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Biomedical subjects

B Spiegelhalder

Publications and source records attributed to B Spiegelhalder.

126 records · Page 7Linked to original sources
PubMed1980

Nitrate and nitrite in saliva.

A survey is given on the occurrence of nitrate and nitrite in human saliva and the influence of the dietary nitrate intake. Nitrate, after its absorption in the upper gastrointestinal tract, reaches the salivary glands via the blood circulation where it is secreted into the oral cavity and partially reduced to nitrite by the oral microflora. There is a linear relationship between the amounts of nitrate ingested and amounts of nitrate and nitrite found in saliva. The ability of the oral microflora to reduce nitrate to nitrite depends on he individual ages. Mean salivary nitrite was found to increase from well below 1 ppm in infants of up to 6 months to about 7 ppm in adults. a remarkably different situation has been found in areas of high esophageal cancer incidence in Iran: although dietary intake of nitrate and nitrite is very low, nitrite levels in saliva, especially in children of this area tend to be much higher than those in children of western European countries.

Adolescent↗
PubMed1980

Occurrence of volatile nitrosamines in food: a survey of the West German market.

More than 3000 food samples from the West German market have been analysed for volatile nitrosamines. N-nitrosopyrrolidine (NPYR) and N-nitrosopiperidine (NPIP) in concentrations above 0.5 micrograms/kg were found in only 3 and 2% of the samples, respectively. N-Nitrosodimethylamine (NDMA) was detectable in 30% of the samples and 6% of them were found to contain more than 5 micrograms/kg. Consumption data given in the "Nutritional Report, 1976" allow calculation of the average daily intake of volatile nitrosamines from food. Intakes for West German males are 1.1 micrograms/day for NDMA and 0.1 micrograms/day for NPYR. With regard to NDMA, the relative contributions are 64% for beer, 10% for meat and meat products and 25% for all other foods (150 types). NDMA in beer originates in the malt, where it is formed during kilning (drying). Technological improvements to eliminate NDMA contamination of beer are reported.

Beer↗
PubMed1979

Carcinogenic N-nitrosodimethylamine as a contamination in drugs containing 4-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (amidopyrine, aminophenazone).

A total of 68 commercially available drugs containing amidopyrine were investigated for contamination with the strong carcinogen N-nitrosodimethylamine (NDMA). All samples contained varying amounts of NDMA. About half of the drugs contained 1--10 micrograms/kg, 40% contained 11--50 micrograms/kg, 7% contained 51--10 micrograms/kg and one sample had 370 micrograms/kg. NDMA-contents in batches of pure amidopyrine that had been utilized for preparation of drugs were higher than those in the respective drugs: about one-third was in the range of 20--50 micrograms/kg, one-third had 51--100 micrograms/kg, and one-third was above 100 micrograms/kg. There was, however, no correlation between NDMA-contents of batches of the pure substance and NDMA-contents of the drugs prepared from these batched. NDMA concentrations in the samples were inhomogenously distributed. It could be demonstrated that amidopyrine in substance reacts extremely rapidly with nitrogen oxides from the air to form NDMA. Ascorbic acid, which prevents nitrosamine formation in aqueous-acidic solution, under these conditions had no protective effect.

Aminopyrine↗
PubMed1978

Urinary excretion of N-nitrosodiethanolamine administered orally to rats.

N-Nitrosodiethanolamine (NDE1A) was administered by gavage to male rats in single doses of 1000, 500 and 100 mg/kg body wt. More than 70% of a given dose was excreted unchanged in the urine, essentially within the first 24 h after exposure. This high excretion rate might explain the relatively low carcinogenic potential of NDE1A, and also offers a possible method of monitoring exposure to this compound under occupational and/or environmental conditions.

Administration, Oral↗
PubMed1978

Volatile and non-volatile N-nitroso compounds in foods and other environmental media.

