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Biomedical subjects

H Iven

Publications and source records attributed to H Iven.

At least 19 recordsLinked to original sources
PubMed2006

Release of vancomycin and teicoplanin from a plasticized and resorbable gelatin sponge: in vitro investigation of a new antibiotic delivery system with glycopeptides.

BACKGROUND: The aim of this study was to evaluate the efficacy of sustained release of vancomycin and teicoplanin from a resorbable gelatin glycerol sponge, in order to establish a new delivery system for local anti-infective therapy. MATERIALS AND METHODS: 60 plasticized glycerol gelatin sponges containing either 10 or 20% gelatin (w/v) were incubated in vancomycin or teicoplanin solution at 20 degrees C for either 1 or 24 h. In vitro release properties of the sponges were investigated over a period of 1 week by determining the levels of vancomycin and teicoplanin eluted in plasma using fluorescent polarization immunoassay. The rate constant and the half-life for the antibiotic release of each group were calculated by linear regression assuming first order kinetics. RESULTS: Presoaking for 24 h was associated with a significant increase in the total antibiotic release in all groups opposed to 1 h of incubation, except for the 10% sponges presoaked in teicoplanin. Doubling the gelatin content of the sponges from 10 to 20% significantly increased the total release of antibiotic load only in teicoplanin-containing sponges after 24 h incubation. In all corresponding groups investigated, release of vancomycin was more prolonged compared to teicoplanin, which allowed a gradual release beyond 5 days. The half-life (h +/- SEM) of both types of vancomycin-containing sponges was significantly prolonged by 24 h incubation in comparison to 1 h incubation (29.1 +/- 5.9 vs 5.9 +/- 1.0; p < 0.001, 30.0 +/- 2.1 vs 11.1 +/- 1.9; p < 0.001). However, neither doubling the gelatin content of the sponges nor a prolonged incubation was associated with a significantly prolonged delivery of teicoplanin. CONCLUSION: This study demonstrated a better diffusion-controlled release of vancomycin-impregnated glycerol gelatin sponges compared to those pretreated with teicoplanin. The plasticized glycerol gelatin sponge may be a promising carrier for the application of vancomycin to infected wounds for local anti-infective therapy.

Anti-Bacterial Agents↗
PubMed2003

Pharmacokinetics and hemodynamic effects of the phosphodiesterase III inhibitor saterinone in patients with chronic heart failure.

UNLABELLED: The introduction of PDE III-inhibitors has been a major innovation for the intravenous drug treatment of patients suffering from heart failure. In this study, the pharmacokinetics and hemodynamic effects of the PDE III-inhibitor saterinone were examined in twelve male patients with severe chronic heart failure. METHODS: Saterinone was given by intravenous infusion for 24 hours at a rate of 1.5 microg/kg per min. According to a standardized protocol, blood samples were drawn for measurement of saterinone plasma levels and hemodynamic measurements were taken in order to analyze the correlation between plasma levels and hemodynamic effects. RESULTS: The correlation coefficient between the increase in cardiac index and the logarithms of saterinone plasma concentrations was r=0.827 (p=0.003). Between the logarithms of plasma concentrations and the decrease in pulmonary capillary wedge pressure a correlation coefficient of r=0.964 (p<0.001) was calculated for the first twelve hours of saterinone infusion. The decrease of saterinone plasma concentrations can be fitted to a three-compartment-model (half-lifes were 4.24 minutes for the alpha-phase, three hours for the beta-phase and 15.7 hours for the terminal phase). Saterinone induced maximal increases of 56.6% in cardiac index, 48.9% in stroke volume index, 28.4% in heart rate and maximal decreases of 17.3% in mean systemic blood pressure, 38.4% in mean pulmonary artery pressure, 74.2% in right atrial pressure, 46.9% in pulmonary capillary wedge pressure, 39.9% in systemic vascular resistance and 71.8% in pulmonary vascular resistance. CONCLUSION: Saterinone was demonstrated to be a safe, potent drug during an intravenous infusion over 24 hours at a rate of 1.5 microg/kg per min.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Human thiopurine S-methyltransferase activity in uremia and after renal transplantation.

