Biomedical subjects
Publications and source records attributed to B Greiner.
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The aims of the population-based, cross-sectional survey "Study of Health in Pomerania" (SHIP) are to describe prevalences and distributions of a broad range of diseases, as well as environmental and behavioural risk factors in the region of Pomerania (North-eastern Germany). The examinations are performed in two study units by different physicians, technicians and interviewers and laboratory analyses in two separate laboratories. In addition, the study will take at least 3 years and approximately 7000 persons will be examined. Because of the design of the study a special concept of quality assurance is indispensable. In the present paper methods are presented for quality assurance and control in anthropometry, ECG, echocardiography, abdominal sonography, carotid ultrasound, sonography of the thyroid gland, blood pressure measurements as well as clinical laboratory analyses. The technical control protocols, the training programmes of the observers and methods to establish observer and method variabilities are presented by means of typical examples. The logistic, personal and technical measures for quality assurance and control require appropriate attention. The methods and procedures presented here are expected to provide an effective instrument to continually monitor the quality of medical examinations in the SHIP study.
Recent data point to the contribution of P-glycoprotein (P-gp) to digoxin elimination. On the basis of clinical observations of patients in whom digoxin levels decreased considerably when treated with rifampin, we hypothesized that concomitant rifampin therapy may affect digoxin disposition in humans by induction of P-gp. We compared single-dose (1 mg oral and 1 mg intravenous) pharmacokinetics of digoxin before and after coadministration of rifampin (600 mg/d for 10 days) in 8 healthy volunteers. Duodenal biopsies were obtained from each volunteer before and after administration of rifampin. The area under the plasma concentration time curve (AUC) of oral digoxin was significantly lower during rifampin treatment; the effect was less pronounced after intravenous administration of digoxin. Renal clearance and half-life of digoxin were not altered by rifampin. Rifampin treatment increased intestinal P-gp content 3.5 +/- 2.1-fold, which correlated with the AUC after oral digoxin but not after intravenous digoxin. P-gp is a determinant of the disposition of digoxin. Concomitant administration of rifampin reduced digoxin plasma concentrations substantially after oral administration but to a lesser extent after intravenous administration. The rifampin-digoxin interaction appears to occur largely at the level of the intestine. Therefore, induction of intestinal P-gp could explain this new type of drug-drug interaction.
Propafenone undergoes extensive metabolism both by phase I and phase II enzymes: cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main metabolite 5-OH-propafenone, CYP3A4/1A2 dependent N-dealkylation and further glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an important drug interaction between rifampicin and propafenone is not to be expected a priori. However, non-CYP2D6-dependent pathways may be induced as a case report described dramatically lowered plasma concentrations of propafenone with loss of dysrhythmia control associated with rifampicin treatment. Therefore, this study aimed to investigate induction properties of rifampicin on propafenone disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once daily for nine consecutive days. The day before the first rifampicin dose and on the day of the last rifampicin dose each individual received a single intravenous (i.v.) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of 300 mg deuterated propafenone orally (p.o.). During enzyme induction maximum QRS prolongation decreased significantly after propafenone p.o. (21 +/- 7% versus 13 +/- 6% in extensive metabolizers, P < 0.01; 15 +/- 6% versus 9 +/- 6% in poor metabolizers, P < 0.01) and not after propafenone i.v. In parallel, there were no substantial differences in pharmacokinetics of propafenone i.v. by rifampicin. However, bioavailability of propafenone dropped from 30 +/- 15% to 10 +/- 8% in extensive metabolizers (P < 0.01) and from 81 +/- 6% to 48 +/- 8% in poor metabolizers (P < 0.001). Following propafenone p.o. clearances through N-dealkylation (4.1 +/- 2.1 ml/min versus 23.5 +/- 12.6 ml/min in extensive metabolizers, P < 0.01; 3.4 +/- 1.3 ml/min versus 16.0 +/- 5.5 ml/min in poor metabolizers, P < 0.001) and glucuronidation (123 +/- 48 ml/min versus 457 +/- 267 ml/min in extensive metabolizers, P < 0.05; 43 +/- 9 ml/min versus 112 +/- 34 ml/min in poor metabolizers, P < 0.01), but not 5-hydroxylation increased regardless of phenotype indicating substantial enzyme induction. Clearances to propafenone sulfate and conjugates of 5-OH-propafenone were significantly enhanced by rifampicin treatment in poor metabolizers (P < 0.01). Thus, induction of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation, sulfation) of propafenone by rifampicin resulted in a clinically relevant metabolic drug interaction which was more pronounced in extensive metabolizers than in poor metabolizers with regard to percentage decrease in bioavailability of propafenone.
