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B Hampel

Publications and source records attributed to B Hampel.

At least 19 recordsLinked to original sources
PubMed2006

Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senescence.

A convenient way to study processes of aging in distinct human tissues consists of a molecular analysis of cells from the tissue in question, that were explanted and grown in vitro until they reach senescence. Using human umbilical vein endothelial cells (HUVEC), we have established an in vitro senescence model for human endothelial cells. A major hallmark of HUVEC in vitro senescence is the increased frequency of apoptotic cell death, which occurs as a determining feature of HUVEC senescence. Senescent endothelial cells are also found in vivo in atherosclerotic lesions, suggesting that the presence of such cells may contribute to the development of vascular pathology. To elucidate mechanisms underlying endothelial cell senescence and age-associated apoptosis, gene expression analyses were carried out. In these experiments, we observed the up-regulation of genes coding for extracellular proteins in senescent HUVEC. In particular, a significant upregulation of interleukin-8, VEGI, and the IGF-binding proteins 3 and 5 was observed. Upregulation of these genes was confirmed by both RT-PCR and Western blot. In the case of interleukin-8, a roughly 50-fold upregulation of the protein was also found in cellular supernatants. The extracellular proteins encoded by these genes are well known for their ability to modulate the apoptotic response of human cells, and in the case of interleukin-8, clear links to the establishment of atherosclerotic lesions have been defined. The results described here support a new model, where changes in the secretome of human endothelial cells contribute to vascular aging and vascular pathology.

Apoptosis↗
PubMed2001

Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis.

Human ageing is characterized by a progressive loss of physiological functions, increased tissue damage and defects in various tissue renewal systems. Age-related decreases of the cellular replicative capacity can be reproduced by in vitro assays of cellular ageing. When diploid human fibroblasts reach their finite lifespan, they enter an irreversible G1 growth arrest status referred to as replicative senescence. While deregulation of programmed cell death (apoptosis) is a key feature of age-related pathology in several tissues, this is not reflected in the standard in vitro senescence model of human fibroblasts, and the role of apoptosis during cellular ageing remains unclear. We have analyzed replicative senescence of human umbilical vein endothelial cells (HUVEC) in vitro and found that senescent HUVEC also arrest in the G1 phase of the cell cycle but, unlike fibroblasts, accumulate with a 4N DNA content, indicative of polyploidization. In contrast to human fibroblasts, senescent endothelial cells display a considerable increase in spontaneous apoptosis. The data imply that age-dependent apoptosis is a regular feature of human endothelial cells and suggest cell type specific differences in human ageing.

Apoptosis↗
PubMed2001

Metabolic stabilization of p27 in senescent fibroblasts correlates with reduced expression of the F-box protein Skp2.

When mortal human cells reach their finite lifespan, they enter an irreversible G1 growth arrest status referred to as senescence. Growth suppression of senescent cells can be explained by the accumulation of several growth-suppressive proteins, acting on mitogenic signal transduction and cell cycle regulation, respectively. We show here that the cdk inhibitor p27(KIP1), which is involved in several forms of G1 checkpoint control, accumulates in senescent cells. Whereas, the rate of p27 synthesis is reduced, accumulation of p27 is accompanied by an increase of the metabolic stability in senescent cells. p27 is a substrate for ubiquitin-mediated proteolysis, and its stabilization in senescent cells correlates with a deregulation of the p27-specific E3 ubiquitin ligase referred to as the SCF complex. Whereas, the Skp1 component of the SCF complex is overexpressed in senescent fibroblasts, the abundance of the F-box protein Skp2 is strongly reduced. In contrast to our findings with p27, the synthesis of the cell cycle regulators p21 and cyclin D1 is increased in senescent cells; however, both proteins are also highly unstable in these cells.

Cell Cycle Proteins↗
PubMed2000

A comparison of the safety and efficacy of moxifloxacin (BAY 12-8039) and cefuroxime axetil in the treatment of acute bacterial sinusitis in adults. The Sinusitis Study Group.