UNLABELLED: In addition to cyclosporin and steroids, azathioprine is frequently used for immunosuppression after renal transplantation. Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. A genetic polymorphism was shown with 1 in 300 homozygous for a TPMT deficiency. These subjects carry the risk of severe myelosuppression when treated with azathioprine. OBJECTIVE: To investigate the influence of hemodialysis on TPMP activity in uremic patients and the effect of azathioprine treatment on enzyme activity. METHODS: The assay for measurement of TPMT activity in packed red blood cells is based on a non-radioactive conversion of 6-thioguanine to 6-methylthioguanine. In 251 patients, TPMT activity was determined before and after a 4-h period of hemodialysis. In 49 patients (26 on azathioprine, 23 on mycophenolate mofetil as control group), TPMT activity was regularly determined during the first 120 days after renal transplantation. RESULTS: TPMT activity is elevated in red blood cells of uremic patients before hemodialysis when compared with TPMT activity after hemodialysis. The latter is comparable to the activity in healthy subjects. In patients treated with azathioprine, the TPMT activity showed a slow increase that declined to pre-treatment values when azathioprine was withdrawn. This could not be observed in patients treated with mycophenolate mofetil. CONCLUSIONS: In uremic patients, TPMT activity is activated by some uremic factors that are removed by hemodialysis. In contrast to what has been observed before, dialysis shifted the TPMT activity close to that of a healthy control group. In patients treated with azathioprine after renal transplantation, the observed increase of TPMT activity could possibly be the result of enzyme induction.

Adult↗
PubMed2000

Methylation of 6-mercaptopurine and 6-thioguanine by thiopurine S-methyltransferase. A comparison of activity in red blood cell samples of 199 blood donors.

OBJECTIVES: To compare 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrates for the methylation reaction catalysed by the enzyme thiopurine S-methyltransferase (TPMT). METHODS: TPMT activity in haemolysed red blood cells of healthy blood donors was determined twice, using the same experimental setting and equal molar concentrations of 6-TG and 6-MP as substrates. After extraction, the reaction products 6-methyl-TG and 6-methyl-MP were quantified using specific high-performance liquid chromatography procedures. RESULTS: The medians of the TPMT activities from 199 blood donors were 54.4 nmol 6-MTG g(-1)Hb h(-1) when measured with 6-TG as the substrate and 35.8 nmol 6-MMP g(-1) Hb h(-1) when measured with 6-MP. The correlation coefficient for the 199 pairs of values was 0.8695. On average, TPMT activity was 34% lower with 6-MP as substrate than with 6-TG as substrate.

Adult↗
PubMed2000

Influence of continuous veno-venous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole.

OBJECTIVE: To compare the elimination of fluconazole by continuous veno-venous haemodiafiltration (CVVHD) and continuous veno-venous haemofiltration (CVVH) at different dosages. INTERVENTION: Patients received doses of 400 mg (n=3), 600 mg (n=1) or 800 mg (n=2) fluconazole as a short-time infusion once a day. Patients underwent CVVHD the first day and CVVH the second day. CVVHD and CVVH were performed using an acrylonitrile hollow-fibre filter at a constant blood flow of 90 ml/min and a substitution flow of 1000 ml/h (predilution). During CVVHD, the dialysate flow was 1000 ml/h. Ultrafiltration rates were 1158+/-90.5 ml/h during CVVHD and 1167+/-81.6 ml/h. Serum and ultrafiltrate/dialysate concentrations of fluconazole were determined on nine occasions over 24 h. PARTICIPANTS: Six critically ill patients with acute renal failure (ARF) and serious fungal infection. RESULTS: Extracorporeal clearance (CVVHD 30.5+/-6.0 ml/min, CVVH 17.5+/-4.0 ml/min) and total clearance of fluconazole (CVVHD 37.9+/-4.4 ml/min, CVVH 25.3+/-6.5 ml/min) were significantly higher during CVVHD (P < 0.05). During CVVHD, the sieving coefficient (S(CVVHD)) was 0.88 (range 0.54-1) and the elimination half-life (t1/2) was 14.8-35.1 h. During CVVH, the S(CVVH) was 0.96 (range 0.56-1.02) and t1/2 was 24.0-51.6 h. CONCLUSIONS: A daily dosage of 400-800 mg fluconazole is recommended in the treatment of life-threatening fungal infections in critically ill patients undergoing CVVHD since the clearance of CVVHD may considerably exceed the clearance in patients with normal renal function, which is about 20 ml/min. Drug monitoring is highly recommended for these patients.

