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G Weigel

Publications and source records attributed to G Weigel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Influence of glycopeptide antibiotics on purine metabolism of endothelial cells.

We provide evidence that the commercially available preparations of glycopeptides for intravenous application are well tolerated by endothelial cells when applied in concentrations less than 5 mg/ml. Since the antibiotics tested are administered at maximal concentrations of 10 mg/ml, the dose range used in our in vitro experiments (5 and 10 mg/ml) mimics possible clinical concentrations at the site of infusion. Similar concentrations may be reached by retrograde intravenous pressure infusion techniques (10-12). We have demonstrated that these high concentrations lead to considerable endothelial cell damage. These findings may explain the common side effect associated with intravenously applied glycopeptides namely pain and phlebitis at the site of infusion (2, 13). Figure 1 shows that a detrimental effect measurable after 20 min occurs only using vancomycin solutions at concentrations of 10 mg/ml, whereas already a dilution to 5 mg/ml renders the solutions more compatible to HUVEC. These data are in line with the observation that slow intravenous application of glycopeptides into large veins can largely prevent the occurrence of local phlebitis. Alternatively, the occurrence of phlebitis should be avoidable by diluting the manufacturers' preparations at least to 2-5 mg/ml and not 10 mg/ml as recommended by the manufacturer of vancomycin. The same aspects need to be considered for use of glycopeptides for retrograde high pressure infusion. The tolerance of intravenously applied antibiotics has previously been tested in animal models (4). Our model of human venous endothelial cells for testing antibiotic solutions for intravenous compatibility provides a valuable alternate model. In conclusion our data show that the commercial preparation of teicoplanin is more compatible for HUVEC than those of vancomycin.

Adenosine Triphosphate↗
PubMed1998

Endothelial cell compatibility of clarithromycin for intravenous use.

OBJECTIVES: Tolerance of intravenously applied clarithromycin has been tested on marginal ear veins of rabbits. Use of human umbilical venous endothelial cells (HUVEC) for testing antibiotic solutions for intravenous compatibility provides a valuable alternate model. DESIGN AND METHODS: In order to evaluate the effect of clarithromycin on intracellular purines, reflecting cell viability, energy production, signal transduction and DNA/RNA synthesis, intracellular adenosine 5' triphosphate (ATP), adenosine 5' diphosphate (ADP), guanosine 5' triphosphate (GTP), and guanosine 5' diphosphate (GDP) levels were measured by means of high performance liquid chromatography (HPLC). RESULTS: Incubation of cells with 2 mg/mL clarithromycin resulted in a rapid decrease of the intracellular ATP from 12.6 +/- 1.1 to 8.87 +/- 0.82 nmol/million cells or 1.5 +/- 0.6 nmol/million cells, after 20 or 60 min, respectively. In addition, ADP was extensively depleted. Purine nucleotide profiles were markedly different following exposure to 1 mg/mL clarithromycin. There was no significant decline of intracellular high energy phosphate levels after 20 min. CONCLUSION: These results show that clarithromycin has a better endothelial compatibility if diluted to a final concentration of 1 mg/mL. These data are in line with our clinical observations that the occurrence of phlebitis could be minimized by diluting the manufacturers' preparation of clarithromycin to 1 mg/mL.

Adenine↗
PubMed1998

Bioflavonoid quercetin scavenges superoxide and increases nitric oxide concentration in ischaemia-reperfusion injury: an experimental study.

