NK1 receptor antagonists under investigation for the treatment of affective disorders

Substance P-neurokinin-1 (NK1) receptor pathways have been repeatedly implicated in the pathophysiology of affective disorders. Anatomical studies in humans have shown a high expression of NK1 receptors in brain regions that are important for the regulation of affective behaviours and stress responses. A large body of evidence that has been generated from animal experiments indicates that treatment with a selective NK1 receptor antagonist might be effective in the treatment of certain forms of anxiety and depressive disorders. Accordingly, numerous NK1 receptor antagonists have either been synthesised and are under clinical development, or have already been tested in clinical trials. However, the initial encouraging clinical results were followed by repeated demonstrations of a lack of effectiveness, thus disappointment and doubt currently surrounds the idea that these compounds may become effective antidepressants. Research continues and novel molecules may show better pharmacokinetic and pharmacodynamic properties and, therefore, may achieve therapeutic success. Furthermore, NK1 receptor antagonists that are ineffective in the treatment of mood disorders may still prove to be effective in the treatment of anxiety problems.     

Malignant transformation of human colon epithelial cells by benzo[c]phenanthrene dihydrodiolepoxides as well as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) ingested with food have repeatedly been suggested to be involved in the malignant transformation of colon epithelial cells. In order to test this hypothesis, HCEC cells (SV40 large T antigen-immortalized human colon epithelial cells) were incubated with a racemic mixture of benzo[c]phenanthrene dihydrodiol epoxides (B[c]PhDE), extremely potent carcinogenic PAH metabolites in vivo, or with 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), the N-hydroxylated metabolite of the most abundant HCA in cooked meat. First, it was shown that HCEC cells express sulfotransferase 1A1, which is needed to metabolize N-OH-PhIP to the corresponding N-sulfonyloxy derivative, the direct precursor molecule of genotoxic nitrenium ions. Thereafter, exponentially growing HCEC cells were exposed five times to 0.1 microg (0.37 nmol) B[c]PhDE/ml for 30 min or 0.72 microg (3 nmol) N-OH-PhIP/ml for 24 h. Chemically treated HCEC cells showed an enhanced saturation density and grew faster than the corresponding solvent-treated cell cultures. After five treatment cycles, HCEC(B[c]PhDE) as well as HCEC(N-OH-PhIP) cells lost cell-cell contact inhibition and started piling up and forming foci in the culture flasks. Furthermore, HCEC(B[c]PhDE) and HCEC(N-OH-PhIP) cells were injected i.m. into SCID mice. Within 6 weeks after injection, eight animals out of eight injected with HCEC(B[c]PhDE) or HCEC(N-OH-PhIP) cells developed tumors at the site of injection, thus demonstrating the high tumorigenic potential of the HCEC(B[c]PhDE) and HCEC(N-OH-PhIP) cell cultures. Taken together, we show for the first time that the abovementioned active PAH metabolites as well as N-OH-PhIP are indeed able to malignantly transform human colon epithelial cells in vitro.     

Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients

Insufficient immunosurveillance is an important aspect in early tumorigenesis and in the pathogenesis of malignant disease. In the later course of cancer, the development of immunodeficiency is considered the major reason for disease progression and death. Within the anti-tumoral host defense reaction, Th1-type cytokine interferon-gamma (IFN-gamma) is of particular relevance. IFN-gamma stimulates several anti-proliferative and thus tumoricidal biochemical pathways in macrophages and other cells and also in tumor cell lines. These include inducible nitric oxide synthase, indoleamine (2, 3)-dioxygenase, an enzyme degrading the essential amino acid tryptophan, and the production of reactive oxygen species and neopterin in human macrophages and dendritic cells. Although the anti-proliferative strategy of the immune system aims to inhibit the growth of malignant cells, it can also affect T-cell response and thus contribute to the development of immunodeficiency. Accelerated degradation of tryptophan and increased production of neopterin were found to parallel the course of malignant diseases. Moreover, a higher degree of these metabolic changes characterizes poor prognosis and is associated with the development of anemia, weight loss and depressive mood in patients. Available data suggest that immunodeficiency in cancer patients may develop as a long-term side-effect of the antiproliferative and pro-apoptotic mechanisms elicited within Th1-type immune response, and enhanced production of pro-inflammatory cytokine IFN-gamma seems to be critically involved.     

In Vitro Antimicrobial Activity of Cinoxacin Against 2,968 Clinical Bacterial Isolates

Cinoxacin demonstrated effective in vitro antimicrobial activity against the Enterobacteriaceae, but negligible activity against Pseudomonas aeruginosa and gram-positive cocci. The activity of cinoxacin was slightly greater than that of nalidixic acid.     

Über die Bedeutung von Kapsel und Epithel für die Phosphatresorption der Linse

Ohne ZusammenfassungMit 3 TextabbildungenDie Arbeit wurde mit Hilfe der Deutschen Forschungsgemeinschaft ausgeführt. Frl.E. Noll und Frl.U. Lob gaben technische Assistenz.