Differential pulse polarographic investigation of micafungin and anidulafungin using a dropping mercury electrode.

The electrochemical behavior of the echinocandin antifungals anidulafungin (AF) and micafungin (MF) has been investigated by differential pulse polarography (DPP). The measurements were carried out in a supporting electrolyte solution consisting of Britton-Robinson buffer and methanol at various substance concentrations and pH values. An amperometric cell with a three electrode system consisting of a dropping mercury electrode (DME) as working electrode, an auxiliary platinum electrode and an Ag/AgCl reference electrode was used in all experiments. AF was electrochemically reduced at potentials between -1.3 and -1.5 V. MF showed a first reduction peak (a) between -1.0 and -1.4 V and a second peak (b) between -1.5 and -1.8 V. A strong pH-dependence was observed, with optimal results at pH 2.0-3.0 for the AF peak, pH 2.0 for the MF peak (a) and pH 5.0 for the MF peak (b). A linear correlation between the concentration and the peak current has been demonstrated for all reduction peaks. MF peak (a) showed a similar behavior to the AF peak regarding shape, peak current and pH-dependence. Therefore, it can be assumed that both reductions are based on the same mechanism, a two-step reduction of the N-acyl group.

Determination of the contamination by azole antimycotics in hospital and house sewage - a pilot project for the city of Dresden.

Medicininal compounds and their metabolites are known to end up in sewerage and may slip through the cleaning process. Azole antimycotics are frequently used in hospitals, in particular for patients with cancer or immunosuppression. The aim of the study was to determine whether measurable azole antimycotic concentrations were introducted in the sewarage drain of an acute care hospital with special interest in oncology and hematology and the extent of removal of antimycotics by the sewerage treatment plant. For this, the concentrations of three commonly used azole antimycotics were measured in the effluent of the sewerage drain at the University Hospital Dresden, as well as in the influent and effluent of the main sewerage treatment plant of the city. To extrapolate the theoretical influent to the sewerage treatment plant, prescription from the regio`s main health insurance the AOK Sachsen and the hospital consumption data were used. Measurable concentrations were obtained for fluconazole and ketoconazole in the influent and effluent of the sewerage treatment plant. Voriconazole's concentrations were under the lower limit of quantification. To determine the azole clearance of the treatment plant a sludge sample was investigated. Sufficient clearance was detected for ketoconazole but not for fluconazole. The consumption and prescription rates were collected and correlated with the measured concentrations. In result, only fluconazole's concentrations provided a good match with the prescription and consumption data.

In-vitro detection of mannan and galactomannan in components of total parenteral nutrition (TPN).

Detection of Candida mannan and Aspergillus galactomannan in serum with the Platelia enzyme immunoassay is applied for diagnosing invasive fungal infections. High risk patients for invasive fungal infections are often receiving parenteral nutrition. It is important to know whether false-positive Platelia test results occur during total parenteral nutrition. Studies to false-positivity in intravenous feeding solutions lack so that we start an in-vitro investigation. We used two different enzyme immunoassays to test the feeding solutions. We tested infusions (n = 19) which are applied for the production of individual parenteral nutrition in the University Hospital Carl Gustav Carus Dresden. We used the Platelia Aspergillus EIA to analyse the Aspergillus antigen galactomannan in the solutions. In addition, the Platelia Candida Ag plus was used to determine the concentration of the Candida antigen mannan. In summary, four solutions (21%) showed measurable concentrations of the Candida mannan. They were considered positive with a concentration > 0.125 ng/ ml mannan (Tracitrans infant, calcium gluconate solution) and borderline with a concentration between 0.0625 and 0.125 ng/ml mannan (Tracitrans plus, SMOFlipid). None of the analysed infusions contained the Aspergillus galactomannan. In conclusion, further investigations on the topic are necessary to determine their in-vivo impact. A positive Platelia test result can simulate the presence of invasive fungal infections. As a consequence the patient may be treated with expensive, systemic antimycotics with a high risk of adverse events. Therefore a definite diagnosis is important.

Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Electrochemical behavior of the antifungal agents itraconazole, posaconazole and ketoconazole at a glassy carbon electrode.

