Biomedical subjects

H U Schulz

Publications and source records attributed to H U Schulz.

At least 55 records · Page 3Linked to original sources

PubMed1997

[Cellular and humoral functions in acute pancreatitis].

Infectious complications are the leading cause of death in acute pancreatitis. Individual factors of immune defence could be of significance, whether or not a patient develops a severe course with infectious complications. In a prospective 5-year trial including 72 patients, we investigated 29 cellular and humoral markers of the body's defence system for their potential to indicate the severity and course of acute pancreatitis. Complement factors C3 and C4 as well as immunoglobulins IgG, IgM and IgA were normal, in general. Measurable levels of IL-1 alpha, IL-1 beta, IL-2 and sIL-2R could be detected only occasionally. Values of alpha 1-AT, TNF-alpha, TNF alpha-Rp75, neopterin, sICAM-1, IL-8, IL-1RA and sIL-6R did not correlate with a severe course. Due to the high magnitude of increase, CRP, IL-6 and granulocyte elastase were the best indicators of the inflammatory process. Delayed-type hypersensitivity response was the only early predictor of a severe course. It was superior over other cellular markers such as monocyte count or CD4+/CD8+ ratio. In vitro function of polymorphonuclear granulocytes (PMN) was not adequate to the severity of the disease already during the first week of illness. During further course, PMN motility and capacities to produce reactive oxygen species even worsened. The compromized PMN function could explain the frequent development of infectious complications in patients suffering from severe pancreatitis. These results should encourage new concepts of infection prophylaxis using stimulants of cellular defence.

Acute Disease↗

PubMed1997

[Modification of energy supply by pancreatic mitochondria in acute experimental pancreatitis].

A disturbed energy metabolism in pancreatic acinar cells is discussed as factor contributing to the development of acute pancreatitis (AP). In this study, we investigated to what extent the mitochondrial ATP producing capacity is impaired in the pancreatic tissue of rats with experimental AP. For preparation of mitochondria from rat pancreas, routine isolation procedures (tissue homogenization and differential centrifugation) were applied. Mitochondria were isolated from rats with edematous pancreatitis produced by hyperstimulation with caerulein, and from rats with mild necrotizing acute pancreatitis. The latter form of AP was induced by a temporary occlusion of the biliary pancreatic duct accompanied by a simultaneous intravenous injection of caerulein plus secretin and an intraabdominal administration of ethanol. As functional parameters of oxidative phosphorylation, the respiration rate, the mitochondrial membrane potential, and the activity of the complex I of the respiratory chain were determined. Mitochondria from rats with caerulein AP showed an enhanced respiration (61% vs. saline control) and a diminished membrane potential (-17 mV) if respiring with succinate in the non-phosphorylating state. This indicates an increased proton leak across the mitochondrial inner membrane. In the mild necrotizing AP, mitochondria were characterized by a decreased respiration with NAD(+)-linked substrates (-33% vs. sham-operated animals). This inhibition of respiration was confirmed by the reduced activity measured for the NADH-cytochrome c reductase (-32%). In both models of experimental AP the potency of mitochondria to produce ATP was significantly diminished. The stronger impairment of mitochondrial functions were found in the necrotizing form of AP. Reactive oxygen species may lead to the observed alterations--to the enhanced permeability of the mitochondrial inner membrane as well as to the inhibition of the complex I of the respiratory chain.

Acute Disease↗

PubMed1997

Influence of food on the bioavailability of a carbamazepine slow-release formulation.

The pharmacokinetics of a multiple-unit carbamazepine slow-release preparation were studied after a 12-hour fast and after a standardized breakfast in 24 healthy male volunteers. There was a small increase in mean values of AUC0-infinity and Cmax when the drug was given with food. The rate of absorption of slow-release carbamazepine, as reflected by HVD, appeared to be unchanged in the presence of food. Bioequivalence was concluded for the AUC0-infinity and HVD ratios applying the inclusion rule, thus demonstrating the lack of food interaction. The results indicate that administration of the investigated carbamazepine slow-release formulation to patients in the fasting or nonfasting state seems not to be a major consideration when deciding on the regimen.

Adult↗

PubMed1996

Oxidative injury to isolated rat pancreatic acinar cells vs. isolated zymogen granules.

