[Indications and contraindications for tonsillectomy and adenoidectomy. Judgement of immunologic status].
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Adenoidectomy↗
Biomedical subjects
M Hartmann
Publications and source records attributed to M Hartmann.
Searching for substitution rate heterogeneity.
A permutation method for detecting regional substitution rate heterogeneity in DNA sequences is described. An estimated phylogeny for the sequences is required. The method is likelihood based and searches through all regions of a DNA sequence to find any regions that have an unusually large (or small) number of substitutions in comparison to an optimal substitution rate for the entire sequence. Likelihood ratio tests do not achieve proper statistical significance levels due to the large number of tests performed. Empirical corrections based on permutations are suggested and shown to give correct statistical accuracy. The ability of the method to detect rate heterogeneity is good even when the region is small and with less than twice the rate of evolution in the remainder of the sequence.
Algorithms↗
Cardioprotective actions of KC 12291. I. Inhibition of voltage-gated Na+ channels in ischemia delays myocardial Na+ overload.
To characterize KC 12291 (1-(5-phenyl-1,2, 4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N-[2-(3,4-dimethoxy phenyl) ethyl] amino] propane hydrochloride), a newly synthezised inhibitor of voltage-gated Na+ channels, the effects of the agent on Na+ current and ischemia-induced Na+ overload were investigated in isolated cardiomyocytes, atria and saline-perfused hearts. As measured by the patch clamp technique, KC 12291 (1 microM) significantly reduced peak Na+ current after activation of voltage-gated Na+ channels in rat cardiomyocytes. Partial depolarization enhanced the inhibitory effects during steady state conditions of the channel. In isolated guinea pig atria, 1 microM KC 12291 had no effect on contractility under basal conditions but effectively delayed the onset and reduced the extent of anoxic contracture. The concentration-response curve was clearly shifted to the left when atria were partially depolarized by increased extracellular K+. As measured by 23Na NMR spectroscopy in isolated perfused guinea pig hearts, intracellular Na+ rose more than four-fold in a linear fashion during 60 min of low-flow ischemia. KC 12291 (1 microM) prevented Na+ overload within the initial 12 min of ischemia; thereafter the slope of Na+ accumulation was identical to controls. Electrical excitability of hearts, evaluated by intracardial ECG, completely ceased within 15 min after the onset of ischemia. KC 12291 (1 microM) accelerated this process by more than 6 min. The data provide first evidence that KC 12291 reduces Na+ influx through voltage-gated Na+ channels during ischemia and thus delays Na+ overload by enhancing the inexcitability of the heart.
Animals↗
Cardioprotective actions of KC 12291. II. Delaying Na+ overload in ischemia improves cardiac function and energy status in reperfusion.
The novel blocker of voltage-gated Na+ channels KC 12291 (1-(5-phenyl-1,2,4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N- [2-(3,4-dimethoxyphenyl)ethyl] amino] propane hydrochloride) delays myocardial Na+ overload in ischemia. To test whether KC 12291 displays cardioprotective properties in the intact heart, cardiac function, energy status and intracellular pH (31P NMR) as well as ion homeostasis (23Na NMR) were investigated during low-flow ischemia (100 microl/min for 36 min) followed by reperfusion. In the well-oxygenated, isolated perfused guinea pig heart, KC 12291 (1 microM) had no effect on left ventricular developed pressure (LVDP; 54+/-19 mmHg). KC 12291 delayed the onset and decreased the extent of ischemic contracture and markedly improved the recovery of LVDP in reperfusion [39+/-14 mmHg (n=4) vs 2+/-2 mmHg in controls (n=5)]. KC 12291 did not influence the rapid drop in phosphocreatine (PCr) following onset of ischemia but attenuated the decline in ATP. It also diminished the ischemia-induced fall in intracellular pH [6.39+/-0.2 (n=6) vs 6.18+/-0.20 in controls (n=6)]. In reperfusion, KC 12291 remarkably enhanced the recovery of PCr (84.8+/-9.6% vs 51.1+/-8.8% of baseline) and ATP (38.2+/-12.9% vs 23.7+/-9.3% of baseline). It also accelerated the recovery of intracellular pH. KC 12291 not only reduced the extent of ischemia-induced Na+ overload, but also enhanced Na+ recovery. It is concluded that KC 12291 delays contracture and reduces ATP depletion and acidosis in ischemia, and markedly improves the functional, energetic and ionic recovery in reperfusion. Blocking voltage-gated Na+ channels in ischemia to delay Na+ overload may thus constitute a promising therapeutic approach for cardioprotection.