Acute Kidney Injury↗
PubMed1999

Inhibition of thiopurine S-methyltransferase activity by impurities in commercially available substrates: a factor for differing results of TPMT measurements.

OBJECTIVES: Thiopurine S-methyltransferase (TPMT) activity, when measured in red blood cells (RBC) with a recently published TPMT activity assay using 6-thioguanine (6-TG) as substrate, could not be reproduced in another laboratory. We investigated factors which could influence the results of the TPMT activity measurement. METHODS: We tested twelve 6-TG and four 6-mercaptopurine (6-MP) compounds from different suppliers as substrates and determined the enzyme kinetic parameters Km and Vmax. Furthermore, we studied the influence of different 6-TG compounds on the affinity of the methyl donor S-adenosyl-L-methionine (SAM) to the TPMT enzyme. RESULTS: All 6-TG products were of equal purity (declared >98% by the supplier): this was ascertained by HPLC. However, the rate of methylation obtained following incubation with 6-TG from different suppliers ranged from 10% to 100% when incubated with the same RBC lysate. The lowest apparent Km value for a 6-TG was 22.3 micromol x l(-1), while the product with the highest methylation rate showed a Km of 156 micromol x l(-1). From these results we assume that there is a contaminant in some 6-TG products, which acts as a strong inhibitor of TPMT activity. Compounds possibly used for the synthesis of 6-TG (guanine, pyridine, 6-chloroguanine) did not affect the methylation rate. Thioxanthine, which is known to be a strong inhibitor of TPMT when added to the assay system to give a 2% contamination, reduced TPMT activity from 100% to 72%. Using 6-MP from different suppliers as substrate resulted in Km values ranging from 110 to 162 micromol x l(-1) and Vmox values ranging from 54 to 68 nmol 6-MMP x g(-1)Hb x h(-1). The Km value for the methyl donor SAM was similar to and independent from the thiopurine substrates tested (range 4.9-11 micromol-l(-1) SAM). In contrast to other investigators, we found non-enzymatic S-methylation, which was negligible under our assay conditions (3% with 128 micromol x l(-1) SAM), but could become relevant in experiments using higher SAM concentrations. CONCLUSIONS: TPMT enzyme activity determined with 6-TG as substrate may be strongly inhibited by a contaminant in some of the 6-TG lots distributed.

Enzyme Inhibitors↗
PubMed1999

Systemic levels of lidocaine after intracameral injection during cataract surgery.

PURPOSE: To evaluate the systemic concentrations of lidocaine after intracameral injection of a 1% solution during cataract surgery and the safety of this application mode. SETTING: Department of Ophthalmology, Medical University of Lübeck, Lübeck, Germany. METHODS: This prospective study included 10 patients who had phacoemulsification and posterior chamber lens implantation with a self-sealing scleral tunnel incision. Topical anesthesia was achieved using cocaine 10% eyedrops combined with 0.5mL of unpreserved lidocaine 1% injected into the anterior chamber. Blood samples were taken from all patients at predetermined intervals before and during the procedure. Consecutive analysis for lidocaine was performed with gas chromatography. RESULTS: In all samples, serum lidocaine concentrations were below a minimum detectable level of 100 ng/mL. No local or systemic intraoperative or postoperative complications were noted. CONCLUSIONS: Intracameral injection of 0.5 mL lidocaine 1% revealed no systemic therapeutic concentrations. In patients in whom other forms of needle-delivered local anesthesia are contraindicated, intracameral injection of lidocaine should be considered to enhance topical anesthesia.

