Liquid chromatography coupled with high-field proton NMR for profiling human urine for endogenous compounds and drug metabolites.
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Biomedical subjects
Publications and source records attributed to M Spraul.
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Therapeutic footwear with cushioned insoles was supplied to 50 diabetic patients with severe peripheral neuropathy and/or peripheral vascular disease (age 59(SD 12) years, known duration of diabetes 17(7) years), 36 of whom had a history of foot ulceration. A follow-up examination was carried out 25(14) months later, except in 8 patients who died from conditions unrelated to their foot lesions, and 1 patient who died from sepsis due to upper limb amputation. Among the surviving 41 patients, intercurrent foot lesions during follow-up occurred in significantly fewer (42%) of the 26 who had worn the shoes regularly than of the 15 who had worn the shoes irregularly (87%, p less than 0.01). At follow-up, only 15% of the 41 patients were being treated for foot-lesions, compared with 78% of these 41 patients before cushioned shoes were provided. It is concluded that the availability of therapeutic shoes with cushioned insoles for diabetic patients at risk of foot lesions decreases the morbidity due to the diabetic foot syndrome.
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A follow-up study of 116 Type 1 (insulin-dependent) diabetic patients on long-term continuous subcutaneous insulin infusion was conducted after 4.5 +/- 0.2 years. The average HbA1c-value of these patients decreased by 1% to 6.7 +/- 0.1% during this observation period. Typical side effects of continuous subcutaneous insulin infusion such as skin inflammation at the catheter insertion site occurred with similar frequency as has been reported previously by other authors. Diabetic ketoacidosis (0.14 per patient year) and disabling hypoglycaemia (0.1 per patient year, including 0.05 hypoglycaemic coma per patient-year) occurred at substantially lower rates than in other comparable studies with Type 1 diabetic patients at a similar degree of metabolic control. Subgroup evaluation suggested that a normal (less than 5.6%) HbA1c-value at follow-up was associated with increased incidence of disabling hypoglycaemia, whereas poor metabolic control (HbA1c greater than 7.5%) was associated with increased rates of skin complications and hospital treatment for ketoacidosis. Thus, under the policies of this diabetes centre, continuous subcutaneous insulin infusion has proved to be beneficial to a large proportion of experienced adult Type 1 diabetic patients, who voluntarily had opted for, and continued with, this particular mode of insulin treatment.
It has been shown, that the elimination rate of intravenously administered tolbutamide shows considerable interindividual variation, due to strong genetic influence. These pharmacogenetic differences in the metabolic clearance rate of tolbutamide may result in drug failure in fast-eliminators, and it may cause an increased incidence of side effects in slow-eliminators. It is not known whether different "pharmacogenetics" exist for other sulfonylurea drugs. Therefore, we have injected glibenclamide (0.02 mg/kg body weight) intravenously in 52 male, normal weight, healthy volunteers. Serum glibenclamide levels were followed for up to 24 h. The terminal phase half-life of glibenclamide was 2.46 +/- 0.67 h (mean +/- SD), total drug clearance was 48.7 +/- 11.0 ml.min-1 and the slow disposition phase rate constant was 0.30 +/- 0.08 h-1. From the individual data of each subject frequency histograms were developed for these and other kinetic parameters and tested with a Kolmogoroff-Smirnoff-test for unimodal normal distribution. There was no significant (p greater than 0.05) deviation from the unimodal normal distribution for these parameters. In contrast to the pharmacogenetics of tolbutamide metabolism the present data indicate that glibenclamide follows an uniform elimination pattern in healthy caucasian males.
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In three different diabetes centers the use of insulin at a strength of 40 IU/ml (U40) and 100 IU/ml (U100) in continuous subcutaneous insulin infusion (CSII) treatment of insulin dependent (Type I) diabetic patients was compared in a randomized cross-over design. Forty-six Type I diabetic patients, all previously treated with CSII for at least one year, completed consecutively two 13-week periods of treatment with U40 and U100. Body weight and insulin requirements were identical at the end of the two periods. Slightly higher levels of glycemia were recorded during U40 when compared to U100 treatment: mean blood glucose was 142 +/- 34 (SD) vs. 133 +/- 34 mg/dl (2 p less than 0.01). The same tendency was observed in the mean glycosylated hemoglobin value (6.84 +/- 1.35 vs. 6.65 +/- 1.13%, 2 p greater than 0.1). There were no significant differences between U40 and U100 in the number of catheters used and the number of catheter blockages reported, while the development of subcutaneous nodules at the insertion sites was significantly more frequent during U40 treatment. It is concluded that the implementation of insulin in the strength of 100 IU/ml is as effective as the use of insulin in the strength of 40 IU/ml for CSII therapy, and might even be associated with slightly improved glycemic control and less subcutaneous side-effects.
