[Etiology of stomach carcinoma--opinions and facts--yesterday and today]. / Atiologie des Magenkarzinoms--Meinungen und Fakten--Gestern und Heute.

Recent research demonstrated that views on the etiology of gastric cancer, which had been considered true over decades do not correspond with the real situation. Therefore, efforts for primary prevention of gastric cancer could not be successful. The bacteria Helicobacter pylori is considered today to be an important but not the only etiologic factor of this disease. Eradication of this bacteria decreases the risk of gastric cancer.

N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori.

Micro-organisms commonly present in human saliva and three DSM strains (Helicobacter pylori, Campylobacter jejuni and Neisseria cinerea), which can be isolated from the human gastro-intestinal tract, were assayed in vitro for their capacity to catalyse N-nitrosation of a series of medicinal drugs and other compounds. Following incubation at pH 7.2 in the presence of nitrate (or nitrite) for up to 24 (48) h, the yield of N-nitroso compounds (NOC) was quantified by HPLC equipped with a post-column derivatization device, allowing the sensitive detection of acid-labile and acid-stable NOC. Eleven out of the 23 test compounds underwent bacteria-catalysed nitrosation by salivary bacteria, the yield of the respective nitrosation products varying 800-fold. 4-(Methylamino)antipyrine exhibited the highest rate of nitrosation, followed by dichlofenac > metamizole > piperazine > five other drugs, whilst L-proline and L-thioproline had the lowest nitrosation rate. Ten drugs including aminophenazone, cimetidine and nicotine, did not inhibit bacterial growth, allowing transitory nitrite to be formed, but no N-nitroso derivatives were detected. Three drugs inhibited the proliferation of bacteria and neither nitrite nor any NOC were formed. Using metamizole as an easily nitrosatable precursor, two strains, Campylobacter jejuni and Helicobacter pylori, were shown to catalyse nitrosation in the presence of nitrite at pH 7.2. As compared to Neisseria cinerea used as a nitrosation-proficient control strain, H. pylori was 30-100 times less effective, whilst C. jejuni had intermediary activity. The results of our sensitive nitrosation assay further confirm that bacteria isolated from human sources, possessing nitrate reductase and/or nitrosating enzymes such as cytochrome cd1-nitrite reductase (Calmels et al., Carcinogenesis, 17, 533-536, 1996), can contribute to intragastric nitrosamine formation in the anacidic stomach when nitrosatable precursors from exogenous and endogenous sources are present.

[In vivo nitrosation of methimazole in humans]. / In vivo Nitrosierung von Metamizol beim Menschen.

Monitoring the excretion of the non-carcinogenic nitroso-methylaminoantipyrine (NMAA) after peroral applications of the analgesic drug metamizole is a useful procedure for evaluating endogenous nitrosation, also in man. The outstanding nitrosatibility of this drug led to high amounts of excreted NMAA, easily detected without derivatisation by HPLC. By nitrate ingestion considered as normal dietary intake the nitrosation is scarcely modified by ascorbic acid, sodium-bicarbonate or sodium-bicarbonate plus metronidazole. These results are an other indication of a third, cell-mediated path of endogeneous nitrosation in man.

Occurrence of the nitrosamide precursor pyrrolidin-(2)-one in food and tobacco.

Pyrrolidinone was identified in food and tobacco samples by gas chromatography combined with NO-specific chemiluminescence detection (TEA). Up to 77 mg/kg pyrrolidinone were detected in cocoa powders, coffee, coffee surrogates, dried vegetables and tobacco leaves. When treated with excess nitrite under acidic conditions, N-nitrosopyrrolidinone was formed in concentrations up to 44 mg/kg. The nitrosation characteristics of pyrrolidinone indicate its possible conversion to nitrosopyrrolidinone under conditions of the gastric tract.

Quality of life of adults with chronic illness: a psychometric study.

Reliability and validity of the Flanagan Quality of Life Scale (QOLS) were tested in four chronic illness groups. Open-ended questions and four instruments, the QOLS, Duke-UNC Health Profile (DUHP), Life Satisfaction Index (LSI-Z), and either the Arthritis Impact Measurement Scales (AIMS) or the Ostomy Adjustment Scale (OAS) were administered by telephone interview and mailed questionnaires to 227 adults three times over 6 weeks. Subjects generated verbal responses that substantiated the content validity of the QOLS. Stability reliability estimates for all instruments ranged from .53 to .90. Cronbach's alpha coefficients averaged .87 for the QOLS. Appropriate validity coefficients indicated both convergent and discriminant construct validity.

[Microbial mutagenicity testing of N-nitrosoiminostilbene and N-nitrosoiminodibenzyl, the nitrosation products of the drugs carbamazepine and trimipramine hydrochloride]. / Mikrobielle Mutagenitätstestungen von N-Nitroso-iminostilben und N-Nitroso-iminodibenzyl, den Nitrosierungsprodukten der Arzneimittelwirkstoffe Carbamazepin und Trimipraminhydrochlorid.

