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Antimicrobial Agents and Chemotherapy Mar 1984A total of 158 volunteers each received 21 repeated oral doses of 500 mg of cefuroxime axetil (CAE) during four comparative cross-over trials. Pharmacokinetics were...
A total of 158 volunteers each received 21 repeated oral doses of 500 mg of cefuroxime axetil (CAE) during four comparative cross-over trials. Pharmacokinetics were studied in 8 volunteers (CAE versus ampicillin), relative bioavailability and tolerance were studied in 100 volunteers (CAE versus pivmecillinam and CAE versus pivampicillin), and tolerance alone was studied in 50 volunteers (CAE versus ampicillin). Overall, urinary recoveries of the active antibiotics ranked absorption of the drugs in the order least to greatest: pivmecillinam, ampicillin, CAE, and pivampicillin. The pharmacokinetics of CAE and ampicillin did not change after repeated dosing. Peak serum levels of cefuroxime were significantly higher than those of ampicillin after doses 1 and 21 but the urinary recoveries of both antibiotics were around 35% of the dose. CAE was as well tolerated as ampicillin but there were smaller numbers of episodes of fluid bowel motions on pivmecillinam and pivampicillin than on CAE, which may have been due to the smaller amounts of active antibiotic in the doses of the pivaloyloxymethyl esters.
Topics: Adolescent; Adult; Amdinocillin Pivoxil; Ampicillin; Biological Availability; Cefuroxime; Cephalosporins; Chromatography, High Pressure Liquid; Enzymes; Female; Humans; Kinetics; Male; Middle Aged
PubMed: 6721467
DOI: 10.1128/AAC.25.3.344 -
Biological & Pharmaceutical Bulletin Jul 2007Bacampicillin was developed as a prodrug to improve the intestinal absorption of its metabolite ampicillin. This study was undertaken to characterize bacampicillin...
Bacampicillin was developed as a prodrug to improve the intestinal absorption of its metabolite ampicillin. This study was undertaken to characterize bacampicillin transport in Caco-2 cells. The uptake of bacampicillin in Caco-2 cells was significantly greater than those of ampicillin and pivampicillin. An Eadie-Hofstee plot obtained from 5-min uptake of 0.2-5 mM bacampicillin was linear, indicating the presence of a saturable transport system for bacampicillin with K(m) and V(max) of 3.6 mM and 23.9 nmol/mg protein/min, respectively. Hydrophilic organic cations such as choline, cimetidine, guanidine, nicotinamide, 1-methylnicotiamide, and tetraethylammonium failed to modulate bacampicillin uptake in Caco-2 cells whereas diphenhydramine, procainamide, and thiamine significantly depressed it. Moreover, when thiamine was preloaded in Caco-2 cells, bacampicillin uptake was significantly increased, indicating that this cationic vitamin was capable of trans-stimulating bacampicillin transport across the apical membrane of Caco-2 cells. However, trans-stimulated bacampicillin uptake was not observed in the presence of diphenhydramine. Bacampicillin uptake increased with elevation of the medium pH, and the known modulators of thiamine transport such as amiloride and oxythiamine significantly inhibited bacampicillin uptake. Thiamine also significantly decreased the apical-to-basolateral transport of bacampicillin across Caco-2 cell monolayers. However, thiamine did not exert any modulating effect on pivampicillin uptake and its apical-to-basolateral permeation in Caco-2 cells. These results suggest that bacampicillin is transported in Caco-2 cells, sharing a carrier-mediated system with thiamine.
Topics: Ampicillin; Anti-Bacterial Agents; Biological Transport; Caco-2 Cells; Diphenhydramine; Humans; Hydrogen-Ion Concentration; Membrane Transport Proteins; Peptide Transporter 1; Pivampicillin; Symporters; Thiamine
PubMed: 17603179
DOI: 10.1248/bpb.30.1344 -
Antimicrobial Agents and Chemotherapy Apr 2005Pivampicillin (PIVA), an acyloxymethylester of ampicillin, is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to...
