In a randomized crossover study, the pharmacokinetics of three new cephalosporin antibiotics, cefaclor, cefadroxil, and CGP 9000, in comparison to cephalexin, were determined after oral administration, by capsules, of 1,000 mg on an empty stomach in 12 normal subjects. Serum concentrations were measured during a period of 8 h, and urine recovery was measured during 24 h. The significant parameters of bioavailability of an orally administered substance were determined. The maximal serum concentrations (y(max)) for cephalexin, cefaclor, cefadroxil, and CGP 9000 (in milligrams per liter) were: 38.8 +/- 8.1; 34.6 +/- 7.8; 33.0 +/- 5.4; and 23.3 +/- 7.3, respectively. The areas under the curve (in hours x milligrams per liter) were: 93.0 +/- 14.8; 74.5 +/- 9.9; 70.1 +/- 9.0; and 108.5 +/- 18.4, respectively. In a further crossover study with six subjects, 1,000 mg of cephalexin and of cefadroxil were given during a standard breakfast. The y(max) of cephalexin decreased to 23.1 +/- 6.6 mg/liter, in contrast to cefadroxil, with an unchanged y(max) of 32.7 +/- 3.4 mg/liter.
Neuropeptide inactivation is generally thought to occur via peptidase-mediated degradation. However, a recent study found increased analgesia after L-kyotorphin (L-Tyr-L-Arg; L-KTP) administration in mice lacking an oligopeptide transporter, PEPT2. The current study examines the role of PEPT2 in L-KTP uptake by astrocytes and compares it to astrocytic L-KTP degradation. L-[(3)H]KTP uptake was measured in primary cultures of neonatal astrocytes from rats and from Pept2(+/+) and Pept2(-/-) mice. Uptake was further characterized using potential inhibitors. L-[(3)H]KTP degradation was examined in primary astrocyte cultures from Pept2(-/-) mice by following the formation of L-[(3)H]tyrosine. The uptake of L-[(3)H]KTP in both rat and Pept2(+/+) mouse neonatal astrocytes was inhibited by known PEPT2 inhibitors. L-[(3)H]KTP uptake was also reduced in Pept2(-/-) astrocytes as compared to those from Pept2(+/+) mice. Kinetic analysis indicated the presence of a high affinity (K(m) approximately 50 microM) transporter for L-[(3)H]KTP, identified as Pept2, and a low affinity transporter (K(m) approximately 3-4 mM), inhibited by amastatin, bestatin and tyrosine. Astrocytes also degraded L-KTP through a low affinity peptidase (K(m) approximately 2 mM). Astrocytic clearance of L-KTP occurs via both peptidase activity and transport. These processes occur at similar rates and may be linked. This supports the contention that oligopeptide transport may have an impact on the extracellular clearance (and potentially activity) of certain neuropeptides.
cedrox 1 mg
To explore the feasibility of targeting human tumor cells via their transport systems, dipeptide uptake was studied in the human fibrosarcoma cell line HT1080 and the human fibroblast cell line IMR-90 by the use of hydrolysis-resistant glycylsarcosine (Gly-Sar). The uptake of [14C]Gly-Sar into HT1080 was time dependent. Kinetic analysis of the concentration dependence of the initial rate of [14C]Gly-Sar uptake showed that a carrier-mediated transport system with a K(m) of 11.4 +/- 3.3 mM and V(max) of 26.8 +/- 4.0 (nmol/15 min/mg protein) and a nonsaturable component (k(d) of 0.80 microl/15 min/mg protein) were responsible for the dipeptide uptake by HT1080 cells. The optimal pH for the maximal uptake was around 6.0. [14C]Gly-Sar uptake was inhibited by various di- and tripeptides and peptide-mimetic drugs, such as bestatin and cefadroxil. [14C]Gly-Sar uptake was not affected by the presence of amino acids or tetra- or pentapeptides. The uptake of cefadroxil was reduced significantly by unlabeled Gly-Sar. Moreover, Gly-Gly and Gly-Leu produced an increase in the apparent K(m) of the uptake of Gly-Sar without altering V(max). On the other hand, dipeptide uptake by IMR-90, which is a normal diploid cell line (not malignant), showed no saturable transport. These results suggest that HT1080 cells take up dipeptides via a pH-dependent transporter. This is the first report showing that a dipeptide transport system, which is similar but not identical to the well-characterized oligopeptide transporters PepT1 and PepT2, exists in fibroblast-derived tumor cells but not in normal fibroblasts. The present finding could be the basis of a novel strategy for the specific delivery of oligopeptide-mimetic anticancer drugs into tumor cells.