Adult↗
PubMed1998

Thiopurine S-methyltransferase activity in human erythrocytes: a new HPLC method using 6-thioguanine as substrate.

OBJECTIVES: To develop a non-radioactive assay to measure thiopurine S-methyltransferase (TPMT) activity. The assay was used to study the distribution of TPMT activity in a healthy German population. METHODS: The assay is based on the conversion of 6-thioguanine (6-TG) to 6-methylthioguanine (6-MTG) using non-radiolabelled S-adenosyl-L-methionine (SAM) as the methyl donor. At the end of the incubation period (60 min) 6-MTG is extracted into chloroform/2-propanol and quantitated by reversed-phase high-performance liquid chromatography (HPLC) with fluorescence detection at Ex 315 nm and Em 390 nm. RESULTS AND DISCUSSION: The method is rapid, sensitive and reproducible, with an interassay CV of 6.7% (quality control sample with TPMT activity of 43 nmol 6-MTG x g(-1) Hb x h(-1)) and thus suitable for routine monitoring of TPMT activity. The TPMT activity of 219 healthy German blood donors showed the known trimodal distribution with a range from 1.3 to 68.3 nmol 6-MTG x g(-1) Hb x h(-1) with a median value of 38.8 nmol 6-MTG x g(-1) Hb x h(-1). When the cut-off value for intermediate to high activity was set at 23.5 nmol 6-MTG x g(-1) Hb x h(-1), 14.1% belonged to the group with intermediate and 83.6% to the group with high TPMT activity. Five individuals had a very low TPMT activity of <2 nmol 6-MTG x g(-1) Hb x h(-1). Genetic analysis revealed that these persons were found either homozygote for the variant allele *3A (n = 3) or they were compound heterozygotes for the variant alleles *3A/*3C (n = 2). With these alleles for low TPMT activity they would run an increased risk of myelosuppression in case of treatment with standard doses of thiopurine drugs.

Alleles↗
PubMed1998

Saterinone, dobutamine, and sodium nitroprusside: comparison of cardiovascular profiles in patients with congestive heart failure.

The acute hemodynamic effects of the phosphodiesterase (PDE) III inhibitor saterinone were compared with dobutamine and sodium nitroprusside in 12 patients with idiopathic congestive cardiomyopathy (NYHA III). Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. At the peak of its dose-response curve, saterinone induced an increase in cardiac index (+102%), stroke volume (+97%), and heart rate (+6%), paralleled by a decrease in pulmonary capillary wedge pressure (-46%), right atrial pressure (-51%), pulmonary arterial pressure (systolic -32%, diastolic -45%, mean -38%), systemic blood pressure (systolic -3%, diastolic -13%, mean -9%), systemic vascular resistance (-54%), and pulmonary vascular resistance (-58%). Dobutamine had similar effects on cardiac index (+106%) and stroke volume (+87%) but lacked vasodilatory characteristics. In contrast to dobutamine, both nitroprusside and saterinone demonstrated more pronounced vasodilatory effects. Nitroprusside was less effective on cardiac index (+66%) and stroke volume (+56%) than was saterinone. The double product was markedly increased by dobutamine (+28%), did not change with saterinone treatment (+2%), and decreased with nitroprusside (-10%). This indicates that according to double product, only the application of dobutamine caused a relevant increase in myocardial oxygen consumption. Saterinone was demonstrated to be a safe and potent drug on short-term application; it combines the vasodilating properties of sodium nitroprusside with the positive inotropic effects of dobutamine without major changes in myocardial oxygen consumption.