The aim of this multicentre, randomized study was to compare the efficacy and safety of moxifloxacin (BAY 12-8039), a new 8-methoxy fluoroquinolone, with that of cefuroxime axetil for the treatment of acute bacterial sinusitis in adults. Diagnosis was made on a range of clinical signs and symptoms combined with radiology and microbiology. A 400 mg dose of moxifloxacin was administered once daily for 7 days to 242 patients and 250 mg twice daily of cefuroxime axetil was administered to 251 patients for 10 days. The clinical success rate at the end of treatment in the evaluable population was significantly higher (96.7%) in the moxifloxacin group (204/211) than in the cefuroxime axetil group (204/225, 90.7%; 95% confidence intervals 1.5%; 10.6%). At follow-up the success rate in the moxifloxacin group was 90.7% and that for the cefuroxime axetil group was 89.2% (95% confidence intervals -4.3%; 5.4%). The predominant pathogens isolated were Streptococcus pneumoniae and Haemophilus influenzae, followed by Moraxella catarrhalis and Staphylococcus aureus. The bacteriological eradication rates were higher for moxifloxacin (94.5%, 103/109) than for cefuroxime axetil (83.5%, 96/115; 95% CI 3.6%; 19.7%). Only one S. pneumoniae infection persisted following moxifloxacin therapy in contrast with three in individuals on cefuroxime axetil. There were slightly more adverse events in the moxifloxacin group than in the cefuroxime axetil group, but there were fewer serious adverse events following moxifloxacin treatment (three vs. eight). The drug was discontinued because of adverse events in 14 moxifloxacin patients and in 11 cefuroxime axetil patients. Overall, in all assessments, moxifloxacin was at least as effective clinically and bacteriologically, and as well tolerated, as cefuroxime axetil in the treatment of acute sinusitis.

Acute Disease↗
PubMed1997

Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis.

OBJECTIVE: The efficacy and safety of oral ciprofloxacin as a maintenance antipseudomonal therapy were evaluated in 44 patients with cystic fibrosis who had completed a 14-day regimen of intensive hospital therapy with intravenous ceftazidime and amikacin, supplemented by amikacin inhalation therapy. METHODS: Twenty-one patients were randomly assigned to oral ciprofloxacin alone (Group I) and 23 received ciprofloxacin plus inhaled amikacin (Group II). RESULTS: Negative sputum cultures were achieved in 34 patients (77%) at the end of intensive therapy (19 Group I and 15 Group II) and were sustained after 3 months of maintenance therapy in 5 of the 19 responders in Group I (26%) and in 8 of the 15 responders in Group II (53%). Resistance to ciprofloxacin was found in 7 of 31 (23%) sputum isolates at the end of ciprofloxacin therapy. During maintenance therapy, continued improvement in clinical symptoms was observed in 14 patients in both treatment groups; 6 in each group had further improvements whereas only 4 patients were clinical failures. There was no correlation between clinical outcome and either elimination of Pseudomonas aeruginosa from sputum culture or development of ciprofloxacin resistance. Both maintenance regimens were well-tolerated by this population of patients which included 28 children younger than 15 years of age. There were no severe or serious adverse events, no signs of quinolone-related arthropathy and no growth impairment. CONCLUSION: Ciprofloxacin was efficacious, safe and well-tolerated as maintenance antipseudomonal therapy in cystic fibrosis patients. These results suggest further evaluation of ciprofloxacin as an oral maintenance therapy is warranted.

Adolescent↗
PubMed1997

Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report.

BACKGROUND: Quinolone-induced cartilage toxicity has been observed in experimental juvenile animal studies and is species- and dose-specific. Accordingly these findings have led to the contraindication of fluoroquinolones in children. Previous data in 634 adolescents and children treated with compassionate use ciprofloxacin demonstrated low rates of reversible arthralgia and a safety profile similar to that for adult patients. OBJECTIVE: This report describes the safety findings in 1795 children who received 2030 treatment courses of intravenous or oral ciprofloxacin. RESULTS: The average doses of intravenous and oral ciprofloxacin in the study population were 8 and 25 mg/kg/day, respectively. Treatment-associated events were reported in 10.9% of children receiving oral ciprofloxacin compared with 18.9% among intravenous recipients. Overall arthralgia occurred during 31 ciprofloxacin treatment courses (1.5%) and the majority of events were of mild to moderate severity and resolved without intervention. More than 60% of arthralgia episodes were in children with cystic fibrosis. CONCLUSION: The adverse event pattern in children receiving ciprofloxacin in this analysis was similar to that observed in adults. Rates of reversible arthralgia were low and unchanged from previously published surveillance data in children.

Administration, Oral↗
PubMed1996

Characterization of indole-negative Bacteroides fragilis group species with use of polymerase chain reaction fingerprinting and resistance profiles.

Biochemical tests alone do not adequately differentiate the various Bacteroides species, groups, and antimicrobial-resistant variants. Consequently, we used a polymerase chain reaction (PCR) fingerprinting technique, with either a single nonspecific primer derived from the t-DNA intergenic spacer region (T3B) or a single primer that anneals to minisatellite DNA sequences (M13 core), to identify and characterize 58 clinical isolates of Bacteroides fragilis group species (B. fragilis, B. distasonis, and B. caccae). In addition to species- and subspecies-specific differences, 4 strains of B. fragilis, 1 of B. distasonis, and 3 of B. caccae that showed increased resistance to imipenem, ampicillin, and ampicillin/sulbactam also produced unique PCR fingerprint profiles. Analysis by the clinical source of isolation (i.e. blood or intraabdominal, skin, or soft-tissue infection) indicated that no particular PCR fingerprint type was associated with greater pathogenicity of any individual clinical source. The PCR fingerprinting technique proves to be a useful tool for species identification and taxonomic studies, as well as for epidemiological studies of Bacteroides species.