The safety and tolerability of linezolid in pediatric patients with Gram-positive infections were determined in four pediatric clinical studies. Study I included pediatric patients with community-acquired pneumonia; Study II included otitis media; Study III included SSSIs; and Study IV included complicated SSSIs, nosocomial pneumonia and bacteremia.
cap cedrox 500 mg
This study determined the antimicrobial susceptibility of Escherichia coli causing community-acquired, acute, uncomplicated, non-recurrent urinary tract infection in unselected women aged 18-65 years and compared the results with those obtained 8 years earlier in the first ECO·SENS study (1999-2000). During 2007-2008, urine samples were taken from 1697 women in Austria, Greece, Portugal, Sweden and the UK. The countries were chosen to represent areas of Europe indicated to have more (Greece and Portugal) or less (UK, Austria and Sweden) problems with resistance. Antimicrobial susceptibility testing of 903 E. coli isolates (150-200 isolates per country) to 14 antimicrobials was performed by disk diffusion using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. In E. coli, resistance to mecillinam, cefadroxil (representing oral cephalosporins), nitrofurantoin, fosfomycin trometamol, gentamicin and the third-generation cephalosporins cefotaxime and ceftazidime was <2%, with the following exceptions: gentamicin in Portugal (2.8%); fosfomycin in Greece (2.9%); and cephalosporins in Austria (2.7-4.1%). Resistance levels were higher for amoxicillin/clavulanic acid (2.0-8.9%) and ciprofloxacin (0.5-7.6%) and much higher to ampicillin (21.2-34.0%), sulfamethoxazole (21.2-31.3%), trimethoprim (14.9-19.1%) and trimethoprim/sulfamethoxazole (14.4-18.2%). Resistance to quinolones and trimethoprim increased between the ECO·SENS I (1999-2000) and ECO·SENS II (2007-2008): nalidixic acid 4.3% to 10.2%; ciprofloxacin 1.1% to 3.9%; and trimethoprim 13.3% to 16.7%. In the previous study, no isolates with extended-spectrum β-lactamase were found; however, in the present study 11 isolates were identified as having either CTX-M or AmpC.
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Thirteen oral cephems (cefprozil, loracarbef, cefaclor, cefuroxime axetil, cefpodoxime proxetil, cefetamet pivoxil, cefixime, cefdinir, cefadroxil, cephradine, cephalexin, cefatrizine, and cefroxadine), the cephalosporin class representative cephalothin, cefazolin, and the macrolides erythromycin, clarithromycin, and azithromycin were compared for their antibacterial activities against 790 recent clinical isolates. These oral agents differed in their spectra and antibacterial potencies against community-acquired pathogens.
cedrox 250 mg
The activity of the renal peptide transporters PEPT2 and PEPT1 determines-among other factors such as metabolic stability in liver and plasma-the circulatory half-life of penicillins and cephalosporins during therapy. This study was initiated to examine systematically the interaction of beta-lactam antibiotics with PEPT2. Interaction of 31 cephalosporins and penicillins with the carrier protein was characterized by measuring their ability to inhibit the uptake of [(14)C]Gly-Sar into renal SKPT cells. Cefadroxil, cefaclor, cyclacillin, cephradine, cephalexin and moxalactam were recognized by PEPT2 with very high affinity comparable to that of natural dipeptides (K(i)=3-100microM). Ceftibuten, dicloxacillin, amoxicillin, metampicillin, cloxacillin, ampicillin, cefixime, cefamandole, oxacillin and cefmetazole interacted with PEPT2 with medium affinity (K(i)=0.1-5mM). For the other beta-lactam antibiotics studied interaction was very low or not measurable (K(i)>5mM). The affinity constants of beta-lactam antibiotics at rPEPT2 and hPEPT1 are significantly correlated, but the rank orders are not identical. Decisive differences between PEPT1 and PEPT2 recognition of the N-terminal part of the compounds became evident. Moreover, this large data set of affinity constants of beta-lactam antibiotics will be useful for structure-transport (binding) analyses of PEPT2.