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The acute toxicity of tris(dimethylamino)silane.

The acute handling hazards of tris(dimethylamino)silane [TDMAS] were investigated. The acute male rat peroral LD50 (with 95% confidence limits) was 0.71 (0.51-0.97) ml/kg, and the acute male rabbit percutaneous LD50 was 0.57 (0.35-0.92) ml/kg. The liquid was severely irritating to the rabbit eye and skin, and the vapor severely irritating to the rat eye. The dynamically generated saturated vapor Lt50 in female rats was 12 (9.7-15) min. The effect of varying the atmospheric concentration of vapor from TDMAS on acute inhalation toxicity was investigated by passing ordinary moist air countercurrent to liquid TDMAS metered into a slightly heated glass tube. Based on nominal concentrations, the 4 hr-LC50 for vapor from TDMAS was 734 (603-893) ppm in female rats by this procedure. Stoichiometrically, this accords with toxicity due to liberation of dimethylamine (DMA) from TDMAS. In a subsequent study designed to assess the influence of relative humidity on vapor toxicity, nitrogen was passed over heated liquid TDMAS and the resultant atmosphere was introduced into the air intake duct of the inhalation exposure chamber. Gas chromatographically measured TDMAS concentrations (+/- SD) were 395 +/- 111, 127 +/- 25, 62 +/- 8 and 23 +/- 21 ppm; the corresponding DMA vapor concentrations were 112 +/- 171, 31 +/- 43, 10 +/- 6 and 26 +/- 44 ppm. The 4-hr LC50 (males and females) was 38 (34-43) ppm TDMAS vapor. Thus, TDMAS is of moderate acute peroral and percutaneous toxicity, a severe primary skin and eye irritant, an aspiration hazard, and of high intrinsic acute inhalation toxicity, but in moist air conditions lethal toxicity may be reduced and in such circumstances DMA may be a significant factor in toxicity.

Administration, Inhalation↗

O6-alkylguanines, dietary N-nitroso compounds, and their precursors in gastric cancer.

Several N-nitroso compounds, present in foods and beverages or formed in the stomach from their precursors, act as alkylating agents. By using a highly reliable technique (high-resolution gas chromatography-mass spectrometry with negative-ion chemical ionization and selected ion recording), we measured a series of specific O6-alkylguanines in snap-frozen paired stomach tissue samples (tumor and noninvolved mucosa) obtained at surgery from 24 gastric cancer patients identified in Florence, Italy. Samples of noninvolved mucosa had higher levels of total O6-alkylguanines and more frequently detectable levels (54%) than tumor samples (29.2%). O6-propylguanine and O6-methylguanine were the single adducts most frequently detected in noninvolved mucosa and tumor tissue, respectively. Tumor samples showed higher levels of total O6-alkylguanines in female patients (p = 0.03) and among those with a diffuse histological type (p = 0.06) or seronegative for Helicobacter pylori CagA antibodies (p = 0.06). Mean dietary nitrate intake was significantly higher in patients with detectable levels of adducts in tumor samples (p = 0.03). Estimated intakes of dimethylamine and N-nitrosodimethylamine correlated with total levels of O6-alkylguanines in noninvolved gastric mucosa. These findings, although based on a small series of cases, support a role for N-nitroso compounds from dietary sources in the etiology of gastric cancer.

Aged↗

Trimetazidine reduces renal dysfunction by limiting the cold ischemia/reperfusion injury in autotransplanted pig kidneys.

