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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Comparative clinical pathology 3 (1993), S. 174-177 
    ISSN: 1433-2981
    Schlagwort(e): Guidlelines ; Harmonisation ; Toxicology
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The aim of this paper is to emphasize the necessity of an international harmonisation of the guidelines in toxicology for the safety evaluation of pharmaceutical products, and the role of the International Conference on Harmonization (ICH). The organisation of the working-groups and the choice of the topics are descibed, and an overview of the achievement and on the difficulties encountered for this purpose is presented, some months before the ICH2 meeting in Orlando (USA).
    Materialart: Digitale Medien
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  • 2
    ISSN: 1432-0428
    Schlagwort(e): Alcohol drinking ; cardiovascular diseases ; cirrhosis ; Type 2 (non-insulin-dependent) diabetes mellitus ; glucose tolerance test ; insulin resistance ; mortality
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The aim of this study was to compare the causes of death and parameters related to alcohol consumption, between subjects diagnosed as diabetic, clinically by their general practitioner, or glucose intolerant and in particular as diabetic, using the epidemiological criteria of an abnormal glucose level following an oral glucose tolerance test. The subjects in this study were 7035 working men, aged between 44 and 55 years, who attended the first follow-up examination of the Paris Prospective Study, between 1968 and 1973. They were classified as ‘clinically diagnosed diabetic’ or, following an oral glucose tolerance test and the World Health Organisation criteria, as having ‘oral glucose tolerance test diagnosed diabetes’, impaired glucose tolerance or normoglycaemia. The relative risk of death by cirrhosis, in comparison with the normoglycaemic group, was 21 (95 % confidence interval: 9.1–49) in the group diagnosed diabetic by the oral glucose tolerance test, significantly different (p 〈 0.02) from the group diagnosed diabetic clinically 3.1 (0.41–24); factors indicative of excessive alcohol consumption at baseline differed accordingly. In contrast, the relative risks for death by coronary heart disease were similar, 2.1 (1.0–4.1) and 2.7 (1.4–5.4) respectively; all of the factors defining the insulin resistance ‘Syndrome X’ (hyperglycaemia, hyperinsulinaemia, hypertension, hyperlipidaemia and also central obesity) and predictive of coronary heart disease were elevated in both groups of diabetic subjects. ‘Diabetes’, as diagnosed by the oral glucose tolerance test, might be the consequence of excessive alcohol consumption which could lead to insulin resistance, then to coronary heart disease, as well as to alcohol-related diseases.
    Materialart: Digitale Medien
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  • 3
    ISSN: 1432-0428
    Schlagwort(e): Epidemiology ; coronary heart disease risk factors ; oral glucose tolerance test ; plasma insulin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The possible role of plasma insulin levels as a risk factor of coronary heart disease has been studied in a population of 7246 non diabetic, working men, aged 43–54 years, initially free from heart disease, and followed for 63 months on average. 128 new coronary heart disease events (non fatal myocardial infarction and coronary related deaths) were detected during this period. The annual risk is analysed by a multivariate model including age, serum cholesterol and triglycerides, blood pressure, smoking, obesity, plasma glucose and insulin fasting and 2 hours after a 75 g oral glucose load. It is shown that the fasting plasma insulin level and the fasting insulin-glucose ratio are positively associated with risk independent of the other factors. The same variables, 2 hours after the glucose load are also positively associated with risk but their contributions are not significant in the multivariate analysis. It is concluded that high insulin levels may constitute an independent risk factor for coronary heart disease complications in middle aged non diabetic men.
    Materialart: Digitale Medien
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  • 4
    ISSN: 1432-0428
    Schlagwort(e): Epidemiology ; risk factors ; coronary heart disease mortality ; diabetes ; impaired glucose tolerance ; plasma insulin level ; plasma triglyceride level
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The Paris Prospective Study is a long-term investigation of the incidence of coronary heart disease in a large population of working men. The first follow-up examination involved 7,038 men, aged 43–54 years. Subjects with impaired glucose tolerance or diabetes (n=943) were selected from the total population for a separate analysis of coronary heart disease mortality risk factors. During a mean follow-up of 11 years, 26 of these 943 subjects with abnormal glucose tolerance died from coronary heart disease. Univariate analysis showed that plasma triglyceride level (p〈0.006), plasma cholesterol level (p〈0.02), and plasma insulin level both fasting and 2-h post-glucose load (p〈0.02), were significantly higher in subjects who died from coronary heart disease compared to those who did not. In multivariate regression analysis using the Cox model, plasma triglyceride level was the only factor positively and significantly associated with coronary death. The distribution of plasma triglyceride levels was clearly higher for the subjects who died from coronary heart disease compared to those who did not die from this cause or were alive at the end of the follow-up. This new epidemiological evidence that hypertriglyceridaemia is an important predictor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes suggests a possible role of dyslipidaemia in the excessive occurrence of atherosclerotic vascular disease in this category of subjects.