Adenosine Triphosphate↗
[Can superparamagnetic contrast media improve MRI-tomographic images of experimental gliomas?].
PURPOSE: To investigate whether the margins of microscopic tumors can be delineated better with monocrystalline iron oxide nanoparticles (MION), a superparamagnetic contrast medium, than with Gd-DTPA by magnetic resonance imaging (MRI). METHODS: MRI and histological examinations were conducted in 28 Wistar rats with sterotactically implanted gliomas (C6 gliomas). Of the 28 animals, 14 were examined after intravenous administration of MION [nine animals received 179 mmol Fe/kg body weight (dose 1), and five, 893 mmol Fe/kg (dose 2)]. The other 14 animals were examined first after i.v. administration of Gd-DTPA (0.2 mmol/kg) and then after i.v. administration of MION. The extent of the tumors as seen on MRI and at histological study were compared. RESULTS: Iron particles were identified microscopically in tumor cells and in the tumoral interstitium. After administration of MION at dose 1, the contrast-enhanced area of tumor was 1.55-fold greater than the extent of tumor identified by histological study, at dose 2,2.15-fold. Compared with Gd-DTPA the area of contrast enhancement was greater by a factor of 1.38 with MION administration at dose 1 and by a factor of 1.91 at dose 2. CONCLUSION: MION provides intra- and extracellular contrast enhancement. The area of the contrast-enhanced tumor is dose-dependently greater with MION than with Gd-DTPA and also greater than the extent of tumor seen at histological study.
Animals↗
[Effect of brain edema on the recurrence pattern of malignant gliomas].
PURPOSE: To assess the influence of initial preoperative brain edema in malignant gliomas on regrowth patterns. SUBJECTS AND METHODS: 79 patients with histologically verified supratentorial malignant glioma were prospectively studied by magnetic resonance imaging (MRI) before and every 2-3 months after surgery. The median follow-up time was 11 months. We correlated the configuration of the initial vasogenic edema on T2-weighted images with tumor regrowth patterns on contrast-enhanced T1-weighted images. RESULTS: 35/47 tumor regrowths (75%) imitated the initial edema configuration, while 11/47 occurred within the initial tumor bed; in one case tumor recurrence was multilocal. CONCLUSION: In glioblastoma, tumor regrowth patterns correlate positively with the configuration of the initial vasogenic brain edema. The initial, "presurgical" peritumoral edema should thus be considered when planning further treatment.
Adult↗
[In which marker-positive patients with germ cell tumors is residual tumor resection of value?].
We analyzed 33 patients with disseminated germ cell tumors (GCT) who underwent residual tumor resection (RTR) during the period from 1991-1997. The patients were marker positive prior to surgery were analyzed. The histopathological examination of the resected masses, the marker dynamics and the relapse-free respectively the progression free survival, were evaluated. The status differed at primary diagnosis: minimal disease n = 1, moderate disease n = 15, advanced disease n = 17. The patients received at average 8.5 cisplatin-containing cycles of polychemotherapy. Only 11 patients underwent surgery after first-line-chemotherapy. The remaining received second- or third-line-chemotherapy prior to surgery. In 12 of 31 evaluable patients, a durable CR was achieved. The median follow-up for this group is 30 months (2-58 months). The histopathologic examination of the resected specimen and the tumor marker level prior to RTR do not permit determination of prognostic outcome. After operation 44% of the AFP-positive and 30% of the beta-HCG-positive patients had a durable remission. If tumor marker levels at time of RTR are within normal range, disease-free survival is 72%; in case of elevated markers 39% will survive. If intensive chemotherapy fails to normalize markers, RTR remains the only option to change the fatal course of the disease.