Ischemia/reperfusion injury leads to delayed graft function, which is a major problem in kidney transplantation. This study investigated the effects of adding trimetazidine (TMZ) to the perfusate of cold-stored kidneys on the function of reperfused autotransplanted pig kidney. The left kidney was removed and cold-flushed with Euro-Collins (EC), or University of Wisconsin (UW) solutions with or without 10(-6)M TMZ and stored for 48 h at 4 degrees C. The kidneys were then autotransplanted and the contralateral kidneys were removed. Several parameters were analyzed over the 14 d after transplantation. The survival rate was 57% in pigs transplanted with kidneys cold-flushed with UW and 43% for those flushed with EC solution; it was 100% for pigs having kidneys cold-flushed with TMZ-supplemented UW and EC solutions. The functions of the transplanted kidneys were also better preserved after cold flush with TMZ-supplemented solutions than with TMZ-free solutions. Creatinine clearance was higher and the urinary excretion of trimethylamine-N-oxide and dimethylamine, used as markers of renal medulla injury, were lower in animals transplanted with kidneys cold-flushed with TMZ-supplemented solutions than with TMZ-free solutions. The cytoprotective action of TMZ also reduced interstitial and peritubular inflammation and the numbers of infiltrating mononuclear CD45+and CD3+ T cells. These results indicate that the tissue damage due to ischemia/reperfusion injury may be prevented, at least in part, by adding TMZ to preservation solutions.

Animals↗

Thawed cod fillets spoil less rapidly than unfrozen fillets when stored under modified atmosphere at 2 degrees C.

The effect of two months of frozen storage at -20 degrees C on the spoilage characteristics and shelf life of thawed and modified atmosphere packed (MAP) cod fillets stored at 2 degrees C was studied. Thawed MAP cod fillets were compared with fresh cod fillets stored in CO2-containing modified atmospheres with and without added oxygen. The shelf life of 11 to 12 days in the fresh MAP cod was extended to more than 20 days in the thawed MAP cod at 2 degrees C. This shelf life extension was most likely due to the inactivation of the spoilage bacterium Photobacterium phosphoreum during frozen storage as reflected both in chemical analyses and sensory evaluation. In contrast to fresh MAP cod fillets no significant production of trimethylamine occurred and almost no amine odor and taste were detected during 20 days of chill storage of thawed MAP cod fillets. The use of frozen fillets as raw material not only provides a more stable product in MAP but also allows much greater flexibility for production and distribution. However, a slightly increased concentration of dimethylamine, a larger drip loss, and detection of weak frozen storage flavor were observed in the thawed MAP cod fillets.

Amines↗

[Climbing-upward inhibition of Oncomelania hupensis by niclosamide combination].

OBJECTIVE: To develop a combination of molluscicide/insecticide with a good molluscicidal effect, especially an inhibitory effect on climbing-upward of Oncomelania hupensis. METHODS: Experiments on molluscicidal and snail-climbing inhibition effect of the combination of niclosamide and shachongding [(dimethylamine) trithacyclohexane hydrochloride] were conducted by immersion and spraying in laboratory. RESULTS: The combination of niclosamide (0.2 mg/L) and shachongding (0.1 mg/L) showed an inhibition of 92.67% of snails to climb up. There was no significant difference in molluscicidal effect between the combination (LC90 0.198 mg/L) and niclosamide alone (LC90 0.207 mg/L). CONCLUSION: The combination showed an effective inhibition on the climbing-upward of snails in water so as to improve the molluscicidal effect and reduce the cost of mollusciciding.

Animals↗

[Guanidino compounds and aliphatic monoamines in acute and chronic renal failure].

Small molecular weight uremic toxins, guanidino compounds and aliphatic monoamines, were measured in the serum of chronic and acute renal failure (CRF and ARF) patients. A close correlation was noticed between guanidinosuccinic acid (GSA) and serum urea nitrogen (BUN) and also between methylguanidine and serum creatinine (Cr) in nondialyzed and dialyzed CRF patients. The same relation was seen in ARF patients showing rapid change of metabolic conditions, which suggested the tight linkage between guanidino compounds and protein metabolites. On the other hand, dimethylamine (DMA) was related with Cr in CRF patients, however, not in ARF patients. Since the production of DMA from Cr is carried out mainly, but relatively slowly, by bacterias in the intestine, the rapid metabolic change of ARF may not affect DMA synthesis. Furthermore, the DMA synthesis from trimethylamine-N-oxide (TMA-N-O) was studied using liver homogenate. The liver homogenate produced DMA by adding TMA-N-O as substrate. However, the kidney homogenate could synthesize it even without substrate. Therefore, the kidney seems to be a major site of DMA production as well as the intestine.

