Effects of nozzle types and 2,4-D formulations on spray deposition.

The objective of this study was to evaluate the effects of nozzle types and 2,4-D formulations on spray deposition on different targets. Two field experiments were carried out in a completely randomized design, and treatments were arranged in a factorial scheme. Species in experiment 1 were Sumatran fleabane (Conyza sumatrensis) and Brazil pusley (Richardia brasiliensis) and in experiment 2 were soybeans (Glycine max) and Benghal dayflower (Commelina benghalensis). For both experiments, the first factor corresponded to spray nozzles with different settings (AD 110.015 - 61 and 105 L ha-1; AD 015-D - 75 and 146 L ha-1; XR 110.0202 - 200 L ha-1; and ADIA-D 110.02 - 208 L ha-1) and the second factor consisted of two formulations of 2,4-D (amine and choline). The formulation of 2,4-D choline has contained Colex-D™ Technology. Similar or higher spray deposition was observed on the leaves and artificial targets when using 2,4-D choline as compared to the 2,4-D amine formulation, and these differences in deposition were more evident for nozzles applying lower spray volumes. Deposition was more affected by nozzle type when amine formulation was used, compared to choline formulation.

Metabolism and disposition of [(14)C]dimethylamine borane in male Harlan Sprague Dawley rats following gavage administration, intravenous administration and dermal application.

1. Dimethylamine borane (DMAB) is used as a reducing agent in the manufacturing of a variety of products and in chemical synthesis. National Toxicology Program is evaluating the toxicity of DMAB in rodents following dermal application. The objective of this study was to evaluate the metabolism and disposition of DMAB in male Harlan Sprague Dawley (HSD) rats. 2. Disposition of radioactivity was similar between gavage and intravenous administration of 1.5 mg/kg [(14)C] DMAB, with nearly 84%-89% of the administered radioactivity recovered in urine 24 h post dosing. At 72 h, only 1% or less was recovered in feces, 0.3% as CO2, and 0.5%-1.4% as volatiles and 0.3%-0.4 % in tissues. 3. The absorption of [(14)C]DMAB following dermal application was moderate; percent dose absorbed increased with the dose, with 23%, 32% and 46% of dose absorbed at 0.15, 1.5 and 15 mg/kg, respectively. Urinary and fecal excretion ranged from 18%-37% and 2%-4% of dose, respectively, and 0.1%-0.2% as CO2, and 1%-3% as volatiles. Tissue retention of the radiolabel was low ∼1%, but was higher than following the gavage or intravenous administration. 4. Following co-adminsitration of DMAB and sodium nitrite by gavage, N-nitrosodimethylamine was not detected in blood or urine above the limit of quantitation of the analytical method of 10 ng/mL. 5. Absorption of DMAB in fresh human skin in vitro was ∼41% of the applied dose: the analysis of the receptor fluid shows that the intact DMAB complex can be absorbed through the skin.

Carcinogenicity of dimethylnitramine in NZR rats in NZO mice.

Lifetime tests were done in NZR inbred rats of dimethylnitramine (DMNO) by addition to the drinking water (average dose 1.83 g/kg body weight) and in NZO mice by repeated subcutaneous injection from birth to 7 months of age followed by administration in drinking water (total average dose 4.72 g/kg body weight). Rats developed hepatocellular carcinomas (85%), some of which metastasized. Mice developed hepatocellular carcinomas (81%) and renal adenocarcinomas (48%). Statistically significant increases of other tumor types also occurred in mice. The main targets for DMNO carcinogenesis appeared to be the liver cell epithelium and, at higher dose rates, renal tubular epithelium.

Interactive mutagenicity of sodium nitrite, dimethylamine, methylurea and ethylurea.

Groups of mice were treated per os with sodium nitrite either alone or in combination with nitrosatable amino compounds and tested in the host mediated assay. When mice were treated with sodium nitrite in combination with dimethylamine a small(4-fold) but significant increase in mutant frequency (MF) was observed. Ethylurea or methylurea in combination with sodium nitrite induced 10- or 850-fold increases in MF, respectively. The response to methylurea was dose-dependent with a 6- and 30-fold increase in MF at 5.4 and 11.5 mg/kg NaNO2 and a 6-fold increase at 108 mg/kg methylurea. That this response reflected gastric nitrosation was shown by the disappearance of the response if NaNO2 administration preceded methylurea treatment by 10 min. High MF's were observed if NaNO2 was administered 10 or 20 min after methylurea.

Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase.