Bacterial Typing Techniques↗
PubMed1996

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Administration, Oral↗
PubMed1990

Pharmacokinetics of FCE 22891, a new oral penem.

FCE 22891 is the oral prodrug of FCE 22101, a new broad-spectrum penem. The pharmacokinetics of FCE 22891 after single-dose administration, its absolute bioavailability, and the effect of food intake on its absorption were investigated in three different randomized crossover studies in healthy volunteers. Drug levels in blood and urine were measured by high-pressure liquid chromatography and bioassay. For optimal comparison of the results of all studies, and since there was good agreement of both methods, only the high-pressure liquid chromatography results are included. The pharmacokinetics of the penem were linear, and its bioavailability after oral administration was 42 +/- 11%. Food intake increased the total area under the curve from 0 h to infinity from 11.9 +/- 3.5 to 14.1 +/- 2.4 mg.h/liter. A specific side effect, i.e., bladder complaints, was registered in some volunteers taking FCE 22891 at doses greater than or equal to 1.0 g.

Administration, Oral↗
PubMed1989

The pharmacokinetics of sultamicillin.

Sultamicillin is a mutual prodrug of ampicillin and sulbactam, a beta-lactamase inhibitor. When administered orally, sultamicillin is readily absorbed and rapidly hydrolyzed to provide high levels of its two constituents in the peripheral circulation. Peak serum concentrations of ampicillin are achieved that are approximately three and one-half times those obtained with an equivalent amount of oral ampicillin. Equimolar concentrations of sulbactam are also provided, with both ampicillin and sulbactam being widely distributed among various body fluids and tissues. The pharmacokinetic parameters of the two components are similar, both being eliminated primarily by renal excretion. Although the elimination half-lives of ampicillin and sulbactam are each approximately 1 hour, the high serum concentrations achieved coupled with their synergistic bactericidal activity permit twice-daily dosing.

Amoxicillin↗
PubMed1988

Comparative pharmacokinetics of sulbactam/ampicillin and clavulanic acid/amoxycillin in human volunteers.

In this study, the pharmacokinetic parameters of 2 different beta-lactamase inhibitors (sulbactam and clavulanic acid) in combination with 2 different aminobenzylpenicillins (ampicillin and amoxycillin) were compared. The study involved 10 healthy volunteers who received sulbactam 250 mg plus ampicillin 500 mg intravenously, clavulanic acid 100 mg plus amoxycillin 500 mg intravenously, sultamicillin equivalent to sulbactam 294 mg plus ampicillin 440 mg orally, and clavulanic acid 125 mg plus amoxycillin 500 mg orally in a crossover, randomised trial. Serum and urine concentrations of ampicillin, amoxycillin and clavulanic acid were assayed by agar diffusion test, and the concentrations of sulbactam by gas chromatography with mass spectrometry. Pharmacokinetic parameters were calculated according to open 1- and 2-compartment models. Test results showed that the addition of sulbactam significantly increases the bioavailability of oral ampicillin when the 2 drugs are administered in the form of the prodrug sultamicillin. Also, sulbactam does not interfere with the kinetics of intravenous ampicillin but increases the absorption of oral ampicillin.

Administration, Oral↗
PubMed1985

Comparative pharmacokinetics of ceftriaxone after subcutaneous and intravenous administration.