The electrochemical behavior of the azole antifungal agents itraconazole, posaconazole and ketoconazole has been investigated at a glassy carbon working electrode using cyclic voltammetry. All measurements were carried out in a supporting electrolyte solution consisting of a 1:1 (v/v) mixture of 0.1 mol L(-1) sodium phosphate buffers and acetonitrile at various substance concentrations and pH values. An amperometric cell with a three electrode system consisting of a working electrode, a palladium reference electrode and a platinum disk as the auxiliary electrode was used in all experiments. All azoles showed a similar electrochemical behavior involving two reactions. An irreversible oxidation occurred at potentials of about 0.5V. A reduction peak was detected at potentials between -0.28V and -0.14V with an associated oxidation peak, which was observed in consecutive repeated measurements at potentials between -0.03 and 0.28 V. The reduction and corresponding oxidation can be regarded as a quasi-reversible process. The proposed reaction mechanisms are an irreversible oxidation of the piperazine moiety at higher potentials as well as a reduction at lower potentials of the carbonyl group of the triazolone moiety in the case of itraconazole and posaconazole or a reduction of the methoxy group of ketoconazole.

Treatment cost of invasive fungal disease (Ifd) in patients with acute myelogenous leukaemia (Aml) or myelodysplastic syndrome (Mds) in German hospitals.

Invasive fungal disease (IFD) causes increasing morbidity and mortality in haematological cancer patients. Reliable cost data for treating IFD in German hospitals is not available. Objective of the study was to determine the institutional cost of treating the IFD. Data were obtained by retrospective chart review in German hospitals. Patients had either newly diagnosed or relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Direct medical cost was calculated from hospital provider's perspective. A total of 108 patients were enrolled at 5 tertiary care hospitals, 36 IFD patients and 72 controls. The vast majority of IFD patients (74%) were diagnosed with invasive aspergillosis. On average, the hospital stay for IFD patients was 12 days longer than in control patients. All patients in the IFD group and 89% of patients in the control group received antifungal drugs. Mean direct costs per patient were €51,517 in the IFD group and €30,454 in the control group. Incremental costs of €21,063 were dominated by cost for antifungal drugs (36%), hospital stay (32%) and blood products (23%). From the perspective of hospitals in Germany the economic burden of IFD in patients with AML or MDS is substantial. Therefore, prevention of IFD is necessary with respect to both clinical and economic reasons.

Differential pulse polarographic investigation of the antifungal drugs itraconazole, ketoconazole, fluconazole and voriconazole using a dropping mercury electrode.

The electrochemical reactions of the antifungal drugs itraconazole, ketoconazole, fluconazole and voriconazole have been investigated by differential pulse polarography (DPP) using a dropping mercury electrode (DME). All investigations were carried out in Britton-Robinson buffer solutions and methanol with varying pH values. Ketoconazole and itraconazole both showed a reduction peak with a potential between -1.5V and -1.6 V. Stable and reproducible conditions for the determination of itraconazole (c = 1 x 10(-7) M) were found within the pH range of 6.0 to 8.0 and for the determination of ketoconazole (c = 5 x 10(-8) M) within pH 6.0 to 7.0. Voriconazole showed a reduction peak with a peak potential of -1.7 V (c = 1 x 10(-5) M) within the pH range of 8.0 to 10.0. In the case of fluconazole no electrochemical activity was found.

Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial.

This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34(+) blood cells to pre-empt relapse in patients with CD34(+) myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34(+) donor chimerism to <80% and received four azacitidine cycles (75 mg/m(2)/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34(+) donor chimerism to ≥80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34(+) donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1-11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56-558) after initial decrease of CD34(+) donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.

Clinical evaluation of a newly developed catheter (SpeediCath Compact Male) in men with spinal cord injury: residual urine and user evaluation.