Antineoplastic Combined Chemotherapy Protocols↗
[Biometric planning of clinical-orthopedic studies. The optimal test].
A determinant for the evidence of a clinical trial is the magnitude of the sample size. The proper sample size can be easily computed with the knowledge of alpha, power and effect size. Standard values for alpha and power in clinical trials are 5% and 90%, respectively. As a consequence, effect size is crucial for the sample size. The effect size has to be determined by the clinician according to medical considerations. Possible consequences of sample sizes that are either too small or too large are discussed with regard to the meaning of alpha, Power and effect size. Trials with improper small sample sizes have a high risk of false negative results, and may subsequently prevent the application of a possibly effective therapy. Trials with improper large sample sizes may result in statistically significant differences without any clinical relevance.
Biometry↗
The two 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase isoenzymes from Saccharomyces cerevisiae show different kinetic modes of inhibition.
Activity of the tyrosine-inhibitable 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase (EC 4.1.2.15) from Saccharomyces cerevisiae that was encoded by the ARO4 gene cloned on a high-copy-number plasmid was enhanced 64-fold as compared to the wild-type. The enzyme was purified to apparent homogeneity from the strain that harbored this recombinant plasmid. The estimated molecular weight of 42,000 of the enzyme corresponded to the calculated molecular mass of 40 kDa deduced from the DNA sequence. The enzyme could be inactivated by EDTA in a reaction that was reversed by several bivalent metal ions; presumably a metal cofactor is required for enzymatic catalysis. The Michaelis constant of the enzyme was 125 microM for phosphoenolpyruvate and 500 microM for erythrose 4-phosphate. The rate constant was calculated as 6 s-1, and kinetic data indicated a sequential mechanism of the enzymatic reaction. Tyrosine was a competitive inhibitor with phosphoenolpyruvate as substrate of the enzyme (Ki of 0.9 microM) and a noncompetitive inhibitor with erythrose 4-phosphate as substrate. This is in contrast to the ARO3-encoded isoenzyme, where phenylalanine is a competitive inhibitor with erythrose 4-phosphate as a substrate of the enzyme and a noncompetitive inhibitor with phosphoenolpyruvate as substrate.
3-Deoxy-7-Phosphoheptulonate Synthase↗
Pharmacoeconomic evaluation of high-dose chemotherapy and peripheral blood stem cell support in high-risk or poor-prognosis malignancies.
Discussion of the total costs and cost-effectiveness ratios of patients receiving high-dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) is controversial. In Germany, no reliable data are available, whereas in other countries this issue has been extensively studied. We performed a pharmacoeconomic evaluation on all patients (n = 37) treated with HDC and PBSCS at our institution between July 1994 and June 1997. Patients suffered from high-risk or poor-prognosis breast cancer (n = 24), Hodgkin's disease (n = 3), high-grade non-Hodgkin's lymphoma (n = 4), multiple myeloma (n = 2), small-cell cervical cancer (n = 1), malignant hystiocytosis (n = 1) and testicular cancer (n = 2). For pharmacoeconomic evaluation, the period from initiation of induction chemotherapy (IC) until reconstitution after the last course of HDC and PBSCS was considered. A total of 18 patients received IC/HDC/PBSCS for locally advanced or systemic disease, and 19 patients received adjuvant or consolidation IC/HDC/PBSCS. Treatment protocols were heterogeneous. Patients were treated with two to five courses (median two) respectively of IC and sequential mono-HDC (n = 26), tandem-HDC (n = 10) or triple-HDC (n = 1). All patients received granulocyte/macrophage-colony-stimulating factor (G-CSF) for stem cell mobilisation and for amelioration of neutropenia after HDC. The relative costs (based on supplier prices) for the total amount of drugs prescribed during the in-patient period was 29.8% for G-CSF, 35.8% for blood products 18.5% for chemotherapy, 2.4% for antiemetics, 5.9% for antimicrobial drugs and 7.6% for other drugs. Contrary to expectations, antimicrobial drugs had only a minor pharmacoeconomic impact during IC/HDC/PBSCS in patients with high-risk or poor-prognosis malignancies, indicating that prolonged septic complications were uncommon in our institution. We conclude that pharmacoeconomic evaluations in IC/ HDC/PBSCS might be integrated into the effort to ensure quality control and monitoring.