    Materialart: Digitale Medien
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  • 5
    ISSN: 1432-0428
    Schlagwort(e): Keywords Non-insulin-dependent diabetes mellitus ; impaired glucose tolerance ; non-esterified fatty acids ; insulin resistance ; insulin secretion ; epidemiology.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Although an increased plasma non-esterified fatty acid (NEFA) concentration has been shown to increase insulin resistance (Randle cycle), decrease insulin secretion and increase hepatic gluconeogenesis, the effect of NEFA on the deterioration of glucose tolerance has not been studied prospectively in Caucasian subjects. Therefore, we investigated whether plasma NEFA may be regarded as predictors of deterioration of glucose tolerance in subjects with normal (NGT, n = 3671) or impaired (IGT, n = 418) glucose tolerance who were participants in the Paris Prospective study. The subjects were first examined between 1967 and 1972 and underwent two 75-g oral glucose tolerance tests 2 years apart with measurements of plasma glucose, insulin and NEFA concentrations. Glucose tolerance deteriorated from NGT to IGT or non-insulin-dependent diabetes (NIDDM) in 177 subjects and from IGT to NIDDM in 32 subjects. In multivariate analysis, high fasting plasma NEFA in NGT subjects and high 2-h plasma NEFA and low 2-h plasma insulin concentrations in IGT subjects were significant independent predictors of deterioration along with older age, high fasting and 2-h plasma glucose concentrations and high iliac to thigh ratio. When subjects were divided by tertiles of plasma NEFA concentration at baseline, there was an increase in 2-h glucose concentration with increasing NEFA in the subjects who did not deteriorate, but no effect of plasma NEFA in those who deteriorated. In subjects with IGT who deteriorated compared with those who did not 2-h plasma insulin concentration was lower but there was no evidence that this resulted from an effect of plasma NEFA. Our data suggest that a high plasma NEFA concentration is a risk marker for deterioration of glucose tolerance independent of the insulin resistance or the insulin secretion defect that characterize subjects at risk for NIDDM. [Diabetologia (1997) 40: 1101–1106]
    Materialart: Digitale Medien
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  • 6
    ISSN: 1432-0428
    Schlagwort(e): Population surveillance ; epidemiological method ; statistics ; glucose tolerance test ; obesity ; diabetes ; blood glucose ; blood insulin ; blood FFA ; blood triglycerides ; blood cholesterol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Beschreibung / Inhaltsverzeichnis: Résumé Un test de tolérance à 75 g de glucose 0-2 h (0-2h OGTT) a été systématiquement effectué chez 721 hommes durant leur examen de santé annuel. L'insuline (I), le glucose (PG), les acides gras libres (FFA) plasmatiques, les triglycérides (Tg) et le cholestérol (Cs) ont été mesurés. L'analyse est faite globalement et après avoir divisé la population selon sa corpulence (sujets minces, replets, et obèses) et sur les taux de PG (G normaux, G0 suspects, G2 suspects, G anormaux). L'étude des corrélations partielles montre que I0 est indépendamment corrélé à la corpulence et, à un moindre degré, à PG et à Tg. I2 est fortement corrélé à G2 et, à un moindre degré, à la corpulence. I0, et par conséquent I2 augmentent avec le poids, même pour quelques Kgs supplémentaires. La distribution de l'insuline normale après transformation logarithmique est conservée dans chaque groupe de corpulence. Les pentes de régression glucose — insuline sont plus fortes chez les sujets replets et les obèses. La possibilité présentée par les sujets obèses de conserver des taux élevés d'insuline en dépit du jeûne n'est pas expliquée par les taux de PG, de FFA ou de Tg; les taux de I, de Tg et de PG sont corrélés et habituellement plus élevés ensemble. Les modifications biologiques rencontrées chez les G suspects sont plus importantes chez les G2 suspects. Des taux élevés de FFA et de Tg sont habituels chez les G suspects et anormaux, groupes responsables de la corrélation Tg-FFA vue dans l'ensemble de la population. Chez les G2 suspects et anormaux, la distribution de I2 est irrégulière et la corrélation PG2-I2 disparaît. Une histoire familiale de diabète est plus fréquente chez les sujets à G2 élevé. Ces observations donnent des arguments supplémentaires pour accorder aux 0-2 h OGTT une place plus étendue dans les examens de santé. Des anomalies mineures de FFA0 et/ou de PG0 reflètent probablement une inégalité individuelle présentée durant le jeûne dans la mobilisation des graisses ou des modifications transitoires de cet équilibre, plutôt qu'un état pré-diabétique. L'augmentation du poids est associé précocément à une augmentation des unités fonctionnelles de I'insulino-sécrétion, tandis que, chez les gens présentant une modification même légère de leur taux de glucose à 2 h il semble qu'il existe une anomalie de la sécrétion insulinique dans la réponse à la charge glucosée.
