Several metabolites, possibly resulting from azo-reduction in the gastrointestinal tract (two identified as aromatic amines, p-cresidine sulfonic acid being the major one), were also found in the feces and urine. Finally, significant retention in the washed intestines of rat was observed, probably due to adhesion to the intestinal wall.
Cresidinesulfonic acid was found to be the major metabolite of Allura Red in the urine of these two species, whereas the parent compound was not measurable. In addition, two other unidentifiable metabolites were found in the urine of the rats. In the rat fecal extracts, cresidinesulfonic acid was a major metabolite along with two unknowns and the parent compound. The dog fecal sample revealed an identical metabolite pattern as seen in the rat, and in addition, a third unknown was discovered. One of the urinary unknowns demonstrated an Rf value which was identical to that of the one of the fecal unknowns suggesting that they were one and the same. The other unknowns exhibited distinctive Rf values which indicated that these metabolites were different. It has been postulated that azo reduction by gut flora of the dye will yield the two components of the parent compound: 2-methoxy-5-methyl-aniline-4-sulfonic acid (cresidine-4-sulfonic acid) and 1-amino-2-naphthol-6-sulfonic acid. It appears that negligible quantities of intact Red are absorbed and excreted in the urine, and that the major portion of the color is excreted as metabolites in the feces.
In this study, the color and its alumina lake were applied to the subjects volvar forearms (200 subjects) as an aqueous solution for 10 alternate days, for 24-hr periods, followed by a 14-day rest period. Challenge batches were then applied under occlusion to fresh skin sites on the subjects scapular backs for 24 hours. The color did not produce either irritation or allergic responses during the induction phase nor contact dermatitis in the challenge period. ... Allura Red and its lake were evaluated on sites under occlusion for five 48-hr, alternate-day periods. These sites had been previously irradiated for 5 min with Xenon light which had been filtered through a window-glass equivalent to limit the exposure to non-erythema-producing, long-wave radiation. A 10-day rest period followed this induction exposure, and then the color was applied to fresh skin sites, irradiated for 5 min with Xenon and subsequently removed and the sites were evaluated. Allura Red was shown not to produce photosensitization on the 25 subjects studied.
In 2006, the Korea Food and Drug Administration reported that combinations of dietary colors such as allura red AC, tartrazine, sunset yellow FCF, amaranth, and brilliant blue FCF are widely used in food manufacturing. Although individual tar food colors are controlled based on acceptable daily intake (ADI), there is no apparent information available for how combinations of these additives affect food safety. In the current study, the potencies of single and combination use of /dyes/ were examined on neural progenitor cell (NPC) toxicity, a biomarker for developmental stage, and neurogenesis, indicative of adult central nervous system (CNS) functions. /allura red AC/ and /amaranth/ reduced NPC proliferation and viability in mouse multipotent NPC, in the developing CNS model. Among several combinations tested in mouse model, combination of /tartrazine/ and /brilliant blue FCF/ at 1000-fold higher than average daily intake in Korea significantly decreased numbers of newly generated cells in adult mouse hippocampus, indicating potent adverse actions on hippocampal neurogenesis. However, other combinations including /allura red AC/ and /amaranth/ did not affect adult hippocampal neurogenesis in the dentate gyrus. Evidence indicates that single and combination use of most tar food colors may be safe with respect to risk using developmental NPC and adult hippocampal neurogenesis...
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Rats were fed a diet containing 5.19% of Allura Red. It was observed that 0.1% and 29% of the intact dye was excreted in the urine and feces respectively. In later studies, rats and dogs were pretreated daily with nonradioactive Allura Red. Subsequently, the animals were dosed with the 35S labelled compound and studied for up to 72 hours for excretion and distribution patterns of the color. Both species showed limited absorption of the compound with the major route of excretion being via the feces. In the dog 92-95% of the recovered radioactivity appeared in the feces within 72 hours while in the rat 76-92% of the recovered radioactivity appeared in the feces within this time period. Urinary recoveries of the color in rats and dogs, respectively varied between 5.7 and 19.8% and 2.7 and 3.6%. After sacrifice, significant retention of radioactivity was located in the intestinal contents of both species and in the washed intestines of the rats. This was thought to be due to adhesion of the compound to the intestinal wall, since the total carcass and viscera of these animals contained <0.4% of the administered dose.
N-AROYL CYCLIC AMINE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
申请人:BRANCH Clive Leslie
公开号:US20080318944A1
公开(公告)日:2008-12-25
Disclosed are N-aroyl cyclic amine derivatives having the formula:
where the variables are as define herein, and their use as pharmaceuticals, specifically as orexin receptor antagonists.
N-aroyl cyclic amine derivatives as orexin receptor antagonists
申请人:SmithKline Beecham Limited
公开号:US07893090B2
公开(公告)日:2011-02-22
Disclosed are N-aroyl cyclic amine derivatives having the formula:
where the variables are as define herein, and their use as pharmaceuticals, specifically as orexin receptor antagonists.