This study compares the susceptibility of pancreatic acinar cells and zymogen granules against oxidative injury and analyzes the mechanisms involved. Zymogen granules and acinar cells, isolated from rat pancreas, were exposed to a reaction mixture containing xanthine oxidase, hypoxanthine, and chelated iron. Cell function and viability were assessed by various techniques. Trypsin activation was quantified by an Elisa for trypsinogen activating peptide. Integrity of granules was determined by release of amylase. The reaction mixture rapidly generated radicals as assessed by deoxyribose and luminol assays. This oxidative stress caused lysis of granules in a matter of minutes but significant cell death only after some hours. Nevertheless, radicals initiated intracellular vacuolization, morphological damage to zymogen granules and mitochondria, increase in trypsinogen activating peptide, and decrease in ATP already after 5-30 min. Supramaximal caerulein concentrations also caused rapid trypsin activation. Addition of cells but not of granules reduced deoxyribose oxidation, suggesting that intact cells act as scavengers. Caerulein pretreatment only slightly increased the susceptibility of cells but markedly that of granules. In conclusion, isolated zymogen granules are markedly more susceptible to oxidative injury than intact acinar cells, in particular, in early stages of caerulein pancreatitis. The results show that oxidative stress causes a rapid trypsin activation that may contribute to cell damage by triggering autodigestion. Zymogen granules and mitochondria appear to be important targets of oxidative damage inside acinar cells. The series of intracellular events initiated by oxidative stress was similar to changes seen in early stages of pancreatitis.

Animals↗

PubMed1996

Lack of influence of pantoprazole on the disposition kinetics of theophylline in man.

The potential influence of pantoprazole (BY1023/SK&F96022), a newly developed selective inhibitor of the gastric H+,K(+)-ATPase, on therapeutic serum theophylline concentrations was investigated in a crossover study in 8 healthy male volunteers (age 25-30 [median 27] years, body weight 63-80 [median 68] kg). Steady-state serum theophylline concentrations were obtained by a two-step intravenous infusion scheme of approximately 350 mg theophylline each over 0.5 h and subsequently over approximately 10 h, respectively. In the test period, 30 mg pantoprazole were injected over 2 min on 5 consecutive days and theophylline was infused on day 4. In the reference period, placebo was administered i.v. on 2 consecutive days and theophylline on day 1. Serum pantoprazole concentrations were measured up to 12 h, serum theophylline concentrations up to 36 h. Pantoprazole was well tolerated with and without theophylline. There were no clinically relevant changes in blood pressure, heart rate, ECG and routine clinical laboratory parameters. Primary characteristic for confirmative assessment of no interaction was the area under the concentration/time curve (AUC). Lack of interaction in the sense of equivalence was concluded both for theophylline (with and without pantoprazole) and pantoprazole (with and without theophylline), as the 90%-confidence intervals of the AUC-ratio test/reference were within the equivalence range of 0.8 to 1.25. Further explorative analysis of theophylline disposition kinetics revealed this inclusion also for clearance and volume of distribution, but not for the half-life. In the case of pantoprazole, the corresponding 90%-confidence intervals for any of the secondary characteristics clearance, volume of distribution and half-life were within the above mentioned range. In conclusion, repeated once-daily i.v. injections of 30 mg pantoprazole have no clinically relevant influence on steady-state theophylline serum concentrations, nor does theophylline at therapeutic serum concentrations influence the pantoprazole disposition kinetics. Hence, in clinical practice theophylline and pantoprazole can be administered concomitantly without dose adjustment.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of influence of glycine on the single dose pharmacokinetics of acetylsalicylic acid in man.

Galenic formulations consisting of acetylsalicylic acid and glycine were developed to improve solubility of the drug, even in case of ingestion without intake of water. It was the aim of this study to investigate the potential influence of glycine on pharmacokinetics after single oral administration of 1,000 mg of acetylsalicylic acid. Therefore, a bioequivalence study using a randomized crossover design (reference = without glycine, test = with glycine) in 12 healthy male volunteers (age 22 - 38 (median 26) years, body weight 64 - 83 (median 75) kg) was performed. Pharmacokinetic characteristics (AUC, Cmax, tmax, t1/2, MRT) were taken or calculated on the basis of plasma concentration/time profiles. For both acetylsalicylic acid and salicylic acid the 90% confidence intervals of the ratios of the expected median values (microT and microR) for the primary characteristics AUC and Cmax of the test and reference formulation were included in the equivalence range of 80 - 125%, which in case of multiplicative model is accepted for concluding bioequivalence. Therefore, lack of influence of glycine on the pharmacokinetics of acetylsalicylic acid including its major metabolite salicylic acid was concluded.

Adult↗

PubMed1995

Effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) on neutrophil elastase release.