Pivampicillin (PIVA), an acyloxymethylester of ampicillin, is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to that of ampicillin. The fate of PIVA in intestinal cells and the exact location of its conversion into ampicillin have, however, never been unambiguously established. Polarized Caco-2 cells have been used to examine the handling of PIVA and the release of ampicillin from PIVA by the intestinal epithelium. Experiments were limited to 3 h. Cells incubated with PIVA (apical pole) showed a fast accumulation of ampicillin and transport toward the basolateral medium, whereas PIVA itself was only poorly accumulated and transported. Cells incubated with free ampicillin accumulated and transported only minimal amounts of this drug. Release of ampicillin from cells incubated with PIVA was unaffected by PEPT1 and OCTN2 inhibitors but was sharply decreased after ATP depletion or addition of bis(4-nitrophenyl)-phosphate (BNPP; an esterase inhibitor). PIVA incubated with Caco-2 lysates released free ampicillin, and this release was inhibited by BNPP. Efflux studies showed that the ampicillin that accumulated in cells after incubation with PIVA was preferentially transported out of the cells through the basolateral pole. This efflux was decreased by multidrug resistance-associated protein (MRP) inhibitors (probenecid, MK-571) and by ATP depletion. A phthalimidomethylester of ampicillin that resists cellular esterases failed to cause any significant release (cell lysate) or transport (polarized Caco-2 cells) of ampicillin. These results show that when PIVA is given to Caco-2 cells from their apical pole, ampicillin is released intracellularly and that ampicillin is thereafter preferentially effluxed into the basolateral medium through an MRP-like transporter.
Topics: Ampicillin; Anti-Bacterial Agents; Biological Transport; Caco-2 Cells; Cell Polarity; Colon; Humans; Pivampicillin; Prodrugs
PubMed: 15793098
DOI: 10.1128/AAC.49.4.1279-1288.2005 -
Molecules (Basel, Switzerland) Feb 2019The problem of determining the formation of complexes of β-lactam antibiotics with cyclodextrins (CDs) and the interactions involved in this process were addressed by...
The problem of determining the formation of complexes of β-lactam antibiotics with cyclodextrins (CDs) and the interactions involved in this process were addressed by machine learning on multispectral images. Complexes of β-lactam antibiotics, including cefuroxime axetil, cefetamet pivoxil, and pivampicillin, as well as CDs, including αCD, βCD, γCD, hydroxypropyl-αCD, methyl-βCD, hydroxypropyl-βCD, and hydroxypropyl-γCD, were prepared in all combinations. Thermograms confirming the formation of cyclodextrin complexes were obtained using differential scanning calorimetry. Transmission Fourier-transform infrared (tFTIR) and complementary attenuated total reflectance FTIR (ATR) coupled with machine learning were techniques chosen as a nondestructive alternative. The machine learning algorithm was used to determine the formation of complexes in samples using solely their tFTIR and ATR spectra at the prediction stage. Parameterized method 7 (PM7) was used to support the analysis by molecular modeling of the complexes. The model developed through machine learning properly distinguished samples with formed complexes form noncomplexed samples with a cross-validation accuracy of 90.4%. Analysis of the contribution of spectral bands to the model indicated interactions of ester groups of β-lactam antibiotics with CDs, as well as some interactions of cephem ring in cefetamet pivoxil and penam moiety in pivampicillin. Molecular modeling with PM7 helped to explain experimental results and allowed to propose possible binding modes.
Topics: Cyclodextrins; Machine Learning; Models, Molecular; Molecular Conformation; Spectrum Analysis; Structure-Activity Relationship; beta-Lactams
PubMed: 30791432
DOI: 10.3390/molecules24040743 -
Antimicrobial Agents and Chemotherapy May 1992Eight healthy volunteers received a 1,000-mg single oral dose of 2085P which consisted of 800 mg of pivampicillin and 200 mg of brobactam. Concentrations of ampicillin...
Eight healthy volunteers received a 1,000-mg single oral dose of 2085P which consisted of 800 mg of pivampicillin and 200 mg of brobactam. Concentrations of ampicillin and brobactam in plasma, inflammatory fluid, and urine were measured over the subsequent 24 h. Pivampicillin and brobactam were moderately rapidly absorbed. The mean (standard deviation) maximum concentration in plasma (Cmax) of ampicillin was 8.2 (1.9) micrograms/ml, and that of brobactam was 2.1 (2.0) micrograms/ml at mean times of 1.9 (0.5) and 2.3 (0.8) h, respectively. The elimination half-lives in plasma were 1.8 (0.5) and 1.6 (2.0) h, respectively. Both agents penetrated the experimentally induced inflammatory fluid, reaching a mean maximum at 3 h. The Cmax of ampicillin was 6.8 (2.3) micrograms/ml, and that of brobactam was 1.0 (0.4) micrograms/ml. The penetration (derived by comparing the area under the concentration-time curve from 0 h to infinity for inflammatory fluid with that for plasma) was 97.3% (26.0%) for ampicillin and 81% (22.3%) for brobactam. The 24-h urinary recovery was 54.2% (16.6%) of the administered dose for ampicillin and 40.2% (11.4%) for brobactam. These data suggest that this combination of beta-lactam and inhibitor should be efficacious in treating infections caused by ampicillin-resistant pathogens.
