed MR contrast agent, can be completely eliminated in the absence of biliary excretion, and whether urinary elimination may compensate for the hepatic dysfunction. In TR^/t- rats elimination of Gd-EOB-DTPA almost completely depended on renal excretion: following intravenous administration of 25µmol kg^–1 Gd-EOB-DTPA only 2.4±0.4% of the injected dose underwent biliary excretion. Nevertheless only 2% of a 10-fold higher dose (250µmolkg^–1 Gd-EOB-DTPA) was still detected in the body 24 hours p.a., and less than 0.5% 7 days p.a. (no statistically significant differences as compared to values in control rats). In TR^– rats, renal and liver signal intensities on T1-weighted MR images returned to baseline within 24 hours following administration of 25µmol kg^–1 Gd-EOB-DTPA. In control rats, return to baseline values was observed already 6 hours after injection of the contrast agent. In conclusion, the hepatobiliary MR contrast agent Gd-EOB-DTPA is effectively and completely cleared from the body even in the virtual absence of biliary excretion. The urinary elimination pathway is able to fully compensate for the deficient hepatic transport system.     

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance

Using a monoclonal antibody based ELISA, 600 pAN7-1 plasmid-tagged mutants of Penicillium paxilli were screened for paxilline accumulation and one paxilline-negative mutant, YI-20, was identified. A molecular analysis of this mutant showed that pAN7-1 was inserted at a single site but was present as 4-6 copies arranged in a head-to-tail tandem array. Rescue of flanking sequences and analysis of the corresponding genomic region revealed that YI-20 has an extensive deletion at the site of pAN7-1 integration. Probing of a CHEF gel with the same sequences showed that associated with the deletion is a rearrangement of chromosome Va. Targeted gene disruption of wild-type sequences adjacent to the site where pAN7-1 inserted, resulted in the generation of two additional paxilline-negative mutants; both were single crossovers with deletions extending outside the region mapped. Neither of these new mutants had a rearrangement of chromosome Va, suggesting that deletion of genes on this chromosome is responsible for the paxilline-negative phenotype. Telomeric fingerprinting of genomic digests of P. paxilli, combined with pulsed-field gel electrophoresis of chromosomal DNA, established that there are a minimum of eight chromosomes in this fungus.     

Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent

Rationale and objectives: Gadomer-17 is a new magnetic resonance (MR) contrast medium presently in clinical development. It is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions. This study investigated the pharmacokinetic behavior of this contrast medium. Methods: The pharmacokinetics of Gadomer-17 were investigated in different species (rat, rabbit, dog, monkey) for up to 7 days after intravenous (i.v.) injection of 25–100 μmol/kg body weight. In addition, elimination and biodistribution were evaluated after single i.v. injection of Gadomer-17 in rats. Results: After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. The volume of distribution (Vc) in the initial or α-phase ranged from 0.04 1/kg (rats, rabbits) to 0.06 1 kg (monkeys) and 0.07 1/kg (dogs), which reflects mainly the plasma volume. The blood/plasma concentration profile was found to be biphasic. The volume of distribution at a steady state is clearly smaller than that of other contrast media, which distribute to the extracellular space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body, mainly via glomerular filtration. No long-term accumulation or retention of the nonmetabolized agent was detectable in organs or tissues. Conclusions: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.