    Kurzfassung: Zusammenfassung Ein Toleranztest mit 75 g Glucose über 2Std (0-2h OGTT) wurde bei 721 Männern systematisch während ihrer jährlichen Vorsorgeuntersuchung durchgeführt. Das Insulin (I), die Glucose (PG), die freien Fettsäuren (FFA), die Triglyceride (Tg) und das Cholesterin (Cs) wurden bestimmt. Die Analyse wurde global und nach Aufteilung des Kollektivs je nach dem Grad des Übergewichtes (schlank, vollschlank, fettsüchtig) und den Glucosespiegeln (normal=G, G0=verdächtig, G2=verdächtig, G′=abnorm) vorgenommen. Die Prüfung der Teilkorrelationen zeigt, daß I0 unabhängig mit der Korpulenz korreliert und — in etwas geringerem Ausmaß —, mit PG und Tg. I2 ist eng mit G2 korreliert und etwas weniger mit der Korpulenz. I0 und daher auch I2 nehmen mit dem Gewicht zu und zwar schon mit einigen zusätzlichen kg. Die normale Insulinverteilung ist nach logarithmischer Transformation bei jedem Grad der Adipsoitas erhalten. Die Steigung der Regressionsgeraden Glucose-Insulin ist bei den Vollschlanken und den Fettsüchtigen stärker ausgeprägt. Der bei den adipösen Probanden gelegentlich anzutreffende Befund erhöhter Insulinspiegel trotz Nüchternzustand läßt sich durch die Plasmaspiegel der Glucose, der FFA oder der Triglyceride nicht erklären. I, Tg und PG sind korreliert und steigen in der Regel gemeinsam an. Die biologischen Abweichungen bei den VP. mit zweifelhaftem Ausfall der GTT sind bei den Schlanken und den zweifelhaften G2 deutlicher. Erhöhte FFA und TG-Spiegel sind bei den zweifelhaften und abnormen G die Regel, wodurch auch die beim Gesamtkollektiv zu beobachtende Korrelation Tg-FFA zustande kommt. Bei den zweifelhaften und abnormen G2 ist die Verteilung I2 unregelmäßig und die Korrelation PG2-I2 verschwindet. Angaben über Diabetes in der Familie finden sich häufiger bei den Probanden mit erhöhtem G2 Diese Beobachtungen liefern zusätzliche Argumente dafür, den 0-2h OGTT bei Reihenuntersuchungen eine größere Bedeutung zuzumessen. Leichtere Anomalien der FFA2 und/oder der PG2 sind wahrscheinlich eher Ausdruck einer individuellen Schwankung, die im Nüchternzustand bei der Fettmobilisation oder vorübergehenden Veränderungen dieses Gleichgewichtzustandes auftritt als eines prädiabetischen Zustandes. Die Gewichtszunahme führt schon frühzeitig zu einer Steigerung der funktionellen Einheiten der Insulinsekretion, während bei den Patienten mit leichter Veränderung der Glucosespiegel nach 2 Std bereits eine Störung der Insulinsekretion nach Glucosereiz vorzuliegen scheint.