The active agents of the drugs Finlepsin and Herphonal, carbamazepine and trimipramine, were nitrosated under simulated human gastric conditions. For both formed N-nitroso compounds, N-nitroso iminostilbene (N-nitroso-5H-dibenz(b,f)azepine) and N-nitroso iminodibenzyl (N-nitroso-10,11-dihydro-5H-dibenz(b,f)azepine), tests for mutagenic potency in the Ames-test gave negative results.

[Effect of various forms of diet on the nitrosation of sodium metamizole (analgin tablets) under simulated conditions of the human stomach]. / Einfluss unterschiedlicher Diätformen auf die Nitrosierung von Metamizol-Natrium (Analgin-Tabletten) unter simulierten Bedingungen des menschlichen Magens.

The influence of a simple and a more complex diet on the formation of nitrosometamizole from sodium metamizole (analgin tablets) under simulated human gastric conditions was estimated with extremely different nitrite concentrations. Only with the complex diet and only with low nitrite concentrations, the formation of nitrosometamizole was distinctly lowered. The quantitative estimation of the formed amounts was done by a colorimetric method after extraction with dichloromethane.

[Drugs from the classes of tricyclic antidepressives and antiepileptics, nitrosatable under simulated human gastric conditions]. / Unter simulierten Bedingungen des menschlichen Magens nitrosierbare Arzneimittel aus den Gruppen der trizyklischen Antidepressiva und Antiepileptika.

The nitrosatability of Pryleugan (imipramine), Herphonal (trimipramine), and Finlepsin (carbamazepine) was investigated under simulated human gastric conditions using a colorimetric measuring method. All of them proved to be nitrosatable even at very low nitrite concentrations. In the presence of ascorbic acid, the formation of N-nitroso compounds under model conditions was inhibited markedly. N-nitroso-dihydrodibenzazepine and N-nitroso-dibenzazepine could be identified by thin layer chromatography as main products. The biological effects of these N-nitroso compounds are not known up to now.

Nitrate as a precursor of the in-vivo formation of N-nitrosomorpholine in the stomach of guinea-pigs.

Reduction of nitrates to nitrites and formation of the carcinogen N-nitrosomorpholine (NMOR) was investigated in the stomach of guinea-pigs. A semisynthetic diet with nitrate plus morpholine was administered intragastrically after a 24-h fast; after treatment, the animals were killed and stomach nitrite contents were determined 6, 12, 18, 24 and 30 min after the treatment using a colorimetric method. NMOR content was determined 18 min after treatment with nitrate plus morpholine using gas chromatography-thermal energy analysis. Reduction of nitrates to nitrites in the stomach was observed that was sufficient to synthesize NMOR in guinea-pigs under the conditions of this experiment.

[Effect of nontoxic inhibitors on the nitrosation of drugs under conditions simulating the human stomach]. / Wirkungen einiger nicht-toxischer Inhibitoren auf die Nitrosierung von Arzneimitteln unter simulierten Bedingungen des menschlichen Magens.

The influence of sulphamic acid, sulfanilamide, p-aminosalicylic acid and ascorbic acid on the nitrosation behaviour of Analgin (active agent: noramidopyrinmethane sulfonate) was investigated in the pH range between 1.2 and 6.0 under simulated conditions of the human stomach. Using a colorimetric measuring method, the three last-mentioned compounds proved suitable as nitrosation inhibitors; preference should be given to ascorbic acid because of its better inhibitory capacity in the very weakly acidic pH range. Sulphamic acid is inadequate because it stimulates nitrosation in this pH range. The distinct inhibitory action of ascorbic acid was verified under simulated conditions of the human stomach in further 9 drugs undergoing nitrosation at different rates, which contain the active agents: aminophenazone, clomipramine, imipramine, desipramine, ampicilline, oxacilline, phenoxymethylpenicilline, ethambutole or piperazine. Despite the use of high doses of ascorbic acid, no complete inhibition of nitrosation could be achieved in the majority of drugs investigated.

[Formation of volatile carcinogenic N-nitroso compounds from drugs under simulated human gastric conditions]. / Bildung flüchtiger kanzerogener N-Nitrosoverbindungen aus Arzneimitteln unter simulierten Bedingungen des menschlichen Magens.

41 commercial drugs approved for peroral application in the GDR, whose active agents contain N,N-dialkylamino groups in their chemical structures, have been investigated under simulated conditions of the human stomach. With the drugs containing aminophenazone, amitriptyline, doxycycline and oxytetracycline as active agents N-nitrosodimethylamine is formed as a result of nitrosation reactions. With the drugs containing clomiphene++, disulfiram, probenecid and a diethylamine-containing liquid hypnoticum, there occurred N-nitrosodiethylamine. In no case N-nitrosodi-n-propylamine or N-nitrosopiperidine were detectable. The isolated active agents amitriptyline, clomiphene++ and probenecid themselves proved not to be nitrosatable. The positive findings with these drugs were caused by not yet identified nitrosatable contaminants of these drugs. The quantitative determination of volatile N-nitroso compounds was done upon steam distillation by means of gas chromatograph and chemiluminescence detector.