Acute Kidney Injury↗

Immobilization of aminoacylase from Aspergillus oryzae on synthetic modified polyacrylamides.

A series of acrylamide-bisacrylamide copolymers modified by the Mannich Reaction was prepared. The immobilization of aminoacylase from Aspergillus oryzae on the copolymers was studied. All the polymers adsorbed the enzyme and the activity of the immobilized enzyme dependent on the amine used, viz. secondary amine, diamine, or aniline derivative. However, the activity was also influenced by the degree of crosslinking of the polymer. The surface morphology of the dimethylamine-modified polymer, with varying degrees of crosslinking, was analyzed by scanning electron microscope; the polymers having the largest pore diameter possessed the highest enzyme activity. One of the best polymers (DMA-A9B8) was used for immobilization of aminoacylase and its properties were studied. It had high enzymatic activity and good operational stability, i.e., retaining 90% of its original activity after being used for 42 days. The use of these copolymers for the preparation of immobilized enzymes is discussed.

Acrylic Resins↗

[The effect of N-(1-methyldodecyl)-N,N-dimethylaminoxide on the conformation of hydrocarbon chains in phospholipid bilayers isolated from Escherichia coli].

Using the method of ESR spectroscopy of stearic acid spin probes labeled by the doxyl group on the 12th or 16th carbon, it has been found that bactericidal surfactant N-(1-methyldodecyl)-N,N-dimethylamine oxide increases the effective energy difference between trans- and gauche conformers Eg and decreases the probability of gauche conformers formation pg in lipid hydrocarbon chains in multilamellar liposomes prepared from Escherichia coli-isolated phospholipids, at low surfactant concentrations. Above the surfactant: phospholipid molar ratio of 1:14 to 1:17, the value of Eg decreases and that of pg increases. The results are interpreted using the cluster model of lipid bilayer. At low concentrations the surfactant molecules are inserted into the dynamical defects between the clusters, thereby increasing the packing density of chains in the bilayer. At high concentrations the surfactant molecules penetrate into the clusters perturbing the dense packing of chains in clusters.

Dimethylamines↗

[The action of inhibitors of the amine nitrosation reaction in human gastric juice and in the body of animals].

The effect of ascorbic, ferulic and caffeic acids on dimethylamine and amidopyrine nitrosation in a medium containing 3 samples of total gastric juice taken from 10 humans (pH = 6.1; 3.2 and 1.7) was studied versus the amount of inhibitor added to the medium. The resultant relationship proved bizarre, the inhibitor at low concentrations stimulating nitrosation in some situations. When gastric juice concentration in the medium was further lowered by dilution with a buffer at relevant value of pH, the paradoxical effect of inhibition gradually disappeared.

Aminopyrine↗

Importance of aliphatic amines in uremia.

Five main aspects were addressed: 1)The demonstration that creatinine is an endogenous precursor of dimethylamine (DMA) in chronic renal failure. 2) The size of the body amine pool measured in transplant patients suggests sequestration in some intracellular compartment. This illustrates the possible error in directly relating serum concentrations to neurological toxicity. 3) Bacterial overgrowth and increased generation of duodenal DMA in the small intestine becomes apparent at a serum creatinine above 8 mg/dl. Two cases show that bacterial overgrowth preceded the increased duodenal DMA. 4)Clinical toxicity is demonstrated by i) correlation of abnormal neurobehavioral parameters with serum amine levels, and ii) by improvement with administration of nonabsorbable broad spectrum antibiotics. Results with adsorption agents are inconclusive. 5) Preliminary tests of behavior modification in a rat model by direct instillation of amines into the brain are positive for TMA but negative for DMA, but no DMA entry into brain cells is demonstrated in the latter. The generation of aliphatic amines represents only one part of a spectrum of alteration induced by proximal intestinal bacterial enzyme action that occurs in renal failure. It is possible that some bacterial activity is beneficial and that the net clinical result is a balance between the "good" and the "evil" bacterial effects.