Adult↗
PubMed1997

Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719. In the present study, we set out to determine the number, types, and frequencies of TPMT variant alleles associated with low enzyme activity in clinical laboratory samples in the United States and to compare those results with data obtained from two different ethnic groups. We identified a total of six different variant alleles for low TPMT activity in the 283 clinical laboratory samples studied. The most common variant was *3A; the second most frequent variant allele, *3C, contained only the nucleotide 719 polymorphism; and four other variant alleles were detected. TPMT*3A also appeared to be the most common variant allele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, *3C was present in samples from the Korean children, as was novel allele, *6. Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype.

Alleles↗
PubMed1997

Comparison of vancomycin and teicoplanin for prophylaxis of sepsis with coagulase negative staphylococci (CONS) in very low birth weight (VLBW) infants.

A prospective randomized study was performed to evaluate the efficacy of a low dose (5 mg/kg/day bid) vancomycin compared with a low dose (5 mg/kg/day once daily) teicoplanin therapy to prevent CONS sepsis in VLBW-infants. All infants received this therapy after their 4th day of life or after an eventual therapy of early onset sepsis as long as an i.v. line was in place or 1500 g body weight. Twenty-seven infants were treated with vancomycin (birth weight 1103 +/- 286 g, gest. age 28.8 +/- 1.9 weeks), 28 with teicoplanin (birth weight 1133 +/- 226 g, gest. age 29.04 +/- 2.2 weeks). The infants were observed for clinical and laboratory signs of sepsis. On day 4 of therapy and every 3rd day during therapy serum creatinine levels, tracheal aspirates, stool cultures and vancomycin/teicoplanin peak and trough levels were obtained. We could not detect any case of blood culture positive sepsis and 1 case of suspected sepsis (neg. blood cultures) in both groups, as compared with a former CONS sepsis rate of 24% in our institution's VLBW infants without antibiotic prophylaxis. Nine patients in the vancomycin and five in the teicoplanin group had tracheal colonization with CONS. In both groups peak and trough levels of antibiotics were in the bactericidal range. Serum creatinine was not normal in both groups. We conclude that teicoplanin is preventing CONS sepsis as well is vancomycin. The minimal inhibitory concentrations of both antibiotics against grampositive isolates in units using this strategy have to be observed carefully to detect emerging resistance.

Anti-Bacterial Agents↗
PubMed1996

Local application of vancomycin for prophylaxis of graft infection: release of vancomycin from antibiotic-bonded Dacron grafts, toxicity in endothelial cell culture, and efficacy against graft infection in an animal model.

Methicillin-resistant strains of Staphylococcus epidermidis cause an increasing number of prosthetic infections. This prompted us to test the uptake of vancomycin in various graft materials in vitro, its influence on graft healing, and its efficacy against graft infection in pigs. Incubation of six different Dacron graft materials in a vancomycin solution (20 gm/L) was performed. Grafts were then placed in plasma, and samples were taken over 72 hours to determine vancomycin levels. Release of vancomycin ranged from 775 micrograms/cm2 to 3691 micrograms/cm2 after 1 hour of incubation. Gelatin-covered grafts increased release of vancomycin fourfold when incubation time was extended to 24 hours: uncovered grafts or the collagen-covered graft did not. Graft healing was not complicated when a vancomycin-bonded, gelatin-impregnated Dacron graft was implanted to replace the common femoral artery in pigs. Four weeks after implantation, histologic examination revealed normal development of neointima and perigraft scar tissue in the vancomycin-treated (n = 4) and untreated (n = 5) grafts. To test the efficacy of local vancomycin against graft infection, grafts were implanted in the groin of pigs and contaminated with 2 x 10(7) colony-forming units of Staphylococcus aureus. Four weeks after implantation, all grafts were infected in the untreated group (n = 6), with abscess, nonincorporated graft, and detection of S. aureus from the graft. In the treatment group (n = 6) vancomycin was added to the contaminated grafts. As a carrier for the vancomycin, we used a resorbable gelatin-glycerol foam. All grafts healed without infection. The difference between the treated and untreated groups is statistically significant (p < 0.05). We conclude that it may be effective to prevent graft infection with local application of vancomycin if an in situ replacement of infected graft (infected by gram-positive bacteria) is necessary or if there is a high risk of infection by methicillin-resistant- staphylococci.