A further series of cured meat products (meat loaf, liver loaf, bologna) has been investigated for their nitrosamine contents before and after frying. Contents in general were in the low microgram/kg range. An extensive study of nitrosamine contents of various types of cheese has been terminated. Although 45% of all samples showed indications of nitrosamine content, only 12% had concentrations of greater than 1 microgram/kg (1-6 microgram/kg); NDMA was more often found in hard and in soft cheese, than in other types. Analytical grade dichloromethane and chloroform have been found to contain N-nitrosomorpholine in concentrations of 2-376 microgram/kg (27-40% of the samples). The origin of the contamination is not known at present. A survey of the nitrosamine content of animal diets showed that 80% of all samples had contents of greater than 1 microgram/kg. NDMA (up to 79 microgram/kg) and NPYR (up to 26 microgram/kg) were most often found. There are indications that fish meal is the main source of contamination. Drugs containing amidopyrine (AP) have invariably been found to contain NDMA. Concentrations varied within wide limits (less than 10 microgram/kg - 371 microgram/kg). No correlation has been found between samples of pure AP and NDMA contents of drugs in which pure AP had been incorporated. Also, strong variations in NDMA contents have been found within individual batches, probably caused by the high reactivity of AP towards nitrogen oxides. The determination of N-nitroso-3-hydroxypyrrolidine has been further improved and a further series of food analyses for contents of this nitrosamine has been carried out. About 30% of the samples were positive with contents below or near 10 microgram/kg. An analytical method for determination of N-nitrosamino acids has been worked out. The method consists of a series of extraction, liquid/liquid distribution and chromatography steps; N-nitrosoamino acids are finally determined, after trimethylsilylation, with a TEA detector. First results on the occurrence of these compounds in various cured meat products are reported.

Animal Feed↗
PubMed1977

Occurrence of volatile N-nitrosamines in animal diets.

46 samples of commercially available diets for experimental animals have been analysed for their content of volatile N-nitrosamines by use of a nitrosamine-specific detection method (TEA-detector). 80% of all analysed samples were positive for N-nitrosodimethylamine with a maximum content of 79 ppb (microgram/kg) found in one sample. 59% of the samples were positive for N-nitrosopyrrolidine with 26 ppb as highest content. In 3 samples trace quantities (less than 1 ppb) of N-nitrosodiethylamine were found, one sample contained N-nitrosopiperidine (4 ppb).

Animal Feed↗
PubMed1977

Determination of verapamil in human plasma by mass fragmentography using stable isotope-labelled verapamil as internal standard.

In the present investigation a mass fragmentographic procedure for the quantitative determination of verapamil in human plasma was developed which makes use of the principle of mass spectrometry and of isotopic dilution: a known amount of isotopically labelled standard ([13C, 2H2]-verapamil) is added to the plasma sample. After an effective extraction procedure the ratio of the main fragments of verapamil (m/e 303) and the labelled standard (m/e 306) is measured by mass fragmentography. The lower limit of detection is at 1 ng/ml for plasma and at 10 pg/injection for pure verapamil. The precision was found to be between 3.4% and 14.4%, depending on the range (32.7 ng/ml and 2.2 ng/ml, resp.) of the concentration of verapamil in plasma.

Chemical Phenomena↗
PubMed1977

[Effect of spirolactones on the urinary excretion of individual 17-oxosteroids and of pregnanediol in man (author's transl)].

The effect of spirolactones on the urinary excretion of individual 17-oxosteroids and of pregnanediol in man was investigated under various conditions. After purification by thin-layer chromatography, the 17-oxosteroids and pregnanediol were determined by gas chromatography. Eleven male subjects (age 21-34 years) received a daily dose of 200 mg spironolactone (Aldactone) orally on seven consecutive days. Five female subjects (age 20-35 years) and ten pregnant women (age 20-35 years; 28th.-39th. week of gestation) were given a daily intravenous injection of 600 mg potassium canrenoate (Aldactone pro injectione) on three consecutive days. In the male subjects, the excretion of individual 17-oxosteroids and of pregnanediol was significantly reduced during administration of spironolactone. In the nonpregnant female subjects, the excretion of etiocholanolone and dehydroepiandrosterone was diminished, whereas in the pregnant women, the excretion of pregnanediol and dehydroepiandrosterone was decreased during treatment with potassium canrenoate. These results suggest that the reduced urinary excretion of steroids may be due to an inhibition of steroid metabolising enzymes by spirolactones. It seems likely that spirolactones affect the enzymatic conversion fo cholesterol to pregnenolone.

17-Ketosteroids↗
PubMed1976

Physiological disposition of verapamil in man.