A series of nine dimethylamino-chalcone derivatives (1,3-diaryl-propenones) was synthesized and screened as potential inhibitors of NO and PGE(2) production in the RAW 264.7 macrophage cell line. 4-Dimethylamino-2',5'-dimethoxychalcone (6) was found to be the most potent and dual inhibitor (IC(50s) in the submicromolar range) of NO and PGE(2) production. 2',6'-Dimethoxylation appeared to be an effective requirement for selective and potent inhibition of nitric oxide synthase induction as it was confirmed by Western blot analysis. Chalcone (6) at 25 mg kg(-1) by oral route, inhibited significantly the formation of oedema in the carrageenan-induced model of inflammation in mice.

Toxicity and pharmacokinetics of 2-(2-dimethylaminoethoxy)ethanol following cutaneous dosing.

A 9-day repeated cutaneous toxicity study in the New Zealand White rabbit was conducted using 6-h occluded contact with 0 (water control), 50, 250 and 500 mg dimethylaminoethoxyethanol (DMEE)/kg. There were no clinical signs, and no effects on body weight, food consumption or serum chemistry. Hematological effects were limted to increased leukocyte count due to heterophil leukocytosis, increased platelet count, and decreased hemoglobin and hematocrit at the high dose. These findings are typical of the response of cutaneous inflammation. Histopathological findings were limited to the DMEE-treated skin, and consisted of acanthosis and ulcerative/necrotizing dermatitis. Thus, there was no evidence for cumulative percutaneous systemic toxicity for DMEE. The pharmacokinetics of DMEE was investigated in the Fischer 344 rats. Rats were given an intravenous dose of 15 or 150 mg/kg, or an occluded cutaneous dose of 150 mg/kg [14C]DMEE, and its fate was followed for 48-72 h. DMEE was readily absorbed through the skin (bioavailability=72-80%). Concentration in plasma rose steadily to a maximum at about 3.5 h after dosing, and then declined in a biphasic manner. 14C-DMEE-derived radioactivity was distributed throughout the body, with no apparent sequestration in any particular organ. The highest concentrations were observed in the kidney, liver and lung, and the lowest concentrations were found in the brain and fat. Urine was the major route of excretion, with minor amounts eliminated in the feces and as expired CO(2). The rate of excretion was moderate, with about 30% of the applied dose eliminated in the first 12 h, and by 72 h after dosing, less than 4% of the dose remained in the carcass. Unchanged DMEE was the principal component detected in the urine. This observation, together with the less than 1% of the dose excreted as CO(2), showed that metabolism was not an important process in the elimination of DMEE in the rat.

Effects of repeated oral doses of Dikamin D (2,4-D-amine Na) on rats.

The toxic effects of repeated, increasing oral doses of Dikamin D (72% 2,4-D-amine Na), a broad leave herbicide product used world-wide, were evaluated on rats by the method of Lim et al. (1961). A comparison of the determined acute oral LD50 and the calculated subchronic oral LD50 values revealed a definite tolerance of the experimental animals to the test compound. This finding indicates that repeated oral treatment is capable of increasing the test animal's metabolizing capacity, which accounts for the development of tolerance.

[Effect of n-nitrosodimethylamine (NDMA) on activity of selected enzymes in blood serum of the rat]. / Wplyw n-nitrozodimetyloaminy (NDMA) na aktywnosc wybranych enzymów w surowicy krwi szczura.

Changes in the activity of GOT, GPT, AP and GGTP in blood of rats intoxicated by low doses of N-Nitrosodimethylamine (NDMA) are presented. A significant increase in the activity of GOT and GPT was found after single doses (20 micrograms/kg b.w.) of NDMA as well as a significant increase in the activity of GOT, GPT, AP and GGTP after a prolonged intoxication per os by doses of 20 micrograms/dm3 given in drinking water.

[Blastomogenic action of low concentrations of nitrosodimethylamine, dimethylamine and nitrogen dioxide]. / Izuchenie blastomogennogo deistviia malykh kontsentratsii nitrozodimetilamina, dimetilamina i dvuokisi azota.

The round-the clock inhalation of the mixture of nitrosodimethylamine (NDMA), dimethylamine (DMA) and nitrogen dioxide, with NDMA concentrations varying within 0.66-0.0026 mg/m3, was followed by development of tumors in the kidney, liver, lungs and at other sites in albino nonbred rats, after a year of exposure. Application of DMA and nitrogen dioxide modified the carcinogenic effect of NDMA. In male rats, the blastogenic effect of the mixture was higher, as compared with that of inhalation of NDMA alone. NDMA inhalation resulted in a lower tumor yield in female rats.