Topics: Administration, Oral; Adult; Ampicillin; Drug Therapy, Combination; Humans; Male; Penicillanic Acid; Pivampicillin; beta-Lactamase Inhibitors
PubMed: 1324634
DOI: 10.1128/AAC.36.5.1002 -
The Journal of International Medical... 2000This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in adults with acute exacerbations of chronic bronchitis (not needing parenteral antibiotic therapy, hospitalization or oxygen support). Clinical success (cure + improvement) rates were similar for both groups at the end of treatment (day 10; azithromycin, 124 of 133 [93%]; pivampicillin, 79 of 92 [86%]) and at follow-up (day 52; 98 of 126 [78%] versus 66 of 81 [81%]). The treatments produced similar levels of pathogen eradication at the end of treatment (49 of 54 [91%] versus 32 of 37 [86%]). Azithromycin-treated patients had significantly reduced chest discomfort at the end of treatment, and a trend towards improved lung function. The two groups were similar with respect to improvements in other clinical symptoms and patient well-being, and to the incidences of adverse events and treatment discontinuations. This oral azithromycin regime is an effective treatment for acute exacerbations of chronic bronchitis, similar in efficacy to the longer pivampicillin regime and may offer superior patient compliance.
Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchitis; Chronic Disease; Consumer Product Safety; Drug Tolerance; Female; Humans; Male; Penicillins; Pivampicillin; Single-Blind Method; Treatment Outcome
PubMed: 10983860
DOI: 10.1177/147323000002800301 -
Pharmacokinetics of bacampicillin compared with those of ampicillin, pivampicillin, and amoxycillin.Antimicrobial Agents and Chemotherapy Jan 1978Bacampicillin, a new oral prodrug which in vivo is rapidly transformed to ampicillin, was compared with ampicillin, pivampicillin, and amoxycillin in a randomized... (Comparative Study)
Comparative Study
Bacampicillin, a new oral prodrug which in vivo is rapidly transformed to ampicillin, was compared with ampicillin, pivampicillin, and amoxycillin in a randomized cross-over study on 11 healthy volunteers. All drugs were given in oral doses equimolar to 400 mg of bacampicillin (800 mumol). The mean of the individual peak concentrations in serum was 8.3 mug/ml for bacampicillin, 7.1 mug/ml for pivampicillin, 7.7 mug/ml for amoxycillin, and 3.7 mug/ml for ampicillin. Furthermore, bacampicillin had a higher absorption rate than all the other drugs, although there were statistically significant differences only versus ampicillin. The peak serum levels of the individual subjects were more dispersed with ampicillin and amoxycillin, suggesting a more uniform absorption of bacampicillin and pivampicillin. The relative bioavailability of bacampicillin and pivampicillin was comparable, whereas ampicillin was only 2/3 that of the others.
Topics: Amoxicillin; Ampicillin; Biological Availability; Humans; Pivampicillin
PubMed: 626496
DOI: 10.1128/AAC.13.1.90 -
Genitourinary Medicine Aug 1988In a randomised single blind study, pivampicillin was compared with erythromycin in women with urogenital Chlamydia trachomatis infections. The pivampicillin dosage was... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
In a randomised single blind study, pivampicillin was compared with erythromycin in women with urogenital Chlamydia trachomatis infections. The pivampicillin dosage was 700 mg twice a day and the erythromycin dosage 500 mg twice a day for seven days. Follow up took place on days 7 and 14 after the start of treatment. All 26 women treated with pivampicillin were culture negative for chlamydiae at the first and second follow up visits. All 23 women who received erythromycin were culture negative at the first follow up visit, but one was culture positive at the second follow up visit. Gastrointestinal side effects were recorded in five patients receiving pivampicillin and in nine receiving erythromycin. Two patients receiving erythromycin were withdrawn from treatment because of gastrointestinal disturbances, compared with none receiving pivampicillin.