[Etiology of colon cancer--current aspects]. / Atiologie des Kolonkarzinoms--Einige aktuelle Aspekte.

Multiple factors such as tumour initiating, tumour promoting, tumour inhibiting are known to be involved in the aetiological process of most colon tumours. Dominant factors are associated with life style habits. Yet in spite of many experimental and epidemiological data it has not been possible, hitherto to give convincing recommendations for the primary prevention of this type of tumours.

[Comparative studies of the nitrosation behavior of drugs by constant pH value and under simulated stomach conditions]. / Vergleichende Untersuchungen des Nitrosierungsverhaltens von Arzneimitteln bei konstantem pH-Wert und unter simulierten Magenbedingungen.

The nitrosation behaviour of 60 orally administered drugs used in the GDR have been investigated. Only those pharmaceuticals were selected whose active agents are assessed as being nitrosatable by their chemical structures. Amounts of active components and nitrite, dissolved in the gastric juice, did not exceed the concentrations permissible for human stomachs in vivo. After one-hour incubation at pH 2.0 and 37 degrees C ten drugs (Aminophenazone, Ampicilline, Clomipramine, Desipramine, Ethambutole, Imipramine, Noramidopyrinmethansulfonate, Oxacilline, Phenoxymethylpenicilline, Piperazine) proved to be nitrosatable using a colorimetric measuring method. Two of the N-nitroso compounds have been identified as known carcinogens. Structure analysis of the remaining ones is not yet finished. Results still more conforming to in vivo conditions have been obtained for all ten nitrosatable drugs by means of a model system simulating the conditions of the human stomach. The pH changes attending the shifts of pH occurring in the course of the digestive process have a distinct effect on the nitrosation reactions. It is only on such measurements of drug nitrosation that decisions on oral application, calculation of the burdening of the organism by N-nitroso compounds, or estimation of risk should be based.

[Nitrosatable drugs (author's transl)]. / Nitrosierbare Arzneimittel.

Out of 61 drugs, considered to be potentially nitrosatable on the basis of their chemical structure and being used for oral administration in the GDR, ten (Aminophenazone, Ampicilline, Clomipramine, Desipramine, Ethambutole, Imipramine, Noramidopyrinemethansulfonate, Oxacilline, Phenoxymethylpenicilline, Piperazine) have been nitrosated in vitro under simulated conditions of the human stomach. Each compound demonstrated an individual nitrosation behaviour. Only two of the N-nitrosocompounds formed could be identified as well known carcinogens. The chemical structure of the others are unknown yet. Using ascorbic acid as inhibitor, an inhibition of nitrosation could be reached in all cases, but even with high amounts the inhibition was not complete. In order to exclude or, least to diminish a possible carcinogenic risk of endogenically formed N-nitrosocompounds from drugs to humans, drugs orally administered and forming carcinogenic N-nitrosocompounds should be replaced by non-nitrosatable ones. Formulations of all other nitrosatable drugs should contain sufficient amounts of ascorbic acid, provided, that the pharmacological quality of the drug is not deteriorated to any greater extent.

Testing of drugs for combined mutagenesis with sodium nitrite in the host-mediated assay.

Mutagenic activity of the drugs analgine and aminophenazone was tested in the intraperitoneal and intrasanguine host-mediated assay after oral application together with equimolar doses of sodium nitrite. Salmonella typhimurium strain G46 was used as genetic indicator system; mice served as host animals for the bacteria. Analgine was found to be weakly mutagenic in the dose 2 mM/kg together with nitrite, aminophenazone was a strong mutagen in combination with nitrite in the doses 2 mM/kg and 0.2 mM/kg using the intrasanguine test with 1 h incubation of bacteria in the liver. In the intraperitoneal variant with 3 h incubation time of bacteria only aminophenazone was slightly mutagenic at the highest dose tested, 2 mM/kg. The relative nitrosation rate for aminophenazone was calculated by means of regression lines for mutagenic activity of dimethylnitrosamine and was found to be in the range of 2% in both systems for a dose of 2 mM/kg precursors.

Nitrosation of orally administered drugs under simulated stomach conditions.

Of a total of 61 drugs considered to be potentially nitrosatable on the basis of their chemical structure, 7 have indeed been nitrosated in gastric juice at pH 2 and under simulated human stomach conditions, where the pH was varied from about 7 to 2 within 60 min. The 7 nitrosatable drugs were ethambutole, despiramine hydrochloride, clomipramine hydrochloride, phenoxymethyl penicillin, aminophenazone, piperazine diadipate and analgine. Inhibition of nitrosation under simulated stomach conditions was also investigated using ascorbic acid, sulfanilamide, p-aminosalicylic acid and sulfamic acid. The first three agents were effective inhibitors, whereas sulfamic acid stimulated nitrosation within a distinct pH range.