Antineoplastic Agents↗
Equipotent inhibition of gastric acid secretion by equal doses of oral or intravenous pantoprazole.
BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 system, and linear pharmacokinetics. The recommended oral dose for treatment of acid-related diseases is 40 mg. METHODS: Using a randomized, crossover study design we compared the ability of 40 mg oral and intravenous pantoprazole to elevate the intragastric pH in healthy volunteers (n = 20, 'per protocol'), during two treatment phases. The duration of each phase was 5 days. Pantoprazole 40 mg was administered once daily either as a tablet or as an intravenous injection. A 24 h pHmetry was used to record the intragastric pH on day 5 of each regimen; this was compared to the baseline curve obtained before each study period. The calculated 90% confidence intervals (90% CI) represent the mean difference in the intragastric pH, attained after intravenous or oral administration. The predefined equivalence range for the 90% CI was +/- 20% for the percentage time at which the gastric pH was at least pH 3 or 4 and +/- 1 unit for the median pH. RESULTS: Pantoprazole was well tolerated during both treatment phases. The mean of the 24 h median pH was 3.3 and 3.1 for the intravenous and oral treatments, respectively; the corresponding differences were 0.2 (90% CI: - 0.03 to 0.44). For the mean percentage time at which the pH was 3 or above, the respective calculated values were 57% and 51%, with a difference between the two administration routes of only 5.7% (90% CI: 1.8 to 9.6). At an intragastric pH of 4 or above, the mean percentage time was 420% and 38% following intravenous and oral treatment, respectively, with a difference between the treatment routes of only 4.4% (90% CI: 0.6 to 8.3). CONCLUSIONS: These results imply that the two formulations of pantoprazole can be assumed to be equipotent. Hence, the intravenous formulation of pantoprazole could be considered as an alternative route of administration.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Comparison of tissue oxygen-tension measurements by different devices. An experimental study in pigs.
UNLABELLED: The aim of this study was to evaluate measurements of subcutaneous oxygen tension (PscO2) generated by three different monitors and to compare measurements obtained with and without the tonometer technique in a standardized animal model. Seven domestic pigs weighing 20-28 kg were anaesthetized and mechanically ventilated. A pulmonary artery catheter was inserted for haemodynamic monitoring and temperature measuring. An external carotid artery was cannulated for blood pressure monitoring and blood sampling. A peripheral venous line was used for fluid and drug infusion. The animals were then subjected to hyperoxia and hypoxia by varying the inspiratory oxygen fractions (FiO2) between 0.1 and 0.8. Arterial and central venous blood gases were analysed at each step of FiO2. Cardiac output was determined using a thermodilution technique. Central, subcutaneous and skin surface temperatures were measured. Three different devices for subcutaneous tissue oxygen-tension (PscO2) measurements were compared: (1) Biogenesis, (2) Continucath and (3) Paratrend 7. Continucath was used both with and without tonometer simultaneously. Inter Class Coefficient of Correlation between PscO2 values obtained by the two Continucath sensors was 76% and between Paratrend 7 and Biogenesis 88%. Absolute values generated by Biogenesis and Paratrend 7 were not different. PscO2 values obtained with the Continucath devices were on average 50% higher than those generated by Biogenesis and Paratrend 7 (p < 0.05). CONCLUSIONS: The new Paratrend 7 and the old Biogenesis sensors generate almost equal tissue oxygen-tension values in response to changes in arterial oxygen tension. The Continucath sensor generates almost 50% higher values compared with the Paratrend 7 and Biogenesis sensors, both with and without tonometer.
