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Brush border membrane vesicles (BBMV) were prepared from the rabbit small intestine for testing drug absorption potency through the enterocyte's apical membrane, which is an important compartment for drug oral absorption. Some modifications have been made to the traditional vesicle assay for adapting it to the 96-well plate format. The accumulation of 23 reference drugs was measured, and the data showed a good correlation with human oral absorption with a correlation coefficient R=0.853 (P<0.001), with the exception of a few false positive results. As the measured drug absorption may contain a membrane/protein binding component as well as drug uptake into vesicles, these two fractions can be discriminated by changing extravesicular osmolarity using different mannitol concentrations. This model can be applied for evaluating drug absorption rate/mechanisms, and helping drug selection in early drug research and development.
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The presence of a proton-coupled electrogenic high-affinity peptide transporter in the apical membrane of tubular cells has been demonstrated by microperfusion studies and by use of brush border membrane vesicles. The transporter mediates tubular uptake of filtered di- and tripeptides and aminocephalosporin antibiotics. We have used expression cloning in Xenopus laevis oocytes for identification and characterization of the renal high-affinity peptide transporter. Injection of poly(A)+ RNA isolated from rabbit kidney cortex into oocytes resulted in expression of a pH-dependent transport activity for the aminocephalosporin antibiotic cefadroxil. After size fractionation of poly(A)+ RNA the transport activity was identified in the 3.0- to 5.0-kb fractions, which were used for construction of a cDNA library. The library was screened for expression of cefadroxil transport after injection of complementary RNA synthesized in vitro from different pools of clones. A single clone (rPepT2) was isolated that stimulated cefadroxil uptake into oocytes approximately 70-fold at a pH of 6.0. Kinetic analysis of cefadroxil uptake expressed by the transporter's complementary RNA showed a single saturable high-affinity transport system shared by dipeptides, tripeptides, and selected amino-beta-lactam antibiotics. Electrophysiological studies established that the transport activity is electrogenic and affected by membrane potential. Sequencing of the cDNA predicts a protein of 729 amino acids with 12 membrane-spanning domains. Although there is a significant amino acid sequence identity (47%) to the recently cloned peptide transporters from rabbit and human small intestine, the renal transporter shows distinct structural and functional differences.
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Fifty-five adult patients with acute uncomplicated pyelonephritis were investigated in an open, prospective, randomized comparative study in which 31 patients were allocated to receive 1000 mg cefetamet pivoxil twice daily (or 2000 mg once daily) and 24 to receive 1000 mg cefadroxil twice daily, given orally for 10 to 15 days. Both groups were comparable for age, sex and body weight. Clinical signs and symptoms, i.e. flank tenderness, dysuria, urgency and pyuria, subsided somewhat more rapidly with cefetamet pivoxil, while defervescence was obtained by Day 3 +/- 1 in both groups. Twenty-nine of the cefetamet pivoxil patients were assessed bacteriologically. The pathogens isolated prior to treatment were E. coli (22), Proteus mirabilis (5), P. vulgaris (1) and P. stuartii (1). All 29 patients had sterile urine at treatment end. In the 22 assessable patients in the cefadroxil group, the pathogens isolated before treatment were E. coli (17), P. mirabilis (3), and K. pneumoniae (2). Six patients had relapsed at treatment end (5 E. coli and 1 P. mirabilis). Patients were re-assessed at follow-up, usually 2 to 4 weeks after the end of treatment. Four of the 29 patients in the cefetamet pivoxil group showed relapse (3 E. coli and 1 P. mirabilis) as did a further 3 in the cefadroxil group (2 E. coli and 1 P. mirabilis). The overall therapeutic outcome was considered as successful, i.e. cure or improvement, in 89.7% of the cefetamet pivoxil patients and 72.7% of those who had received cefadroxil. Tolerability was satisfactory for both trial drugs and there were only a few mild to moderately severe adverse events reported.(ABSTRACT TRUNCATED AT 250 WORDS)
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A 20-yr-old pharmaceutical worker who developed attacks of shortness of breath and wheezing 9 months after beginning work on a process in which cefadroxil powder was bottled or encapsulated will be described. Skin test with cefaxodril was negative. Baseline spirometry and methacholine inhalation test were normal. A controlled bronchial challenge test was carried out in a closed-circuit system with assessment of respirable dust concentration. Exposure to cefadroxil powder at a mean concentration of 10 mg x m(-3) for 10 min elicited an isolated immediate asthmatic response, but no response was observed to control challenge with lactose. Single-blind oral challenge test with amoxicillin up to 500 mg was well tolerated, whereas the oral challenge with cephalexin (25 mg) elicited an immediate asthmatic response. This patient had developed occupational asthma caused by inhalation of cefadroxil as confirmed by specific inhalation test. Since she tolerated oral amoxicillin, a synthetic penicillin with the side-chain identical to that of cefadroxil, it seems that she may be sensitized to the dihydrothiazine ring of cephalosporins.
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Clinical efficacy achieved with cefovecin in dogs was equivalent to that observed with cefadroxil. At the final assessment, 14 days following the completion of treatment (on day 28 or 42), 92.4% (109/118) of the cefovecin group and 92.3% (108/117) of the cefadroxil group were treatment successes. There were no serious adverse events or deaths related to treatment.
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Minimum inhibitory concentrations (MICs) of cefadroxil were determined for 749 defined clinically-significant bacteria isolated in a London teaching hospital and for 63 strains from an international collection of Gram-negative bacilli. Assuming a breakpoint of 16 mg/l, for the hospital isolates 81.8% of Gram-negative bacilli and 83.4% of Gram-positive cocci were sensitive. No significant difference between in-patient, out-patient or community-acquired isolates was found. Ninety-five and a half per cent of Escherichia coli, Klebsiella aerogenes (including gentamicin-resistant strains), Proteus mirabilis, and (with the exception of Streptococcus faecalis and methicillin-resistant Staphylococcus aureus) all Gram-positive cocci were sensitive. Of 41 strains of Enterobacter spp., were resistant. Most indole-positive Proteus, and all Serratia and Acinetobacter spp. were resistant, including 36 additional strains taken from an international collection. Of 30 strains of Haemophilus influenzae, only six had MICs of 16 mg/l or less. For disc susceptibility testing, the standard disc containing 30 micrograms of cefadroxil reliably gave zones of greater than 17 mm for organisms with MICs of less than 16 mg/l. A zone of less than 14 mm corresponded to MICs of greater than 64 mg/l. Despite a lack of controlled clinical trials, the results of this study (taken with favourable pharmacokinetics) suggest that cefadroxil has potential as an oral cephalosporin in hospital practice in the U.K.