Recently, we reported that in rat, cyclosporine A (CsA) markedly decreases the levels of calbindin-D (CABP-D) 28 kDa in kidney. CABP-D 28 kDa is a calcium-binding protein which is highly expressed in calcium-transporting tissues such as kidney or brain. In this study, we investigated whether, in addition to the kidney, CsA also has an effect on CABP-D 28 kDa in rat brain. Three groups of male Wistar rats received 15 mg/kg/day or 50 mg/kg/day of CsA orally for 12 days, whereas controls received vehicle solution for the same period. CABP-D 28-kDa protein and CsA were quantified in homogenates of kidney, cerebral cortex and cerebellum, and the localization of CABP-D 28 kDa was assessed in the different tissue sections by immunohistochemistry. In kidney, CABP-D 28 kDa was strongly and dose dependently decreased, and was located in tubular epithelial cells. In brain, CABP-D 28 kDa was not changed and was mainly located in pyramidal cells of the cortex and in cerebellum exclusively in Purkinje cells. High CsA concentrations were measured in kidney, more than 17-fold greater than those found in cortex. In cerebellum, CsA was below the limit of detection. These data suggest that at clinically relevant doses, CsA may not affect CABP-D 28-kDa levels in brain.
This paper reviews findings from 58 prospective studies of illicit substance use (ISU) among adolescents. It arranges 384 findings according to three types of influence (viz., social, attitudinal, and intrapersonal) and four levels of influence (viz., ultimate, distal, proximal, and immediate). The bulk of evidence reconfirms the importance of several predictors of ISU (e.g., intentions and prior substance-related behavior, friendship patterns and peer behaviors, absence of supportive parents, psychological temperament), reveals that a few variables thought to be well-established predictors may not be (e.g., parental behaviors, parental permissiveness, depression, low self-esteem), and uncovers several variables where findings were either sparse or inconsistent (e.g., the role of public policies concerning ISU, mass media depictions of ISU, certain parenting styles, affective states, perceptions of parental disapproval for ISU, and substance-specific refusal skills). Directions for future research are discussed.
BACKGROUND/AIMS: The proinflammatory effects of endotoxemia, which is often observed in alcohol-abusing patients with various degrees of liver disease, may be modulated by changes in the concentration of endotoxin binding factors. Therefore, the plasma endotoxin concentration and the overall endotoxin binding capacity of whole blood were measured in these patients. METHODS: Patients with minor (A1; n=27), more pronounced (A2; n=13), cirrhotic alcoholic liver disease (A3; n=18), and non-alcoholic cirrhosis (NC; n=6), and 15 healthy control persons (HC) were included in the study. Endotoxin plasma levels were determined using a standardized limulus assay. A modified assay was applied to additionally detect tightly bound endotoxin. To measure the endotoxin-binding capacity, aliquots of whole blood were incubated with serial dilutions of endotoxin, supernatants were obtained, and endotoxin retrieval was estimated by addition of limulus lysate, followed by photometric measurement of the maximal reaction velocity (dODmax). Endotoxin binding capacity equals the endotoxin concentration at which dODmax reaches a predefined threshold. RESULTS: All groups of alcohol abusers had significantly elevated endotoxin plasma levels with a considerable portion of 'bound' endotoxin. Conversely, the endotoxin binding capacity was markedly diminished, mainly in patients with more advanced liver disease (A1: 85.8% of the control value [non-significant vs. controls]; A2: 25.4% [p<0.05]; A3: 43.6% [p<0.02], NC: 43.2%). CONCLUSIONS: The endotoxin-binding capacity is diminished in patients with alcoholic and non-alcoholic cirrhosis, as well as in less advanced alcoholic liver disease. Reduced endotoxin binding may contribute to the adverse effects of endotoxemia.