Animals↗
Local fibrinolysis and aspiration of intracerebral hematomas in rats. An experimental study using MR monitoring.
Serial magnetic resonance (MR) imaging has not yet been validated in the therapy of experimental intracerebral hematomas in a rat model. It is possible to test the effect of local fibrinolysis and aspiration on the clot volume using serial magnetic resonance imaging and different MR-sequences. Experiments were carried out in 22 male Sprague-Dawley rats. Intracerebral hematoma was produced by injection of fresh autologous blood into the caudate nucleus using a double injection technique. Thirty minutes later 10 rats were treated by injecting 12 microliters of recombinant tissue plasminogen activator. MR-imaging was performed immediately after generation of the hematoma and after clot lysis. The clot volume measured in the magnetic resonance images was compared with that obtained in stained histological serial sections at the end of the experiment. Serial MR scanning demonstrated a significant reduction (p < 0.01) of hematoma volume after fibrinolysis followed by aspiration of the blood clot. The best correlation between MR- and histological volumetry was found on RF-spoiled FLASH 2D-images. This study documents the efficacy of MRI in detecting and delineating the size of acute intracerebral hematomas and its time course. Local fibrinolysis and aspiration can be simulated in an experimental rat model.
Animals↗
Disturbance of DNA damage recognition after UV-irradiation by nickel(II) and cadmium(II) in mammalian cells.
Nickel(II) and cadmium(II) have been shown previously to inhibit the incision step of nucleotide excision repair. By applying a gel-mobility-shift assay and HeLa nuclear extracts the effect of both metals on the damage recognition step of the repair process was investigated. Two proteins of 34 and 40 kDa were identified that bind with high affinity to a UV-irradiated synthetic oligonucleotide. When applying nuclear extracts from HeLa cells treated with 50 microM nickel(II) and higher, there was a dose-dependent decrease in protein binding; this effect was largely reversible by the addition of magnesium(II) to the binding reaction. In the case of cadmium(II), a dose-dependent inhibition of DNA-protein interactions was detected at 0.5 microM and higher, which was almost completely reversible by the addition of zinc(II). Therefore, compounds of both metals disturb DNA-protein interactions essential for the initiation of nucleotide excision repair most likely by the displacement of essential metal ions.
Binding Sites↗
Pharmacokinetics of pantoprazole in patients with end-stage renal failure.
BACKGROUND: Pantoprazole is a selective inhibitor of the gastric H+/K+-ATPase with a low potential to interact with the cytochrome P450 enzyme system. Since pantoprazole is metabolized in the liver to metabolites which are mainly cleared by the renal route, it was the aim of this study to investigate its pharmacokinetics in patients with end-stage renal failure undergoing regular haemodialysis. METHODS: Eight patients with end-stage renal failure (creatinine clearance < 5 ml/min, age 45-65 years) on regular haemodialysis (duration of haemodialysis 4-5 h, cuprophan-dialyser Hemoflow E3, surface 1.3 m2) were given single i.v. doses of 40 mg pantoprazole one day before haemodialysis (A) and on a haemodialysis day immediately before the start of the haemodialysis (B). Concentrations of pantoprazole and metabolite M2 were determined in plasma and urine over 24 h and in timed samples of the dialysis fluid by HPLC. The protein binding was determined using equilibrium dialysis. RESULTS: The pharmacokinetic characteristics of pantoprazole AUC, t(1/2), CL and V(d area) (geometric means) were 2.4 mgxh/l, 0.63 h, 0.227 l/h/kg and 0.206 l/kg on day A (without dialysis) and 2.3 mgxh/l, 0.8 h, 0.237 l/h/kg and 0.273 l/kg on day B (with dialysis), respectively. The protein binding was 96%. Pantoprazole was found in small amounts in the dialysis fluid (max. 2.1% of the dose) but not in the urine. Pantoprazole was well tolerated. In particular, there were no clinically relevant changes in blood count, electrolytes or liver enzymes. CONCLUSIONS: Haemodialysis has no influence on the pharmacokinetic characteristics of pantoprazole. Thus, pantoprazole is not dialysed to any relevant degree, and therefore no dose-adjustment is required for patients with end-stage renal failure undergoing regular haemodialysis treatment.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Beta interferon is produced by Chlamydia trachomatis-infected fibroblast-like synoviocytes and inhibits gamma interferon-induced HLA-DR expression.