OBJECTIVE: To evaluate the performance of a new 30-cm-long, telescoping male intermittent catheter (SpeediCath Compact Male; Coloplast A/S, Humlebæk, Denmark) in urinary bladder emptying, safety and subject acceptance vs a standard-length male intermittent catheter (SpeediCath). MATERIALS AND METHODS: In a prospective, randomized, multicenter, crossover non-inferiority study, 37 male intermittent catheter users self-catheterized three times with the test catheter on one test day and three times with the standard-length male (reference) catheter on another test day. Residual urine (RU) volume in the bladder after catheterization was measured by ultrasound. Safety was assessed in the entire study period in terms of adverse events (AEs) and adverse device events (ADEs). Subjects evaluated their experience, sensation, disposal, bleeding and discomfort with the test and reference catheters and final catheter preference. RESULTS: SpeediCath Compact Male did not differ from the reference catheter in terms of performance (bladder emptying). The upper confidence limit of the mean difference between absolute RU volumes for the test and reference catheter groups did not exceed a pre-established non-inferiority limit of 20 ml, thereby showing the test catheter's non-inferiority to the reference catheter (that is, no worse at bladder emptying). The only AE/ADE reported was one instance of mild urethral burning for 30 min after catheterization, which was judged possibly related to the test catheter but resolved quickly. CONCLUSIONS: The SpeediCath Compact Male catheter is as efficient as a conventional intermittent catheter (SpeediCath) at emptying the bladder with the additional benefit of being more discreet and easier to use.

Intragastric acidity during administration of generic omeprazole or esomeprazole - a randomised, two-way crossover study including CYP2C19 genotyping.

BACKGROUND: Generic omeprazole has been approved in many countries for the treatment of acid-related gastrointestinal disorders. However, clinical studies comparing generic to original proton pump inhibitors are limited. AIMS: To compare the effect of generic omeprazole 20 mg/day with esomeprazole 20 mg/day on intragastric acidity and to investigate the influence of the CYP2C19 metabolizer status. METHODS: In this randomised, single-blinded, two-way crossover study, 24 healthy Helicobacter pylori-negative subjects, received generic omeprazole (Omep; Hexal AG, Holzkirchen, Germany) 20 mg once daily or esomeprazole 20 mg once daily for five consecutive days. Twenty-four-hour intragastric pH was recorded on day 5 of each treatment. CYP2C19 status was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Over all, there were no statistically significant differences between generic omeprazole and esomeprazole with respect to median intragastric pH (3.5 and 3.9, P = 0.07), the total hours with intragastric pH >4 (10.4 and 11.3, P = 0.29), and during upright (9.6 and 9.1, P = 0.77) or supine (2.2 and 2.2, P = 0.94) position. However, in CYP2C19 rapid metabolizers, esomeprazole was superior to omeprazole, with the percentage of time with intragastric pH >3.0 and pH >3.5 being higher with esomeprazole than with generic omeprazole [Δ = 9% (P = 0.026) and Δ = 8% (P = 0.046), respectively]. CONCLUSIONS: Overall, generic omeprazole 20 mg appears to provide a similar intragastric acid control when compared with esomeprazole 20 mg. However, esomeprazole might be advantageous in subjects with a rapid CYP2C19 metabolizer status.

Differential pulse polarographic investigation of lansoprazole and rabeprazole using dropping mercury electrode.

The electrochemical reduction of the proton pump inhibitors (PPI) lansoprazole and rabeprazole has been investigated by differential pulse polarography (DPP) using a dropping mercury electrode (DME). The results were compared not only among both substances but also among other proton pump inhibitors depending on the varying chemical structures of the agents. All investigations were carried out in Britton-Robinson buffer solutions with pH values from 3.0 to 11.0. It was shown that both PPI undergo an extensive decomposition decreasing with increasing pH values forming two main compounds, a cyclic sulfenamide and a dimer. In this case lansoprazole was found to be stable at pH 8.0 and rabeprazole at pH 9.0. The decomposition of rabeprazole ran considerably quicker and also up to higher pH values than those of lansoprazole. The peak currents varied linearly with the concentration of both PPI in the range from 1 x 10(-6) M to 7 x 10(-5) M at pH 9.0. Both substances showed similarities in reaction as well as individual differences based on their varying chemical structures and characteristics.

Intragastric acidity during treatment with esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily--a randomized, two-way crossover study.