The proinflammatory cytokine interleukin-6 (IL-6) and its potential opponent, transforming growth factor-beta (TGF-beta 1), have been discussed as being involved in the regulation of inflammatory processes following trauma and infections. The aim of this study was to investigate the effect of these cytokines on the regulation of neutrophil degranulation. The posttraumatic time courses of the plasma concentrations of IL-6, and the elastase-alpha 1-proteinase-inhibitor complex as marker of degranulation in patients undergoing severe trauma were found to be highly correlated, whereas TGF-beta 1 levels were determined to be not significantly altered. The close temporal correlation of IL-6 and elastase levels could be confirmed by investigation of exudates derived from the surgical area. To prove these in vivo findings, the effect of IL-6 and TGF-beta 1 on the degranulation of isolated neutrophils of healthy donors was investigated in vitro. Pathological high IL-6 concentrations were found to be capable of inducing a significant release of lysosomal elastase in a concentration-dependent manner, whereas the degranulation was unaffected by TGF-beta 1. In conclusion, these data suggest an involvement of IL-6 in the regulation of neutrophil degranulation under pathological conditions. However, TGF-beta 1 seems to have no direct regulatory effects besides its described chemotactic function on neutrophils.

Cell Degranulation↗

PubMed1995

Lazaroids protect isolated rat pancreatic acinar cells against damage induced by free radicals.

Lazaroids, 21-aminosteroids without gluco- and mineralocorticoid activity, protect against oxidative injury in nervous system cells and may therefore also have a potential for treatment of pancreatitis, where oxidative stress contributes to cell injury. The present study evaluates the protective potential of the lazaroids U-78518F, U-74500A, and U-74389F against damage to isolated pancreatic acinar cells exposed to two models of oxidative stress: (a) a XOD/HX model, consisting of xanthine oxidase, hypoxanthine, and chelated FeCl3; and (b) an ADP/Fe model, consisting of FeSO4 and the reducing agent ADP. Both models caused time-dependent cell injury as assessed by uptake of trypan blue and release of lactate dehydrogenase. Short-term peak production of free radicals in the XOD/HX model--as monitored by the deoxyribose assay--was more injurious to cells than continuous radical generation at lower levels in the ADP/Fe model. In general, lazaroids at 1-10 microM reduced oxidative damage and deoxyribose oxidation in both models. The degree of reduction of cell damage and deoxyribose oxidation depended on the type and concentration of the lazaroid and the model used. Lazaroid concentrations < 0.1 microM were ineffective, and concentrations > 50 microM even accelerated cell injury, although lazaroids still served as scavengers at high concentrations. At least part of the noxious effects of high lazaroid concentrations is due to nonspecific membrane damage because these concentrations caused cell injury also in the absence of oxidative stress. The limited range of protective concentrations has to be observed in further in vivo studies. Interestingly, acinar cells in the absence of lazaroids also reduced radical-induced deoxyribose degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

PubMed1995

Acinar cell respiration in experimental acute pancreatitis.

The early pathogenetic steps that finally lead to acinar cell necrosis in acute pancreatitis have been characterized only scarcely as yet. Among a lot of hypotheses, one concept favors disturbances of cellular energy metabolism as a major factor that contributes to preterm cell decline. To investigate, whether an experimental acute pancreatitis alters cell respiration, the respiratory capacities of acinar cells isolated from rats with acute pancreatitis were measured. Acute pancreatitis was induced using Popper's model, i.e., a combination of duct obstruction, secretory stimulation, and mesenteric short-term ischemia with subsequent reperfusion. Acinar cells were isolated using a collagenase digestion technique. The respiratory rates of the isolated cells in suspension were measured at 37 degrees C in 100% oxygen-saturated N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid-buffered Eagle's-minimal essential medium. Resting respiration of the acinar cells uniformly amounted to about 60 pmol of O2/s x 10(6) cells in both the control and the pancreatitis group. Cellular respiration could significantly be stimulated by stepwise uncoupling of oxidative phosphorylation by means of 2,4-dinitrophenol in all cell suspensions investigated. The maximum rate of stimulated respiration was diminished in the cells isolated from rats with acute pancreatitis as compared with the controls (79.3 +/- 5.0 vs. 160.2 +/- 15.5 pmol of O2/s x 10(6) cells, p < .05), however. This reduced respiratory load capacity of the acinar cells in acute pancreatitis reflects the restricted ability of the cells to increase respiration on enhanced cellular demand. Since mitochondrial respiration is coupled to oxidative phosphorylation, an altered energy-transforming potential of the acinar cells in acute pancreatitis becomes evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1995

New injectable aqueous carbamazepine solution through complexing with 2-hydroxypropyl-beta-cyclodextrin: tolerability and pharmacokinetics after intravenous injection in comparison to a glycofurol-based formulation.