BACKGROUND: L-Arginine-depleted environments accompanying ischaemia-reperfusion enhance superoxide production, leading to the formation of reactive oxygen species and a concomitant reduction in basal nitric oxide levels. The bioflavonoid quercetin may prevent these undesirable effects by scavenging superoxide. METHODS: Untreated rabbits were compared with those infused with quercetin (5 mg/kg for 2 min) during hindlimb ischaemia (2.5 h) and reperfusion (2 h). In both groups, nitric oxide concentration was measured (porphyrinic microsensor) in the femoral artery wall. Microvasculature changes (morphometry) and superoxide concentration (chemiluminescence) were measured intermittently in biopsies. RESULTS: Approximately 6 min into the period of ischaemia a rapid increase in nitric oxide level from a mean(s.e.m.) basal level of 50(20) to 450(30) nmol/l was observed. In untreated animals, nitric oxide concentration dropped to an undetectable level (less than 1 nmol/l) during reperfusion. In quercetin-treated animals, the decrease in nitric oxide concentration was slower, such that substantial amounts (60(20) nmol/l) accumulated during reperfusion. In biopsies after ischaemia-reperfusion maximal calcium ionophore A23187-stimulated nitric oxide concentration increased (25-30 per cent) in the presence of quercetin, while the superoxide concentration decreased. CONCLUSION: Quercetin treatment mollified ischaemia-reperfusion injury to skeletal muscle by scavenging destructive superoxide and enhancing the cytoprotective nitric oxide concentration.

Animals↗
PubMed1998

Endothelial cell compatibility of glycopeptide antibiotics for intravenous use.

The use of human venous endothelial cells for testing antibiotic solutions for intravenous compatibility provides a valuable alternative to animal models. In order to evaluate the effect of vancomycin and teicoplanin on the viability of human umbilical venous endothelial cells, intracellular ATP levels were measured by a luciferin-luciferase assay. Prostacyclin (PGI2) and thromboxane A2 (TXA2) were determined by direct radioimmunoassay. Vancomycin at concentrations of 5 and 10 mg/mL reduced the intracellular ATP content by 18.7% and 69.9%, respectively, within 60 min. In contrast, cellular energy charge remained significantly higher after incubation with teicoplanin at 5 and 10 mg/mL (reduction 8.7% and 15.5%, respectively). Neither vancomycin nor teicoplanin at a concentration of 2 mg/mL led to significant ATP decline. However, endothelial cells incubated with vancomycin resulted in significantly lower release of PGI2 and TXA2 compared with teicoplanin. These results show that teicoplanin is more compatible with endothelial cells than vancomycin, and that both antibiotics are well tolerated if diluted to a final concentration of 2 mg/mL.

Adenosine Triphosphate↗
PubMed1997

Endothelial eicosanoid metabolism and signal transduction during exposure to oxygen radicals injury.

Several physiological agonists that induce elevation of cytosolic free calcium (Ca2+)-levels act via receptor coupled G-proteins, involving activation of phospholipase C (PLC) and hydrolysis of phosphatidylinositol 4,5-bisphosphate. Activation of the inositol signal transduction pathway that precedes Ca2+ ion mobilization is a well accepted signaling pathway in endothelial cell eicosanoid synthesis. This study was designed to examine possible involvement of phosphoinositides in the effects of oxygen free radicals on Ca2+ liberation and eicosanoid synthesis in human umbilical venous endothelial cells (HUVEC). Hydrogen peroxide (H2O2) was chosen as oxygen radicals generating agent. Stimulation of HUVEC with H2O2 (0.1 mmol/l) led to significant rises in inositol phosphate and diacylglycerol (DAG) levels within 300 seconds and an inhibition of Ca2+ release from internal stores. Eicosanoid formation was detectable despite unchanged levels of cytosolic free Ca2+ and no detectable activation of membrane associated phospholipase A2 (PLA2). This suggests that eicosanoid formation may be mediated through the activation of a Ca2+ independent, cytosolic 40 kDa PLA2 isoenzyme and that DAG could serve as an alternative source for arachidonic acid and seems to sensitize a cytosolic PLA2.

Cells, Cultured↗
PubMed1997

Surgical treatment of aortic arch aneurysms in profound hypothermia and circulatory arrest.