Animals↗
PubMed1995

Topical cyclosporin in oral lichen planus: a controlled, randomized, prospective trial.

The published studies of topical cyclosporin (CyA) therapy in chronic oral lichen planus (OLP) have shown conflicting results. We report an investigator-blinded study of 13 patients with OLP, who were randomly assigned to treatment with CyA (500 mg as a swish-and-spit medication for 5 min three times daily) or a corticosteroid oral paste (triamcinolone acetonide). The duration of treatment was 6 weeks. Thereafter, patients on corticosteroid therapy were treated with CyA. Only slight, transient clinical improvement was observed in both groups after 6 weeks of treatment, compared with baseline. No significant differences could be demonstrated between the two groups. CyA therapy following corticosteroid treatment did not produce any further clinical improvement. During follow-up of the disease for up to 1 year after treatment, neither the CyA nor the corticosteroid group exhibited long-term improvement in disease activity. Contradictory results from earlier reports are discussed.

Administration, Topical↗
PubMed1992

Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies.

A massive digitoxin (DGTX) intoxication in a 36-year-old man (35 mg DGTX) was treated by prolonged and repeated i.v.-infusions of Fab fragments of anti-digitalis antibodies (FAB). Blood and urine samples were collected over a 98 h period for monitoring the efficacy and adequacy of FAB treatment. DGTX concentrations were determined after protein precipitation (release of FAB-bound and protein-bound DGTX) in unprocessed serum and urine samples, and after aliquots of these samples had been dialysed in vitro against DGTX-free buffer (elimination of DGTX not bound to FAB). The difference in DGTX concentration between the unprocessed and dialysed samples was the amount of DGTX bound to plasma proteins and the small fraction of unbound DGTX being relevant for the therapeutic and toxic effects of the drug. Before FAB therapy was started, the total serum DGTX concentration was 535 nmol/l. The first FAB infusion (320 mg) was started 11 h after drug ingestion. Since this amount of FAB was insufficient to bind all DGTX present in the serum, cardiac DGTX toxicity (total AV-block) persisted. During a second FAB infusion (400 mg) the patient reverted to regular AV-conduction. At this time most of the DGTX in serum was FAB-bound. Toxic symptoms (sinus arrest) reappeared twice and were accompanied by increasing amounts of non-antibody-bound DGTX in the serum. Additional application of FAB (2 x 80 mg) resulted in the immediate disappearance of arrhythmia. During FAB-treatment total DGTX serum concentrations and renal DGTX clearance rose, indicating redistribution of drug from tissue to serum and urinary elimination of FAB-bound DGTX, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[Absolute bioavailability of beta-acetyldigoxin from tablets and drops in healthy subjects].

In a crossover design in random order 12 healthy male volunteers were given either beta-acetyldigoxin (Novodigal, CAS 5511-98-8) tablets, oral solution or i.v. application at a digoxin equivalent dose of 0.284 mg. To reach steady state each preparation was given for 10 days on a once-daily schedule. On days 8, 9 and 10 of each observation period blood was sampled to determine trough concentrations of digoxin in steady state. In addition, on day 10 blood was collected repeatedly at appropriate time intervals and urine was sampled concomitantly for 24 h. Trough values during steady state and 24 h AUC were used to calculate digoxin bioavailability for tablets and oral solution. From trough values, the mean bioavailability for beta-acetyldigoxin tablets was 91.2% (range 73.1-118.1) and for solution 93.8% (range 65.7-114.8). Using the AUCs 0-24 h at steady state bioavailability was calculated 77.7% for the tablets and 84.5% for the solution. Since trough values in steady state represent the body burden of digoxin which is supposed responsible for the therapeutic effect, trough values should be given priority for the determination of digoxin bioavailability from beta-acetyldigoxin tablets and solution. All formulations were well tolerated. No clinically relevant side effects were observed.

Acetyldigoxins↗