Animals↗

Microbial nitrosamine formation in palm wine: in vitro N-nitrosation by cell suspensions.

The ability of certain species of bacteria and yeasts that usually contaminate fresh palm sap to induce the formation of the carcinogen dimethylnitrosamine from suitable precursors (trimethylamine, dimethylamine, nitrate, and nitrite) was investigated in vitro under neutral and acid pH conditions. In the incubation media containing cell suspensions of each species of test organism, namely, Aerobacter, Micrococcus, Serratia, Saccharomyces, and two unidentified yeasts and the precursors, added in varying concentrations, the presence of dimethylnitrosamine was indicated. The possible role of indwelling microorganisms in the elaboration of the hazardous compound in fermenting palm wine is discussed.

Bacteria↗

[DNA alkylation during endogenous synthesis of N-nitrosodimethylamine].

The simultaneous administration of 14C-dimethylamine and sodium nitrite to rat stomach produces the formation of O6-methylguanine and 7-methylguanine in the liver DNA as a result of the endogenic synthesis of N-nitrosodimethylamine (NDMA). Methylation of DNA was also observed in the rat kidney and lung. Alkylation of O6-position of guanine and removal of its methylated product from the DNA occurred in the liver to a greater extent than in the other NDMA target organs. Pretreatment of rats with sodium nitrite increased the alkylation of liver DNA caused by endogenic synthesis of NDMA. The formation of alkylated products in DNA may be used as a marker for the endogenic formation of NDMA from precursors.

Alkylation↗

Analysis for and intestinal metabolism of precursor nitroso compounds in normal subjects and in patients with chronic renal failure.

We have demonstrated that patients with chronic renal failure generate increased amounts of both dimethylamine and N-nitrosodimethylamine in the small bowel in association with aerobic and anaerobic bacterial overgrowth. The significance of these findings in relation to the reported increased incidence of cancer in patients with chronic renal failure has not yet been defined.

Chromatography, Gas↗

In-vivo nitrosation of amines in mice by inhaled nitrogen dioxide and inhibition of biosynthesis of N-nitrosamines.

Inhalation of nitrogen dioxide (NO2) by mice administered orally morpholine (MOR) or dimethylamine (DMA) resulted in the biosynthesis of N-nitrosomorpholine (NMOR) or N-nitrosodimethylamine (NDMA), respectively, as determined by the analysis of frozen whole-mouse powder, using gas chromatography with a Thermal Energy Analyzer detector. Significant levels of NMOR were detected following exposure of mice to 0.38 mg/m3 NO2 for 0.5 h (26 ng NMOR/mouse) and there was a two-fold increase when NO2 exposure was extended to 4 h. NMOR levels also increased in a time-dependent manner at 28.4 and 47.3 mg/m3 NO2 exposure levels, reaching a maximum of 450 and 725 ng NMOR/mouse, respectively, at 4 h. Oral administration of sodium ascorbate (50-250 mg), ammonium sulfamate (50-100 mg) or DL-alpha-tocopherol (67-167 mg) immediately after MOR or DMA, but prior to NO2 exposure, significantly inhibited both NMOR and NDMA biosynthesis, sulfamate being the most effective (greater than 90% NMOR and NDMA inhibition), followed by ascorbate (83-90% NMOR and 58-90% NDMA inhibition) and alpha-tocopherol (22-42% NMOR and 46-69% NDMA inhibition). Low levels of NDMA were found in untreated control mice (less than 13 ng/mouse) and in most samples of commercially obtained animal feed (10-15 micrograms/kg); NMOR, however, was not detectable or was detected in negligible amounts in these cases. Various control experiments indicated that most of the recovered nitrosamine resulted from in-vivo nitrosation in mice, with only up to 1-2% of NMOR and approximately 10% of NDMA yields being attributed to artefact formation, possibly during work-up of the mouse-powder samples.