Infection of fibroblast-like synovial cells with Chlamydia trachomatis (serotype D strain IC Cal 8) in culture induced the secretion of beta interferon (IFN-beta). Chlamydial infection inhibited IFN-gamma-induced expression of HLA-DR antigen in the cells. Addition of IFN-beta antibody directly to infected cultures mitigated HLA-DR inhibition, suggesting involvement of produced IFN-beta.
Cells, Cultured↗
The central, surface-exposed region of the flagellar hook protein FlgE of Campylobacter jejuni shows hypervariability among strains.
In a previous study, we observed that monoclonal antibodies raised against the hook protein FlgE of Campylobacter jejuni LIO 36, isolate 5226, bound exclusively to this strain. The aim of this study was to elucidate the molecular basis for these binding specificities. The hook protein-encoding gene flgE of C. jejuni was cloned in Escherichia coli and sequenced. The flgE genes of four additional C. jejuni strains were amplified by PCR and also sequenced. Comparison of the deduced amino acid sequences revealed a high degree of variability in the central parts of the FlgE proteins among the strains, including variable and hypervariable domains. These findings may indicate a selective pressure of C. jejuni hosts, forcing the bacteria to generate variations in surface-exposed antigenic determinants.
Amino Acid Sequence↗
Differences in pH-dependent activation rates of substituted benzimidazoles and biological in vitro correlates.
Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs that require an acid-induced activation. Its rate depends on the reactivity of the molecule relative to the environmental pH and determines the drug's tissue selectivity. Factors affecting the exposure of moderately acidic tissues to the activated PPI are the area under the serum concentration-time curve (AUC), serum protein binding, the partition coefficient logP and the serum elimination half-life relative to the chemical activation half-life at a critical tissue pH of about 5. These parameters have therefore been determined in a comparative fashion in the present study. The data shows that pantoprazole is less likely to undergo unwanted activation at moderately acidic targets as opposed to the parietal cell, compared to omeprazole. Actually, although 40 mg pantoprazole (steady state) gave a slightly higher serum AUC of the total parent compound than 40 mg omeprazole (10.5 vs. 7.1 micromol x h x l[-1]), a higher serum protein binding of pantoprazole versus omeprazole (98 vs. 96%) reversed the AUC values for the free drug in favor of a lower value for pantoprazole (0.19 vs. 0.28 micromol x h x l[-1]). It is the free parent compound that equilibrates across cell membranes to be activated in acidic tissue compartments. At pH 5.1, the activation half-life of pantoprazole was 4.7 versus 1.4 h for omeprazole, the latter being in the order of the common serum elimination half-life determined in an intraindividual comparison (1.24 vs. 1.25 h). Thus, pantoprazole is eliminated faster from blood than it is activated at a pH of about 5, while omeprazole is as quickly activated at this pH as it is eliminated from blood. Biological in vitro experiments confirmed that pantoprazole displays a lower liability to interfere with unwanted biological targets. This has been demonstrated in vitro for inhibition of both renal Na+/K+-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils.
2-Pyridinylmethylsulfinylbenzimidazoles↗