    Notizen: Summary The 75 g 0-2 h oral glucose tolerance test (0-2h OGTT) was systematically carried out on 721 men during their annual check up. Plasma insulin (I), glucose (PG), free fatty acids (FFA), serum triglycerides (Tg) and cholesterol (Cs) were measured. The analysis was done globally and after dividing the population on the basis of corpulence (slim, plump and obese), and of PG values (G normals, G0 suspects, G2 suspects and abnormals). Partial correlation analysis shows that fasting insulin is independently correlated to the corpulence and less strongly to the PG and Tg levels. I2 is strongly correlated to the G2 level and less to the corpulence. Both 0 and 2 h insulin increase with weight even for a few kg more. The distribution of insulin kept to the pattern in each corpulence group. The glucose insulin regression slope is steeper in plump and obese than in slim. The possibility for the obese people of keeping a high insulin level despite the fasting state is not explained by the PG, FFA or Tg levels; insulin, Tg and glucose values are correlated and usually higher when together. The biological modifications seen in the G suspect groups are greater in the G2 suspects. High FFA, Tg and blood pressure are common to the G0 and G2 suspects. In both G2 suspects and abnormals, the distribution of the 2 h insulin is irregular and the 2 h PG-insulin correlation disappears. Higher G2 values without related insulin increase is more frequent in people with family history of diabetes. These data support arguments for giving the 0-2h OGTT a larger place in the health examination. Minor abnormalities of fasting FFA and/or glucose seem to be due rather to the inequality of people in the balance of their fat mobilization during the fasting challenge or to transient effects than to a prediabetic state. Increase in functional units of the insulin secretion is seen in overweight, while in some people even with slight impairment of their 2 h glucose level, it seems there is a misfit in the insulin secretion in response to the glucose load.
    Materialart: Digitale Medien
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  • 7
    ISSN: 1432-0428
    Schlagwort(e): Epidemiology ; Paris Prospective Study ; coronary heart disease risk factors ; plasma insulin level ; insulin resistance
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The Paris Prospective Study is a long-term, largescale study of the factors predicting coronary heart disease. The first follow-up examination included, for subjects not known as having diabetes mellitus, a 75 g oral glucose tolerance test with measurement of plasma insulin and glucose levels, fasting and 2 h post-load. Between 1968 and 1973, 6903 men aged 43–54 years were thus examined. Causes of death were ascertained within this group after 15 years of mean follow-up. The baseline variables were tested as predictors of death from coronary heart disease by a Cox regression analysis. Significant independent predictors of coronary heart disease death were: systolic blood pressure, number of cigarettes per day, plasma cholesterol level, and 2 h post-load plasma insulin level when entered as a categorical variable (below or above 452 pmol/l, i.e. the lower limit of the fifth quintile of the distribution). This dichotomization was performed to account for the non-linear univariate distribution of deaths with increasing post-load insulin values. Fasting plasma insulin level was not an independent predictor of death by coronary heart disease over this long-term follow-up. Levels of blood glucose were not significant independent predictors of death by coronary heart disease when plasma insulin levels were included in the model. The same applied to abnormalities of glucose tolerance when the 125 men with known non-insulin-treated diabetes at baseline were added to the group. Under the assumption that hyperinsulinaemia is a marker of insulin resistance, the results are consistent with the hypothesis that insulin resistance is associated with a higher risk of coronary heart disease mortality. However, it is doubtful that circulating insulin per se is a direct cause of arterial complications.
    Materialart: Digitale Medien
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  • 8
    ISSN: 1432-0738
    Schlagwort(e): Key words In vitro metabolism ; Cyclosporin A ; Renal and hepatic microsomes ; HPLC-mass spectrometry ; FPIA
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  Cyclosporin A (CsA) is in vivo mainly metabolized by hepatic cytochrome P450 IIIA to more than 21 metabolites, the major ones known as: M1, M17 and M21. The aim of this work is to explore the in vitro metabolism of CsA after incubation, in the presence of NADPH, with renal or hepatic microsomes obtained from rabbits pretreated with rifampycin (enzyme inducer) or erythromycin (enzyme inhibitor). The presumed metabolites were separated by semi-preparative high-performance liquid chromatography (HPLC) and identified in each collected fraction by fluorescence polarization immunoassay (FPIA) (HPLC-FPIA) using a non-specific polyclonal antibody. They were also analyzed by HPLC-mass spectrometry (MS) using fast atom bombardment (HPLC-MS-FAB). Five collected fractions gave positive results with FPIA. The major metabolites found were M1, M17 and M21 after identification by HPLC-MS-FAB and comparison with three corresponding standard metabolites. The CsA biotransformation rates were calculated by the amount of unmetabolized CsA and were linear with time. These mean rates (Vm) for 12-min incubation by renal microsomes of rabbits treated with rifampicin or erythromycin or untreated (control) were 0.11, 0.02 and 0.04 nmol/min×mg microsomal protein, respectively. These rates were 15 -, 37 -, and 30-fold lower than those obtained with hepatic microsomes of rabbits treated identically. As CsA metabolites are less cytotoxic than the parent drug, this weak renal biotransformation of CsA after in vitro incubation should be one of the mechanisms of its in vivo nephrotoxicity.
    Materialart: Digitale Medien
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