Animals↗

Rapid formation of N-nitrosodimethylamine from gramine, a naturally occurring precursor in barley malt.

The two tertiary amine alkaloids, hordenine and gramine, which are biosynthesized in malt during germination, were subjected to nitrosation under conditions typical for the study of tertiary amine nitrosation. At 65 degrees C in dilute aqueous acid (pH 4.4 or pH 6.4), nitrosation of both amines resulted in formation of N-nitrosodimethylamine (NDMA). At 24 degrees C in dilute acid (pH 3.4), the initial rate of NDMA formation from gramine was nearly equal to the initial rate of NDMA formation from dimethylamine. At the same temperature, the ratio of initial rates of formation of NDMA from gramine and trimethylamine was 6250:1. At 23 degrees C, the ratio of initial rates of formation of NDMA from gramine and hordenine was 5200:1. The rapid reaction of gramine with nitrous acid and the nature of the gramine nitrosation reaction products both indicated that gramine did not undergo nitrosation by the expected mechanism of nitrosative dealkylation. A new mechanism if proposed to explain the labile nature of the dimethylamino group of gramine and to account for the fact that NDMA is the only N-nitrosamine formed during the nitrosation of gramine.

Alkaloids↗

[The effect of alcohol on DMNA synthesis from its precursors in vivo and in vitro].

The study was concerned with a comparison of the effects of ethanol on N-nitrosodimethylamine (NDMA) synthesis from amidopyrine and sodium nitrite in rat stomach and on the same synthesis from dimethylamine (DMA) and sodium nitrite involving a 30-min incubation of their mixture at 37 degrees C in acid medium. Alcohol was found to inhibit DMA nitrosation thus lowering the yield of NDMA both in rat stomach and in a medium containing human gastric juice or glycine-hydrochloride buffer (pH = 3.4).

Animals↗

Formation of methylamines from ingested choline and lecithin.

Humans ingest substantial amounts of choline and lecithin as part of common foods. Physicians have recently begun administering large doses of these compounds to individuals with neurological diseases. A significant fraction of ingested choline is destroyed by enzymes within gut bacteria, forming trimethylamine (TMA), dimethylamine (DMA) and monomethylamine (MMA). Some of these methylamines are eventually excreted into the urine, presumably after being absorbed and carried to the kidneys via the bloodstream. The methylamines formed after choline is eaten could be substrates for the formation of nitrosamines, which have marked carcinogenic activity. Twenty-seven millimoles of choline chloride, choline stearate or lecithin were administered to healthy human subjects. It was found that these treatments markedly increased the urinary excretion of TMA, DMA and MMA, with choline chloride having the greatest effect. Rats were treated with 2 mmol/kg b.wt. of choline chloride or lecithin, and it was found that these treatments significantly increased urinary TMA excretion and did not alter DMA or MMA excretion. Our choline chloride preparation contained no MMA, DMA or TMA; however, it was found that our choline stearate and all the commercially available lecithins tested were contaminated with methylamines. Prior removal of methylamines from our lecithin preparation minimized the effect of oral administration of this compound on methylamine excretion in urine of rats and humans.

Administration, Oral↗

Gas chromatographic determination of primary and secondary amines as pentafluorobenzamide derivatives.

An analytical method is described for the determination of mono- and dialkylamines in foodstuffs. Amines are derivatized to their pentafluorobenzamides which may be separated by gas chromatography (GC) and determined using an N-P detector. Analysis of the derivatives by GC-mass spectrometry indicated they were all mono-substituted. The amines were isolated from foodstuffs by alkaline distillation of greater than or equal to 75% sample volume. The distribution of dimethylamine (DMA) in distillate volumes indicated 2 maxima from barley and malt, which could represent 2 or more sources of DMA. DMA concentrations of 6.6-8.8 ppm in barley, 11 ppm in malt, and 1.2 ppm in beer are higher than previously reported.

Amines↗