BACKGROUND: This study was undertaken to define the factors that influence mortality rate and neurologic outcome after repair of the aortic arch and various portions of the thoracic aorta in patients with profound hypothermia and circulatory arrest. METHODS: Between November 1986 and January 1996, 105 patients were treated surgically for aortic disease involving the transverse aortic arch. Profound hypothermic circulatory arrest and selective brachiocephalic perfusion was used in all patients. In 19 patients retrograde cerebral perfusion was instituted during the period of circulatory arrest. Independent predictors for 30-day mortality and permanent neurologic deficits were evaluated by multiple logistic regression. RESULTS: Thirty-day mortality for the entire group was 19% (20/105); 21.2% for urgent versus 15.4% for elective cases, respectively. Statistical analysis showed that age is the most important factor that significantly influences mortality rate (p < 0.0145) and neurologic outcome (p < 0.006). Variables such as circulatory arrest time (p < 0.24), previous cardiac or aortic operations (p < 0.19), and sex (p < 0.55) failed to show any influence on mortality rate. Permanent neurologic deficits were diagnosed in 12.9% (11/85) of the patients. CONCLUSIONS: The incidence of permanent neurologic dysfunction as well as the mortality rate are predominantly related to the age of the patient. In this patient group, statistical analysis failed to show a direct correlation between duration of circulatory interruption and neurologic outcome.

Adolescent↗
PubMed1997

Endothelial cell compatibility of fluoroquinolone solutions for intravenous use.

One local side-effect closely related to the use of parenteral fluoroquinolones is phlebitis. The occurrence of this phenomenon is largely thought due to the damage of endothelial cells with subsequent inflammation. In order to evaluate the effect of ciprofloxacin, fleroxacin, and ofloxacin on the viability of human umbilical venous endothelial cells (HUVEC), intracellular ATP levels were measured by a luciferin-luciferase assay. Prostacyclin (PGI2) and thromboxane A2 (TXA2) were determined by means of direct radioimmunoassay. Commercially available preparations of ciprofloxacin (2 mg/ml) and fleroxacin (4 mg/ml) reduced the intracellular ATP content by 75.9 +/- 1.9% and 82.1 +/- 0.6%, respectively, within 20 minutes, indicating severe damage of endothelial cells. Incubation with ofloxacin (2 mg/ml) did not have any detrimental effect. All fluoroquinolones were tolerated well by endothelial cells at low concentrations up to 20 micrograms/ml. Concentrations between 100-200 micrograms/ml gradually led to functional alterations such as increased PGI2 release. The tolerance of intravenously applied antibiotics has been tested in animal models. Use of human venous endothelial cells for testing antibiotic solutions for intravenous application provides a valuable alternate model for tolerability.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

IMP-dehydrogenase inhibition in human lymphocytes and lymphoblasts by mycophenolic acid and mycophenolic acid glucuronide.

Inosine 5'-monophosphate dehydrogenase (IMP-DH) activities were measured in human lymphocytes (exhibiting type I IMP-DH activity) and human lymphoblasts (exhibiting type II IMP-DH activity) in the presence of various amounts of mycophenolic acid (MPA) (0-20 mumol/L) and MPA glucuronide (MPAG) (0-200 mumol/L). Moreover, the influences of human serum albumin (HSA) and human plasma on the MPA- and MPAG-mediated effects were investigated. In the presence of water, 2.5 mumol/L MPA decreased the IMP-DH activity measured in lymphocytes by 60%, whereas in lymphoblasts a 80% inhibition was detectable. In the presence of > or = 10 mumol/L MPA, lymphocytic as well as lymphoblastic IMP-DH activities were reduced in a similar manner. The concentration of MPAG required for 50% inhibition was for both cell types > 25 mumol/L and < 50 mumol/L, respectively. MPAG (200 mumol/L) reduced lymphocytic as well as lymphoblastic IMP-DH activity by approximately 80%. With 100 g/L HSA or human plasma as diluent, the inhibitory effects of MPA and MPAG were significantly (P < 0.05) diminished, whereas HSA concentrations < or = 25 g/L only slightly influenced the inhibition of IMP-DH activity by MPA and MPAG. In summary, it can be clearly demonstrated that not only MPA but also MPAG contributes to the inhibition of both IMP-DH isoenzymes, which might be relevant for the immunosuppressive properties of mycophenolate mofetil in transplant patients.

Blood Proteins↗
PubMed1995

Influence of glutamine on the phenotype and function of human monocytes.