BACKGROUND: Patients with severe or complicated reflux disease may require higher than standard doses of a proton pump inhibitor for sufficient acid suppression. AIM: To test the hypothesis that esomeprazole 40 mg twice daily is superior to pantoprazole 40 mg twice daily in lowering intragastric acidity. METHODS: In a randomized, single-blinded, two-way crossover study, healthy subjects received esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily orally for five consecutive days. Continuous ambulatory 24-h intragastric pH was recorded on day 5 of each treatment. RESULTS: Thirty subjects were analysed. Esomeprazole provided significantly higher intragastric pH-values over the 24-h period [median intragastric pH 6.4 for esomeprazole and 5.1 for pantoprazole (P < 0.00005)]. Intragastric pH > 4 was maintained for 21.1 h with esomeprazole and 16.8 h with pantoprazole (P < 0.0001). An intragastric pH > 4 for more than 16 h was achieved in 96.7 and 56.7% of subjects, respectively (P = 0.0002). During night-time the proportion of time with intragastric pH > 4 was 85.4% with esomeprazole and 63.6% with pantoprazole (P = 0.0001). Nocturnal acid break through occurred less frequently on esomeprazole. CONCLUSIONS: Esomeprazole 40 mg twice daily provides better and more consistent intragastric acid control than pantoprazole 40 mg twice daily.

[Electrochemical behaviour of pantoprazole]. / Das elektrochemische Verhalten des Protonenpumpenhemmers Pantoprazol (5-Difluormethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl-sulfinyl]-benzimidazol).

The electrochemical behaviour of the proton pump inhibitor pantoprazole was analysed. The similarity of the DPP- and DC(T)-curves including all important characteristics suggest that the postulated mechanism of the electrochemical reduction of omeprazole is transferable to pantoprazole.

Industry-sponsored economic studies in oncology vs studies sponsored by nonprofit organisations.

The purpose of this analysis of health economic studies in the field of oncology was to investigate among sponsored studies whether any relationship could be established between the type of sponsorship and (1) type of economic analysis, (2) health technology assessed, (3) sensitivity analysis performed, (4) publication status, and (5) qualitative conclusions about costs. The Health Economic Evaluations Database (HEED, version 1995-2000) was searched on the basis of oncological ICD-9 codes, sponsorship, and comparative studies. This search yielded a total of 150 eligible articles. Their evaluations were prepared independently by two investigators, on the basis of specific criteria. When evaluators disagreed, a third investigator provided a deciding evaluation. There was no statistically significant relationship between the type of sponsorship and sensitivity analysis performed (P=0.29) or publication status (P=0.08). However, we found a significant relationship between the types of sponsorship and of economic analysis (P=0.004), the health technology assessed (P<0.0001), and qualitative cost assessment (P=0.002). Studies with industrial sponsorship were 2.56 (99% lower confidence interval (CI)=1.28) times more likely to involve cost-minimisation analyses, were 0.04 (99% higher CI=0.39) times less likely to investigate diagnostic screening methods, and were 1.86 (99% lower CI=1.21) times more likely to reach positive qualitative conclusions about costs than studies supported by nonprofit organisations. In conclusion, our results suggest that there is a greater probability that industry-sponsored economic studies in the field of oncology tend to be cost-minimisation analyses, to investigate less likely diagnostic screening methods, and to draw positive qualitative conclusions about costs, as compared to studies supported by nonprofit organisations.

[An analysis of the diagnostic information derived from screening as against films during radiological examination of the stomach (author's transl)]. / Analyse des diagnostischen Informationswertes von Aufnahmen und Durchleuchtung bei der Röntgenuntersuchung des Magens.

The value of screening procedures (with image intensifiers and television monitor) was compared with films during the radiological examination of the stomach, using a double contrast method. In one experiment, the diagnostic accuracy of experienced radiologists using screening only was compared with standardised films. There was a definite improvement using films. The reason for this was not the difference in the technical excellence of the images, but depended on the cognitive processes which lead the doctor to a diagnosis. For this purpose, static pictures provide a better basis than dynamic, rapidly changing and brief views seen during screening. The results lead to certain considerations concerning the methods for the radiological examination of the stomach.