[Possibility of endogenous dimethylnitrosamine synthesis in rats administered dimethylamine and nitrite with the food]. / Izuchenie vozmozhnosti éndogennogo sinteza dimetilnitrozamina pri vvedenii krysam s pishchei dimetilamina i nitrita.

Concurrent peroral administration of dimethylamine (DMA) and sodium nitrite to rats produced necrosis of liver parenchyma and increased the activity of glutamicoalanine transaminase. Similar changes were recorded after administering dimethylnitrosamine (DMNA) that points to potential synthesis of this carcinogen from the precursors. Prolonged (over 2.5 years) feeding with DMA and nitrite resulted in part of the rats in tumours of the lungs and in other neoplasms. Ascorbic acid that blocks the endogenous synthesis of DMNA interfered with the development of tumour and pretumour lesions that emerged as a result of concurrent feeding with DMA and nitrite.

[Effect of small amounts of 2,4-dichlorophenoxyacetic acid derivatives on thiamine and riboflavin metabolism in the animal body]. / Vliianie malykh kolichestv proizvodnykh 2,4-dikhlorfenoksiuksusnoi kisloty na obmen tiamina i riboflavina v zhivotnom organizme.

Administration of the herbicide 2,4-DN (amine salt of 2,4-dichlorphenoxyacetic acid) to weanling rats in a dose of 1/20.000 and 1/2000 of the LD50 for 3 months brought about a 40-50% reduction of thiamine content in the organs and tissues of experimental animals as compared with control. The herbicide was introduced into a balanced formula diet. In the liver of rats given 2,4-DA, there was a 2-fold decrease in the content of flavine adeninedinucleotide, whereas the content of flavine mononucleotide showed a 2-fold rise. Besides, the rats given a lesser herbicide dose manifested a reduced excretion of riboflavine with urine, and an inhibition of liver succinate dehydrogenase. The same animals demonstrated an increase in the relative mass of the adrenals with a concurrent diminution in them of ascorbic acid content.

Pancreatic cell tracing, lineage tagging and targeted genetic manipulations in multiple cell types using pancreatic ductal infusion of adeno-associated viral vectors and/or cell-tagging dyes.

Genetic manipulations, with or without lineage tracing for specific pancreatic cell types, are very powerful tools for studying diabetes, pancreatitis and pancreatic cancer. Nevertheless, the use of Cre/loxP systems to conditionally activate or inactivate the expression of genes in a cell type- and/or temporal-specific manner is not applicable to cell tracing and/or gene manipulations in more than one lineage at a time. Here we report a technique that allows efficient delivery of dyes for cell tagging into the mouse pancreas through the duct system, and that also delivers viruses carrying transgenes or siRNA under a specific promoter. When this technique is applied in genetically modified mice, it enables the investigator to perform either double lineage tracing or cell lineage tracing combined with gene manipulation in a second lineage. The technique requires <40 min.

Randomized controlled trial of the combined monoaminergic and opioid investigational compound GRT9906 in painful polyneuropathy.

GRT9906 is an investigational novel compound with µ-opioid receptor agonism and inhibition of noradrenalin/serotonin re-uptake. In this randomized, double-blind, placebo-controlled, three-way cross-over trial in painful polyneuropathy, the efficacy and safety of GRT9906 was assessed and compared with tramadol. During 4-week treatment periods, daily oral doses of either GRT9906 120-240 mg, or placebo, or tramadol 200-400 mg were given. These were separated by 1-week washout periods. The primary endpoint was the average pain intensity (average of daily current pain intensity over the last 3 days of each treatment period rated on a 0 to 10-point numeric rating scale). One hundred seventeen patients were enrolled and 64 were randomized to one of six treatment sequences. Forty-seven patients qualified for the per protocol analysis. GRT9906 reduced average pain intensity by 2.1 points compared with a reduction of 0.6 points on placebo (p < 0.0001) and 2.4 points on tramadol. GRT9906 also improved scores on the sleep problem scale and the neuropathic pain symptom inventory and scored better than placebo on the patient global impression of change. Numbers needed to treat to obtain one patient with more than 50% pain relief was 3.9 (95% CI 2.4-11.5) for both GRT9906 and tramadol. The most frequently reported adverse events were nausea, fatigue, constipation and sleep disorder for GRT9906 and tramadol. Four patients dropped out due to adverse events during both GRT9906 and tramadol treatment and two dropped out during placebo treatment. In conclusion, in painful polyneuropathy, GRT9906 demonstrated analgesic efficacy with a magnitude of effect comparable with tramadol and was well tolerated.