The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD "placebo" formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ:glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by decreasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 12-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of approximately 3.6 micrograms/ml were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma levels determined after p.o. administration of CBZ to dogs with peak CBZ levels previously determined after p.o. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1995

Active pancreatic digestive enzymes show striking differences in their potential to damage isolated rat pancreatic acinar cells.

Active digestive enzymes are involved in the pathophysiology of acute pancreatitis. Previous studies have mainly focused on the role of trypsin in the autodigestive process. The present study compares the noxious potential of different pancreatic enzymes to damage acinar cells. Acinar cells were isolated from rat pancreas by collagenase digestion. Cell viability was studied by (1) exclusion of trypan blue, (2) release of lactate dehydrogenase, and (3) release of newly synthesized proteins identified with methionine labeled with sulfur 35. Cells were then incubated in oxygenated N-2-hydroxyethylpiperazine-N-'-2-ethanesulfonic acid-Ringer solution containing different concentrations of various active digestive enzymes. Uptake of trypan blue was the most sensitive and reliable test of cell damage when compared with release of lactate dehydrogenase or radiolabeled newly synthesized proteins. All active digestive enzymes studied caused dose-dependent cell damage. The noxious potential, however, was strikingly different for the various enzymes. Pancreatic elastase in nanomolar concentrations caused marked cell damage after 45 to 90 minutes of incubation. Lipase and chymotrypsin caused a similar damage only at micromolar concentrations, whereas even millimolar concentrations of trypsin failed to cause significant damage. The present results confirmed recent work showing that lipase and phospholipase A2 probably cause cell damage through release of free fatty acids and lysolecithin. Although activation of trypsin might be the trigger to start the activation cascade in acute pancreatitis, trypsin itself is markedly less noxious to acinar cells when compared with other digestive enzymes. Elastase by far had the greatest noxious potential of all enzymes evaluated. Studies analyzing therapeutic effects of protease inhibitors should evaluate not only the inhibitory potential against trypsin but also that against other digestive enzymes, particularly elastase.

Acute Disease↗

PubMed1995

[The solubility and bioequivalence of silymarin preparations].

Seven silymarin products (pharmacies only), two of them with two batches each, were analysed for their ingredients, in particular silibinin (CAS 22888-70-6) and tested in vitro for their liberation of active agents. Founded on the results of these tests three products were checked for bioequivalence. Therefore, a typical phase I 3 fold crossover study was performed showing one product (Legalon) to be qualified by an approx. 2 fold higher silibinin availability compared to the two other preparations.

Adult↗

PubMed1994

[Mechanisms for cell damage in acute pancreatitis using isolated acinar cells].

Due to the complexity of interacting organ systems, in vivo the interpretation of results obtained from whole-animal experiments of acute pancreatitis remains difficult. To enlighten cause-and-effect-relationships, functional isolated parts of the pancreas are applied increasingly in research into the pathogenesis of the disease, therefore. By means of a collagenase digestion technique, intact acinar cells from normal as well as from pretreated rat pancreas could reproducibly be obtained in high yield. Animals were pretreated in situ by induction of either mesenteric ischemia/reperfusion, juice edema, or acute pancreatitis (AP). Pancreatic acinar cells isolated from these pretreated rats consumed oxygen at comparable rates under resting conditions throughout all experimental groups. A reduced stress capacity of cell respiration as well as a preterm decline in short-term culture was observed in the cells of the AP group, however. These results demonstrate that the induction of AP has found its reflection within the acinar cells themselves. Interestingly, these effects were not clouded by the isolation procedure. The manner of in-situ pretreatment of the respective animal proved to be decisive for later viability of isolated acinar cells in short-term culture. Uncoupling of oxidative phosphorylation by 2,4-dinitrophenol (DNP) lead to an accelerated decline of the acinar cells in all groups. The intactness of cellular energy metabolism seems to play a crucial role in maintaining cellular integrity, therefore. In additional experiments in vitro, the intracellularly mediated cell damage by DNP was compared with one induced from the extracellular environment of isolated cells by antibodies directed against cell surface antigens plus complement.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1994

[Pharmacokinetics of two theophylline sustained-release preparations in healthy humans].

In an open, randomized change-over study the steady state profile of two theophylline (CAS 58-55-9) sustained-release preparations (Theophyllard resp. reference preparation) in 24 healthy volunteers was evaluated with respect to AUC, Cmax, Cmin, and tmax. Cmax of the test preparation is higher than that of the reference. During the daytime the adjusted Cmax-values are about 25% higher than the Cmax-values of the reference, during the night they are 10% higher. Tmax of the test preparation is 6 h; tmax of the reference is 5 h.