14C-D,L-verapamil was administered intravenously (10 mg) and orally (80 mg) to five volunteer patients. Plasma concentrations of verapamil, which were determined by mass fragmentography, declined bi-exponentially with half-lives of the chi-phase ranging from 18 to 35 min and of the beta-phase from 170 to 440 min. The apparent volume of distribution ranged from 270 to 460 litre and plasma clearance from 730 to 1980 ml/min. Following oral administration absorption was almost complete as judged from the area under the curve (AUC) of 14C-activity and cumulative urinary excretion of 14C. After intravenous infusion of verapamil about 80% of the radioactivity administered could be recovered in urine and faeces within 5 d. Despite its almost complete absorption after oral administration verapamil was shown to undergo extensive first pass metabolism as the bioavailability was only 10 to 22%. Rapid biotransformation had occurred as only a small percentage of AUC of 14C was seen to correspond to unchanged verapamil after both intravenous and oral administration.

Administration, Oral↗
PubMedDate not supplied

Caffeine-derived N-nitroso compounds. II. Synthesis and characterization of nitrosation products from caffeidine and caffeidine acid.

Caffeine on alkaline hydrolysis produces caffeidine [1-methyl-4-(methylamino)-5-(N-methylcarbamoyl)imidazole] and caffeidine acid [N-[4-(5-carboxy-1-methylimidazolyl)]-N,N'-dimethylurea]. We now report the synthesis and chemical characterization of mononitrosocaffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methylcarbamoyl)i midazole], dinitroso-caffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methyl-N-nitrosocarb amo yl) imidazole], and mononitrosamidocaffeidine [1-methyl-4-(methylamino)-5-(N-methyl-N-nitrosocarbamoyl)-Imidazole] based on spectral analysis. The characterization of nitrosated byproducts obtained during the synthesis of these compounds is also presented. Caffeidine is shown to undergo rapid nitrosation in acidic medium to form mononitrosocaffeidine (MNC), an asymmetric N-nitrosamine, and dinitrosocaffeidine (DNC), a N-nitrosamide. Although the reaction proceeds with preferential nitrosation of the amino group in caffeidine, the results also support partial involvement of a mononitrosamide intermediate in the formation of MNC and DNC through transnitrosation of the amino group. The stability data suggest that the nitroso group at the amino nitrogen in DNC influences the reactivity of amide nitroso group. The presence of a trisubstituted ureide moiety in caffeidine acid has been confirmed by NMR nuclear Overhauser effect experiments. Nitrosation of caffeidine acid under acidic conditions produced N,N'-dimethylparabanic acid (DMPA, N,N'-dimethylimidazolidinetrione) as a major product with low amounts of mononitrosocaffeidine and N,N'-dimethyl-N-nitrosourea, whereas nitrosation with NOBF4/pyridine in aprotic medium gave rise to an anhydride, 1,4-dimethyl-4,5-dihydro-5,7-dioxo-1H,7H-imidazo[4,5-d][1,3]oxazine. The nitrosation of methyl ester of caffeidine acid resulted in the formation of a N-nitrosourea derivative, N-[4-(5-carboxy-1-methylimidazolyl)]-N'-nitroso-N,N'-dimethylurea. (ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine↗
PubMedDate not supplied

The nitrosation of hexetidine and hexedine: characterization of the major nitrosamine from common antimicrobial agents.

The acidic nitrosation of hexetidine and hexedine, common antimicrobial agents and drug constituents, leads to a mixture of nitrosamines. The major nitrosamine product, "HEXNO", forms rapidly in yields as high as 60% over the pH range 1-4.8 at incubation times of 1 h at 37 degrees C with 40 mM NO2- and 10 mM hexetidine. On the basis of extensive spectroscopic characterization and independent synthesis HEXNO has been assigned the structure of 1-(2-ethylhexyl)-3-nitroso-4-methyl-4-[[N-(2-ethylhexyl)-N- nitrosoamino]methyl]imidazolidine (7). The synthesis of HEXNO involves the novel interception by potassium nitrite in ether/18-crown-6 of an imminium ion produced from the reaction of hexedine with benzyl chloroformate. Collapse of the alpha-amino nitrous ester produced by this reaction yields the nitrosamine containing carbamate 8, which yields HEXNO after removal of the carbamate with trimethylsilyl iodide and subsequent nitrosation. The rapid formation of HEXNO from hexetidine and hexedine supports the hypothesis that tertiary geminal diamines will produce nitrosamines rapidly by a mechanism which involves the cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom. This process is deemed to be of possible importance in the endogenous production of potentially carcinogenic nitrosamines because of its low nitrite requirement and high nitrosation rate. The available data suggest the probable formation of HEXNO and other nitrosamines from hexetidine under conditions of its use.

Chromatography, High Pressure Liquid↗