Topics: Adolescent; Adult; Ampicillin; Chlamydia Infections; Chlamydia trachomatis; Drug Evaluation; Erythromycin; Female; Genital Diseases, Female; Humans; Pivampicillin
PubMed: 3169754
DOI: 10.1136/sti.64.4.247 -
Antimicrobial Agents and Chemotherapy Jul 2004The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of...
The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of ester prodrugs. Pivampicillin and cefcapene pivoxil hydrochloride (CFPN-PI), ester-type oral antibiotics, were chosen as model ester prodrugs. The level of esterase activity in Caco-2 cells was lower than that measured in the rat jejunum when p-nitrophenyl acetate was used as a substrate. Almost complete ester hydrolysis occurred before the ester prodrugs reached the basolateral side of the monolayer, and the disappearance of prodrugs was thought to be due to metabolism or transport after addition to the apical side of the monolayer. When pivampicillin and CFPN-PI were used, the amounts of ampicillin and cefcapene (CFPN) produced by hydrolysis of prodrugs were increased because intracellular degradation of prodrugs resulted in intracellular accumulation. On the other hand, when ampicillin or CFPN was used, only a small amount of the drug reached the basolateral side of the monolayers and no intracellular accumulation was observed. The permeability of CFPN-PI, the solubility of which is dependent on the acidity of gastric juice, across a Caco-2 monolayer or rat intestine, was also investigated by using an in vitro system that mimics the physiological state of the human gastrointestinal tract. The oral absorption of CFPN-PI in humans is predicted to be good either in the Caco-2 model or in the rat intestine model. It is concluded that our system may be a valuable tool for evaluation of oral absorption of ester prodrugs metabolized during permeation through the intestinal epithelium. Broader evaluation of such a system is warranted.
Topics: Animals; Caco-2 Cells; Cephalosporins; Epithelial Cells; Escherichia coli; Esters; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Nitrophenols; Prodrugs; Rats; Rats, Wistar; Serratia; Spectrophotometry, Ultraviolet; Staphylococcus aureus
PubMed: 15215116
DOI: 10.1128/AAC.48.7.2604-2609.2004 -
Genitourinary Medicine Jan 1989The efficacy of ceftriaxone 250 mg given as a single intramuscular dose to treat genitourinary and pharyngeal gonorrhoea is compared with the outcome of the Danish...
The efficacy of ceftriaxone 250 mg given as a single intramuscular dose to treat genitourinary and pharyngeal gonorrhoea is compared with the outcome of the Danish standard treatment for uncomplicated genitourinary gonorrhoea, pivampicillin 1.4 g and probenecid 1 g, both given by mouth. The study comprised 327 patients for whom the diagnosis of gonorrhoea was made by microscopy of a methylene blue stained smear at their first visit to the clinic and for whom the diagnosis was later confirmed by culture of Neisseria gonorrhoeae. One hundred and seventy patients with genitourinary gonorrhoea (18 with and 152 without concomitant pharyngeal infection) were treated with ceftriaxone. One hundred and fifty seven (17 with and 140 without concomitant pharyngeal infection) were treated with pivampicillin. One week after treatment N gonorrhoeae was isolated from none of 18, 1/152, (1%), 11/17 (65%), and 6/140 (4%) patients, respectively. At a second attendance two weeks after treatment no further treatment failure was found. During the study period, a further 52 patients with pharyngeal infection (with or without concomitant genitourinary infection) that was shown by culture only were treated with a single intramuscular injection of 250 mg ceftriaxone. No treatment failure was observed in this group. Only minor adverse drug reactions were seen. Ceftriaxone 250 mg as a single intramuscular injection is therefore safe and effective in treating gonorrhoea, including pharyngeal infection.
Topics: Adolescent; Adult; Aged; Ceftriaxone; Female; Genital Diseases, Female; Genital Diseases, Male; Gonorrhea; Humans; Injections, Intramuscular; Male; Middle Aged; Pharyngeal Diseases; Urinary Tract Infections
PubMed: 2921047
DOI: 10.1136/sti.65.1.14