Reduced concentrations of glutamine (GLN) in plasma and skeletal muscle, defective host defense systems, and a diminished expression of the HLA-DR antigen on monocytes are important diagnostic parameters for late post-injury sepsis. In this in vitro study, we investigated whether blood monocyte-derived macrophage antigen expression and function from healthy donors is influenced by GLN. Lowering the GLN concentration in culture medium from 2 mmol/L to 200 mumol/L reduced the expression of HLA-DR by 40% (P < .001) on monocyte-derived macrophages, and decreased tetanus toxoid-induced antigen presentation. In addition, low GLN levels downregulated the expression of intercellular adhesion molecule-1 (ICAM-1/CD54), Fc receptor for IgG (Fc gamma RI/CD64), and complement receptors type 3 (CR3; CD11b/CD18) and type 4 (CR4; CD11c/CD18). A correlation was found between the phagocytosis of IgG-sensitized ox erythrocytes or opsonized Escherichia coli and the decreased expression of Fc gamma RI and CR3. Monocyte expression of CD14, CD71, and Fc gamma RIII/CD16 and capacity to phagocytose latex beads were not affected by altering the level of GLN. Depletion of GLN was associated with a significant reduction in cellular adenosine triphosphate (ATP), which may have influenced cell surface marker expression and phagocytosis. It remains to be seen whether these in vitro findings are of clinical significance in the treatment of sepsis.

Adenosine Triphosphate↗
PubMed1994

The protective potency of two commonly used cardioplegic solutions on cultured endothelial cells exposed to free-oxygen radicals injury.

Human umbilical vein endothelial cells were incubated with Bretschneider and St. Thomas II cardioplegic solution followed by a stimulation with cumene hydroperoxide (CHPO), which was used as an oxygen radicals generating agent. A statistically significant decrease of intracellular high energy phosphates (adenosine-5-trisphosphate: ATP; creatine phosphate: CP) compared to controls was observed in response to Bretschneider cardioplegia and CHPO. Furthermore, significant rises in prostaglandin I2 (prostacyclin; PGI2) production and lipidperoxidation were measured. The authors failed to record such alterations of endothelial cell metabolism for the St. Thomas II cardioplegic solution. They could also demonstrate that the cellular protection against oxygen radicals exerted by the St. Thomas II solution is attributable to procaine. The enhanced cytotoxicity of CHPO observed in presence of the Bretschneider solution was found to be partially caused by its constituent L-histidine, which led to significant decreases of high energy phosphates and increased lipidperoxidation when cells were subsequently treated with CHPO. However, alterations of high energy phosphate content initiated by CHPO and amplified by the Bretschneider solution could not be inhibited by adding procaine. Simultaneous pretreatment of cells with the Bretschneider solution and procaine and stimulation with CHPO resulted in decreases of ATP and CP, as observed using the Bretschneider cardioplegia alone.

Adenosine Triphosphate↗
PubMed1993

The H2O2 induced effects on purine metabolism in human endothelial cells.

The effects of hydrogen peroxide (H2O2) on the purine metabolism of human endothelial cells were investigated. An incubation with 0.01 mM H2O2 over 60 min led to an increase in the intracellular adenosine-5-triphosphate (ATP) and creatine phosphate (CP) levels by 51.3% and 18.2%, respectively. A 60 min incubation with 0.1 mM H2O2 showed no effect. The uptake and salvage of 14C-adenine (14C-AD) and 14C-adenosine (14C-ADO) was significantly (p < 0.005) increased using 0.01 mM H2O2. Only an increase of 14C-ADO incorporation was observed using 0.1 mM H2O2. A concentration of 0.01 mM H2O2 reduced 5-phosphoribosyl-1-pyrophosphate synthetase (PRPP-S) activity by 60% and at the same time increased the activity of purine nucleoside phosphorylase, which converts inosine to hypoxanthine (PNP I), by 24%. Adenosine kinase (AK) activity was reduced by H2O2, whereas adenine phosphoribosyltransferase (APRT) activity was found to be elevated. In conclusion, the observed elevation of cellular ATP and CP levels could be partially caused by an increased purine salvage resulting from changes in purine enzyme activities.

Adenine Phosphoribosyltransferase↗