No abstract

Cefditoren is the active form of cefditoren pivoxil, an oral cephalosporin antibiotic used for the treatment of respiratory tract infections and otitis media caused by bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, and methicillin-susceptible strains of Staphylococcus aureus. ␤-Lactam antibiotics, including cefditoren, target penicillin-binding proteins (PBPs), which are membrane-associated enzymes that play essential roles in the peptidoglycan biosynthetic process. To envision the binding of cefditoren to PBPs, we determined the crystal structure of a trypsin-digested form of PBP 2X from S. pneumoniae strain R6 complexed with cefditoren. There are two PBP 2X molecules (designated molecules 1 and 2) per asymmetric unit. The structure reveals that the orientation of Trp374 in each molecule changes in a different way upon the formation of the complex, but each forms a hydrophobic pocket. The methylthiazole group of the C-3 side chain of cefditoren fits into this binding pocket, which consists of residues His394, Trp374, and Thr526 in molecule 1 and residues His394, Asp375, and Thr526 in molecule 2. The formation of the complex is also accompanied by an induced-fit conformational change of the enzyme in the pocket to which the C-7 side chain of cefditoren binds. These features likely play a role in the high level of activity of cefditoren against S. pneumoniae.

Ethyl acetate extracts from the flowers and leaves of Peroeskiu abrotunoides Karel., Nepetu juncea Benth. and Thymus linearis Benth. growing wild at 2000-3500 in a.s.1. in the Karakoram-Himalaya district were analyzed by GC/MS. The majorvolatileconstituentswere 1,tl-cineole (24.4-27.1%) anda-pinene (18.2-23.2%) for P. abrotunoides, and nepetalactone (71.8%) for N . juncea. Two cheinotypes of T. linearis were found in different area, a thymoll carvacrol type in the areas of Hunza and Rupal Valley, and a geraniollgeranyl acetate type in the area of Rakaposhi Valley. Herbs and their major constituents of N . juncea and T. linearis showed potent antifungal activity by vapor contact, but those of P. abrotanoides showed no significant activity.

This study was designed to characterize the effect of medetomidine (Med) on canine electroencephalography (EEG), to evaluate the use of quantitative EEG for assessing sedation levels and to explore the correlation between the serum concentration of Med and the quantitative EEG. Four groups of dogs were given Med at doses of 20, 40, 80 and 160 microg/kg (Med-20, Med-40, Med-80 and Med-160 groups). Following Med administration, there was synchrony between each unipolar EEG lead. On EEG power spectrum analysis of the bipolar leads, all groups showed a significant depression of the 14-30 Hz components. The power of the 1-3 Hz component in the Med-80 and Med-160 groups was significantly increased, although there were few changes in the other groups. Similar results were obtained from raw data analysis. As a result of quantitative EEG analysis, spectrum edge frequency 90 analysis (SEP90) showed that the frequency was significantly reduced in all groups after Med administration. A dose-response effect was observed in all groups except for the Med-160 group. Both of these EEG analyses were significantly correlated with the serum concentration of Med. However, the result of the SPF90 analysis sugested a stronger correlation than that for median edge frequency analysis. In conclusion, care must be taken in veterinary clinical diagnoses when Med is used during EEG recording, as Med may cause increased activity in the low frequency band and a decrease in high frequency band activity. In addition, quantitative EEG analysis may be useful in assessing the depth of sedation and in further studies on Med administration.

We evaluated the pharmacological profiles of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel tetrahydrocarbazole derivative as a neuropeptide Y (NPY) Y5 receptor antagonist. This compound showed a highly selective in vitro affinity for Y5 (IC 50 ϭ 4.3 Ϯ 0.4 nM) relative to other NPY receptor subtypes like Y1 or Y2. Its binding to Y5 was found to be fully antagonistic from cyclic AMP accumulation assays in human embryonic kidney 293 cells. Pharmacokinetic analysis revealed sufficient oral availability and brain permeability of this compound accompanied with clear dose relation. We attempted to assess the selectivity of FMS586 and, thereby, to infer the physiological role of Y5 in the following feeding experiments in normal rats. An intracerebroventricular injection of NPY and Y5-selective agonist peptide induced acute and robust feeding responses in satiated rats, and prior administration of FMS586 at the doses from 25 to 100 mg/kg clearly inhibited these responses by approximately 55 and 90%, respectively. This compound also showed dose-dependent but transient suppression in natural feeding models of both overnight fasting-induced hyperphagia and spontaneous daily intake. FMS586 did not modulate food intake induced by the topical injection of norepinephrine, galanin, or ␥-aminobutyric acid receptor agonist muscimol to the paraventricular nucleus. In addition, we confirmed the Y5-specific activity profile of FMS586 by immunohistochemical analysis. Taken together, we propose not only that our compound potentially expresses specific blockade of central Y5 signals but also that Y5 receptor would certainly contribute to physiological regulation of food intake in normal rats, as suggested from its origin.