Adult↗

PubMed1994

Oxidative stress-induced changes in pancreatic acinar cells: insights from in vitro studies.

Oxidative stress is regarded a major factor in the pathogenesis of both acute and chronic pancreatitis. The mechanisms by which free radicals damage the acinar cells are not yet clear. Standard models of oxidative stress were applied to investigate the susceptibility of isolated rat pancreatic acinar cells and zymogen granules to oxidant attack and to explore the potential of several antioxidants and radical scavengers to prevent such injury. Short-term peak production of free radicals by xanthine oxidase was more injurious to the acinar cells than continual radical generation at a lower level by iron/adenosine diphosphate. Isolated zymogen granules were much more susceptible to oxidative damage that isolated acinar cells. In both models, a combination of catalase and superoxide dismutase effectively prevented cell damage. In contrast, the classical hydroxyl radical scavengers mannitol, dimethyl sulphoxide and dimethyl thiourea, as well as the iron chelator deferoxamine were ineffective and at a higher concentration were even toxic. The novel low molecular weight 21-aminosteroid substances called "lazaroids" showed a highly protective potential when applied at a concentration of 1-50 mumol/l and are therefore considered to be the substances most likely to protect the pancreas cells against oxidative injury. Higher concentrations of the lazaroids, however, also caused additional damage to the cells. The results indicate that multiple radical species and several mechanisms are involved in oxidative injury to the pancreatic acinar cell. From present in vitro data, no single substance can be recommended for use in animal experiments or human studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

PubMed1993

Rhein and aloe-emodin kinetics from senna laxatives in man.

Therapeutic doses of two laxatives (Agiolax and Sennatin) were repeatedly administered to 10 healthy volunteers in a two-way change-over design. Blood samples were collected up to 96 h after the first dose, and plasma levels of total aloe-emodin and rhein were determined simultaneously with a sensitive (lower limit of quantification: 0.5 ng aloe-emodin and 2.5 ng rhein per millilitre plasma) and specific fluorometric HPLC method. Aloe-emodin was not detectable in any plasma sample of any subject. Rhein concentration time courses showed highest levels of 150-160 ng/ml and peak maxima at 3-5 h and 10-11 h after dosing probably according to absorption of free rhein and rhein released from prodrugs (e.g. sennosides) by bacterial metabolism, respectively.

Adolescent↗

PubMed1993

Current conservative treatment of acute pancreatitis: evidence from animal and human studies.

Primary treatment of patients suffering from acute pancreatitis is conservative, irrespective of its etiology and initial severity. There is no effective specific therapy for treating the underlying disease process. As a result, the current therapeutic approach involves the provision of supportive care, the elimination of causal (biliary tract) disease, and the treatment of complications. Since complications may develop at any time, patients with moderate or severe disease should be admitted to an intensive care unit for interdisciplinary assessment and constant observation of their clinical status and computed tomography findings. Basic therapy should include total fasting, replacement of deficits in volume, electrolyte and albumin, as well as adequate analgesia. Depending on the patient's specific clinical condition, nasogastric suction, respiratory support, antibiotics, insulin and heparin may become necessary. The use of enzyme inhibitors and drugs capable of inhibiting pancreatic exocrine secretion has not proved effective in clinical trials. The value of prostaglandins, non-steroidal anti-inflammatory drugs and cholecystokinin receptor antagonists remains to be established. Early endoscopic retrograde cholangiopancreatography should be performed in patients with suspected underlying biliary disease. Papillotomy should be carried out only when calculi are present in the common bile duct. Local complications, such as pseudocysts and abscesses can often be treated by ultrasound- or CT-guided aspiration and drainage. However, when bacterial infection of pancreatic necrosis becomes evident, surgical intervention should be considered. Future evaluation of new therapeutic approaches by controlled studies needs to include a sufficient number of patients with severe acute pancreatitis.

Acute Disease↗

PubMed1992

Determination of apovincaminic acid in serum by means of high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of low concentrations in serum of apovincaminic acid, the main metabolite of vinpocetine, is reported. The assay includes a two-step ion-pair extraction with tetrabutylammonium as counter ion. Recovery is ca. 40%. Separation is performed on a narrow-range 5 microns particle size octadecylsilane modified silica packing. Heptanesulphonic acid is the pairing ion in the eluent, and the ultraviolet detection wavelength is 224 nm. Yohimbine serves as the internal standard. The assay is fast, accurate and sensitive quantifying at least 5 ng/ml apovincaminic acid in serum. The method was applied to the analysis of serum samples from aged subjects, treated with a 20-mg dose of vinpocetine.

Chromatography, High Pressure Liquid↗