The effects of red blood cell transfusion on the incidences of apnoea, bradycardia, tachycardia and oxygen desaturation over periods of 72 hours before and after transfusion were assessed in 25 infants with a gestational age of < or = 32 weeks (mean (SEM) 29.2 (0.4) weeks, birthweight 1170 (73) g; postnatal age at transfusion 39 (4) days). During transfusion haemoglobin rose from 78 (2) g/l to 117 (2) g/l. Significant decreases were observed in daily frequencies of apnoeas longer than 15 seconds (median from 2.7 to 0.9 events a day), tachycardias of more than 200 beats per minute (from 34 to 25 events per day), bradycardias below 100 beats per minute (from 65 to 12 events per day) and 80 beats per minute (from 8.4 to 3.3 events per day). Oxygen saturation improved in 20 of the infants. Transfusion improves cardiorespiration in preterm infants for several days.
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The nature and location of cells responding to tumour necrosis factor-alpha (TNF-alpha) were investigated in situ by immunohistochemistry using monoclonal antibodies (mAb) directed against the p75 and p55 proteins of the TNF receptor. Receptor expression was found in the thymus and secondary lymphoid tissues. In the thymus the p75 receptor was confined to medullary lymphoblasts and dendritic cells, which co-stain with the Tac protein of the interleukin-2 (IL-2) receptor. In lymph nodes and other secondary lymphoid tissues, the p75 receptor was expressed on activated lymphocytes and interdigitating reticulum cells of the T-cell area, whereas the p55 receptor was confined to the germinal centre dendritic reticulum cells (DRC), which is the main site of TNF-alpha production. TNF receptor (TNFR) proteins were up-regulated in reactive hyperplasia together with increased TNF-alpha expression. Surprisingly, no TNFR was detectable on non-lymphoid tissues. The species specificity of these TNFR antibodies was high: whereas the antibodies cross-reacted with epitopes in non-human primates, no immunoreactivity was detected in lower animal species, e.g. dog, rabbit and rodents. The data presented suggest that TNF-alpha, which is produced by germinal centre DRC, might regulate an in vivo immune response through autocrine and paracrine pathways, e.g. through the p55 and p75 receptor proteins, which are expressed at different sites of the lymphoid tissue.
Cyclophilin (CYP) is the major intracellular binding protein for the immunosuppressive drug cyclosporine (CS). CYP distribution was investigated in human tissues by solid-phase immunoassay, Western and Northern blot analysis as well as immunohistochemistry. CYP was found in all tissues examined at concentrations in the range of 1 microgram/mg protein. Furthermore, mRNA specific for CYP was found in every tissue, indicating local production of the protein. Immunohistochemical investigations revealed preferential parenchymal and only little stromal localization. Within certain organs, e.g. kidneys, regional differences of immunoreactive CYP was evident. The presence of CYP was also investigated in several lymphoid and non-lymphoid cell lines and was found at comparable concentrations. Immunogold staining confirmed cytosolic, but revealed also nuclear localization of CYP. The possible role of this abundant CS binding protein is discussed.
Recombinant interleukin-2 was biotinylated using a N-hydroxyl-succinimidyl [3H]biotin ester. The biotinylated lymphokine retained full binding and growth-promoting activities when assayed on the interleukin-2-dependent murine cell line HT-2. In preliminary studies, biotinylated interleukin-2 was used in conjunction with immunogold staining to demonstrate cell surface interleukin-2 receptors using both light and electron microscopy techniques. In addition, with rabbit anti-biotin antibodies, biotin-interleukin-2 was able to precipitate the 55 kDa IL-2 receptor from murine HT-2 cells. Thus, biotin-interleukin-2 represents a useful, non-radioactive tool for studying the structure and function of the interleukin-2 receptor.