A procedure for the structure specific determination of diethylene glycol from wine is described. The analysis can be performed without pretreatment of the samples. The detection limit is 10 mg/l.
Four carbohydrate diets with different glycaemic index were fed to 10 type I diabetic patients on continuous subcutaneous insulin infusion (CSII). Every diet consisted of 4 meals with identical carbohydrate content, being consumed during one day each at 8.00, 12.00, 16.00 and 18.00 h. CSII was conducted according to the patients' experiences, aiming at plasma glucose values between 70 and 160 mg/dl. From 8.00 to 20.00 h, plasma glucose was measured every 2 h. Plasma glucose profiles were near-normal with all of the diets; differences between the diets were statistically insignificant. The premeal insulin dosages, as delivered by the patients, varied significantly in relation to the time of the day, and to the premeal plasma glucose concentration. The patients varied their prandial insulin doses also in relation to the 4 diets, indicating that the glycaemic index was helpful for the prediction of their prandial insulin requirements. It is concluded that near-normoglycaemia can be achieved in type I diabetic subjects on CSII irrespective of the glycaemic index of their diet, if the prandial insulin requirements are met adequately.
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Nine macrocyclic trichothecenes, thought to cause toxic effects in herbivors, were isolated from the Brazilian shrub Baccharis coridifolia. The structures of two new components, named miophytocene A and B, are described. Structure analysis was mainly accomplished by application of two-dimensional Fourier transform NMR techniques. The trichothecenes are most likely produced by the soil fungus Myrothecium verrucaria, which was isolated from soil samples around B. coridifolia. It is concluded that the plant is able to absorb and accumulate these mycotoxins. Histopathological studies on rabbits which received roridin E and A per os revealed mainly necrosis and hemorrhages of the mucosa of the colon and in the case of roridin A also of the caecum. Lethality in mice was generally low, intoxication proceeding slowly. It has to be considered, however, that all trichothecenes tested are practically insoluble in aqueous solutions and were applied as emulsions (i.p. and per os application). No trichothecenes or other toxic substances were detected from the Brazilian species Baccharis dracunculifolia, although slight toxic effects have been reported in cattle.
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Pattern recognition approaches were developed and applied to the classification of 600 MHz 1H NMR spectra of urine from rats dosed with compounds that induced organ-specific damage in either the liver or kidney. Male rats were separated into groups (n = 5) and each treated with one of the following compounds; adriamycin, allyl alcohol, 2-bromoethanamine hydrobromide, hexachlorobutadiene, hydrazine, lead acetate, mercury II chloride, puromycin aminonucleoside, sodium chromate, thioacetamide, 1,1,2-trichloro-3,3,3-trifluoro-1-propene or dose vehicle. Urine samples were collected over a 7 day time-course and analysed using 600 MHz 1H NMR spectroscopy. Each NMR spectrum was data-reduced to provide 256 intensity-related descriptors of the spectra. Data corresponding to the periods 8-24 h, 24-32 h and 32-56 h post-dose were first analysed using principal components analysis (PCA). In addition, samples obtained 120-144 h following the administration of adriamycin and puromycin were included in the analysis in order to compensate for the late onset of glomerular toxicity. Having established that toxin-related clustering behaviour could be detected in the first three principal components (PCs), three-quarters of the data were used to construct a soft independent modelling of class analogy (SIMCA) model. The remainder of the data were used as a test set of the model. Only three out of 61 samples in the test set were misclassified. Finally as a further test of the model, data from the 1H NMR spectra of urine from rats that had been treated with uranyl nitrate were used. Successful prediction of the toxicity type of the compound was achieved based on NMR urinalysis data confirming the robust nature of the derived model.