The pharmacokinetics of ceftriaxone (CRO) after subcutaneous and intravenous administration was studied in 10 healthy volunteers (5 males, 5 females, age 22-43 years, body weight 64.3 +/- 9.5 kg). Each of them received 2.0 g CRO i.v., and then 0.5 g i.v. and 0.5 g CRO s.c. in a randomized cross-over design. Subcutaneous administration of ceftriaxone was tolerable in combination with lidocaine. Serum and urine concentrations were determined by high performance liquid chromatography and for comparison with a bioassay. Mean serum concentrations were high after intravenous administration: 258 +/- 40 mg/1 (0 min, 2 g i.v.) resp. 84 +/- 40 mg/1 (0 min, 0.5 g i.v.). They declined to 11.6 +/- 4.2 mg/1 (2 g) resp. 6.5 +/- 2.2 mg/1 (0.5 g i.v.) within 24 h. Following subcutaneous application peak serum concentrations of 37.1 +/- 5.6 mg/1 were found after 138 +/- 49 min and a mean serum concentration of 6.6 +/- 1.6 mg/1 after 24 h. Concentrations of free ceftriaxone, determined by ultrafiltration, were 9.2 +/- 2.7% of total concentrations from 25 to 200 mg/1. Cumulated urine recoveries over a period of 24 h were: 51.2 +/- 8.9% (2 g i.v.), 47.1 +/- 7.9% (0.5 g i.v.) and 39.7 +/- 9.5% (0.5 g s.c.). There was no evidence for the presence of a microbiologically active metabolite in urine. Comparison of pharmacokinetic parameters for the 0.5 g dose did not show relevant differences between intravenous and subcutaneous administration (using an open two-compartment model): t beta 1/2 (min) 514 +/- 104 (s.c.), 592 +/- 133 (i.v.), VD,Area (1) 11.9 +/- 3.8 (s.c.), 13.3 +/- 3.8 (i.v.) and AUCtot (mg X h/1) 515 +/- 106 (s.c.) and 549 +/- 125 (i.v.). Bioavailability of the subcutaneous application was 0.96 +/- 0.26. For the 2 g i.v. dose the known nondosis-dependent kinetics was observed. Subcutaneous administration of ceftriaxone appears to be a possible alternative to the intravenous route in selected clinical situations or cases.

Adult↗
PubMed1985

Pharmacokinetics of temocillin in volunteers.

The pharmacokinetics of temocillin, a new semisynthetic parenteral penicillin, were studied in 10 healthy volunteers. Doses of 0.5, 1.0, and 2.0 g were administered by intravenous bolus injection at weekly intervals, and serum and urine samples were assayed by an agar diffusion method. Mean peak serum concentrations were: 77.9 (+/- 28.4) mg/L (0.5 g), 160.8 (+/- 58.2) mg/L (1.0 g), and 236.1 (+/- 93.3) mg/L (2.0 g), with serum concentrations still being measurable after 12 hours for all doses [7.9 (+/- 3.7) mg/L, 12.9 (+/- 5.2) mg/L, 14.8 (+/- 6.3) mg/L]. According to a 2-compartment open model, the mean terminal half-lives of 0.5, 1.0, and 2.0 g doses were 5.2 (+/- 0.3), 5.0 (+/- 0.2), and 5.0 (+/- 0.2) hours, respectively. The total volume of distribution averaged 0.15 (+/- 0.01), 0.17 (+/- 0.01), and 0.24 (+/- 0.01) L/kg bodyweight, respectively, mean renal clearances were 18.5 (+/- 3.2), 19.6 (+/- 5.0), and 29.8 (+/- 2.6) ml/min, respectively, and the area under the serum concentration time curve (AUC) was 344.1 (+/- 18.7), 573.3 (+/- 27.8), and 784.5 (+/- 47.1) mg X h/L, respectively. At 74 (+/- 12.9)%, the 24-hour urinary recovery was highest for the low dose, followed by 68.1 (+/- 6)% for the 2.0 g dose, and 66.1 (+/- 16.8)% for the 1.0 dose. No untoward side effects were recorded. Thus, temocillin appears to be a penicillin with a prolonged half-life and high AUC.

Adult↗
PubMed1982

Pharmacokinetics of cefadroxil and cefaclor during an eight-day dosage period.

The concentrations of cefadroxil and cefaclor in serum were studied in eight healthy volunteers receiving 1,000 mg of both substances three times per day for 8 days. Intraindividual comparisons showed an increase in peak serum levels of cefadroxil from days 1 to 8 in seven of eight volunteers. Cefaclor peak concentrations did not rise during the 8 days.

Adult↗
PubMed1980

[Doxycycline pellets: a suitable formulation with guaranteed bioequivalence].

Basing on the physico-chemical properties of doxycycline relevant to an optimisation of the administration of this drug a new formulation (pellets) was developed. The bioavailability and tolerability of this formulation were studied in normal subjects in a cross-over design. The drug liberation profile of the new product excludes the risk of oesophageal irritation. The gastric tolerance of the pellet formulation is significantly better than that of the comparative product. No statistically significant differences were observed in the plasma AUC, indicating bioequivalence of the dosage forms. The values for plasma peak levels did not differ significantly, and were in agreement with the results of other studies on doxycycline bioavailability. Using the experimental data, a pharmacokinetic computer simulation of the doxycycline plasma levels for multiple-dose treatment was carried out: During the usual therapeutic dosage regimen the plasma levels are maintained above the MIC value.

Adult↗