Although cyclosporine has high specificity for the immune system, immunosuppressive therapy with CsA is often complicated by nephrotoxicity. The main morphologic targets of CsA nephrotoxicity include the tubular epithelial and endothelial cells. These cells were investigated in vitro. CsA caused a dose- and time-dependent inhibition of cell growth, vacuolization and fatty change in adherent cells, detachment, and cell death. Inhibition of 3H-TdR incorporation in cells of both tubular epithelial and endothelial origin occurred between 3 microM and 10 microM. Electron microscopy studies revealed cellular swelling, dilatation of the endoplasmic reticulum, and the presence of lipid droplets and giant mitochondria. The content of the main CsA-binding protein, cyclophilin, in these cell-lines was 5-10 micrograms/mg protein and did not differ in various cell lines, including T cells. Immunohistochemistry using rabbit anticyclophilin antibody revealed diffuse distribution of cyclophilin in the cytosol, nuclear membrane, and nucleolus. Whereas lymphoid cell functions are inhibited at 10-100 nM, CsA had no effect on tubular epithelial and endothelial cells at these concentrations. At concentrations of 3-10 microM, CsA caused growth inhibition and cytotoxicity on cells of lymphoid and nonlymphoid origin. Present evidence shows little, if any, relationship of side-effects to the mode of action of CsA.
In a research programme lasting one year a computer-supported technique for the MMPI-Test has been developed in co-operation of the Clinical-Psychology and the Bio-Medical. Engineering Departments. The use of the microelectronically operated test apparatus has proved extremely economic.
Metabolites of (14C) tetrahydronorharmane (THN, tetrahydro-beta-carboline) have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy. Two metabolic pathways are suggested: Hydroxylation of the benzene ring--most probably with an epoxide as intermediate--though no hydroxylated THN could be detected in the urine samples of male and female rats but conjugated compounds as the main metabolites. The intermediary epoxide is supported by the fact, that the hydroxy substituent of THN is positioned on C-6 or C-7 with a ratio of 55:45 in female rats and of 45:55 in male rats. Dehydrogenation yielding norharmane. This substance possibly gives rise to another metabolite--1,2-dihydro-beta-carboline-1-one. The pharmacological and toxicological implications of these findings are discussed.
The distribution, metabolism and elimination into the urine of (14C)-tetrahydronorharmane (THN) as well as of (14C)-6-hydroxy-tetrahydronorharmane (6-OH-THN) are investigated in female and male rats. Following intravenous injection of (14C)-THN radioactivity was detected in all organs examined, namely blood, brain, lung, adrenal gland, small intestine, fat tissue, kidney and liver. In the brain the elimination half life of THN was calculated to be 1.8 h, the elimination half life of the radioactivity in the blood 6.24 h, and the accumulation half life in the urine 9.24 h. The elimination of 6-OH-THN into the urine is faster than that of THN. At least four metabolites of (14C)-THN were found in the urine of female rats. Two different metabolic pathways are discussed, firstly, hydroxylation followed by conjugation with glucuronic and sulfuric acids and secondly, dehydrogenation, followed by oxygenation. In female rats only traces of the conjugated metabolites are hydrolysed by arylsulfatase, whereas in male rats approximately 2/5 are cleaved by this enzyme. Pretreatment of male rats with 3-methylcholanthrene induced conjugation, whereas phenobarbital had no obvious effect on the pattern of metabolites. SKF 525 A and CFT 1201 both prevented almost completely the formation of conjugates from THN.
Two sensitive and specific methods are presented for the determination of 6-OH-tetrahydronorharmane (6-OH-THN, 6-OH-THBC) and harmane (1-Me-BC). The concentration of 6-OH-THN in blood platelets from men was found 5.19 +/- 0.57 ng (mean +/- SEM) per 10(9) platelets, of acute schizophrenic patients 2.66 +/- 0.38 ng per 10(9) platelets, p less than 0.02, and in rats 6 - 13 ng x 10(9) platelets. The concentration of harmane in the urine of rats was measured 9.72 +/- 1.56 ng per 16 h. A load with ethanol caused an increased excretion of the beta-carboline in some rats. In pharmacological experiments substantial evidence was detected for a correlation between the (3H)-flunitrazepam displacing potency and the conflict-augmenting effects of beta-carbolines. Furthermore, a good correlation was found between the results of binding experiments and the antagonism of the beta-carbolines with respect to the activating effect of low doses of diazepam. No such correlation exists for the sedative effect.
The metabolism of THN in the rat was studied in vivo by use of 14C-radiolabelled compound. Structures of major urinary metabolites were determined by exact spectral data. Their concentrations were measured by liquid scintillation counting. It was found that THN is submitted to endogenous transformation, and that the excreted derivatives form three groups of similar concentration: unchanged substance, hydroxylated/conjugated compounds, and aromatic metabolites. Structures and proposed pathways are summed up in the diagram on the following page.