Blood levels after parenteral injection are low and comparison of the radioactivity and chemical determinations suggest rapid metabolism of the Triclocarban. Human metabolism of TCC involves direct glucuronidation to form N- and N'- glucuronides as well as ring hydroxylation to 2'-hydroxy-TCC and 6-hydroxy-TCC, which are further metabolized to sulfate and glucuronide conjugates. In human subjects given a single oral dose of TCC, 27% of the dose was excreted in the urine within 80 hours. About 70% of the administered dose was excreted in the feces within 5 days. The major urinary metabolites were N-glucuronides (average levels, 30 ng/mL) and a major plasma metabolite was the sulfate conjugate of 2'-OH-TCC (levels ranged from 0-20 ng/mL. The maximum plasma level occurred 2.8 hr after dosing and was 3.7 nmol-equivalents of TCC per g of plasma (approximately 1.2 ppm). Biotransformation of TCC was rapid but did not appear to involve splitting of the basic TCC structure. The major plasma metabolites were N- and N'-glucuronides of TCC which were eliminated with half-life approximately 2 hr to the urine and 2'-hydroxy-TCC sulfate and 6-hydroxy-TCC sulfate (the o-hydroxy-TCC sulfates) which were removed with half life approximately 20 hr (presumably into the bile).
The metabolism and disposition of (14)C-TCC (3,4,4'-trichlorocarbanilide) have been evaluated in humans following oral exposure to 2.2 umol/kg body wt. Fecal elimination (70% of dose) was complete 120 hr after dosing and the urinary excretion (27% of dose) was completed in 80 hr. ... Biotransformation of TCC was rapid but did not appear to involve splitting of the basic TCC structure. The major plasma metabolites were N- and N'-glucuronides of TCC which were eliminated with half life approximately 2 hr to the urine and 2'-hydroxy-TCC sulfate and 6-hydroxy-TCC sulfate (the o-hydroxy-TCC sulfates) which were removed with half life approximately 20 hr (presumably into the bile). ...
Plant uptake and metabolism of emerging organic contaminants, such as personal-care products, pose potential risks to human health. In this study, jalapeno pepper (Capsicum annuum) plants cultured in hydroponic media were exposed to both (14)C-labeled and unlabeled triclocarban (TCC) to investigate the accumulation, distribution, and metabolism of TCC following plant uptake. The results revealed that TCC was detected in all plant tissues; after 12 weeks, the TCC concentrations in root, stem, leaf, and fruit tissues were 19.74 +/- 2.26, 0.26 +/- 0.04, 0.11 +/- 0.01, and 0.03 +/- 0.01 mg/kg dry weight, respectively. More importantly, a substantial portion of the TCC taken up by plants was metabolized, especially in the stems, leaves, and fruits. Hydroxylated TCC (e.g., 2'-OH TCC and 6-OH TCC) and glycosylated OH-TCC were the main phase I and phase II metabolites in plant tissues, respectively. Bound (or nonextractable) residues of TCC accounted for approximately 44.6, 85.6, 69.0, and 47.5% of all TCC species that accumulated in roots, stems, leaves, and fruits, respectively. The concentrations of TCC metabolites were more than 20 times greater than the concentrations of TCC in the above-ground tissues of the jalapeno pepper plants after 12 weeks; crucially, approximately 95.6% of the TCC was present as metabolites in the fruits. Consequently, human exposure to TCC through the consumption of pepper fruits is expected to be substantially higher when phytometabolism is considered.
Previous studies of triclocarban suggest that its biotransformation could yield reactive metabolites that form protein adducts. Since the skin is the major route of triclocarban exposure, present work examined this possibility in cultured human keratinocytes. The results provide evidence for considerable biotransformation and protein adduct formation when cytochrome P450 activity is induced in the cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a model Ah receptor ligand. Since detecting low adduct levels in cells and tissues is difficult, we utilized the novel approach of accelerator mass spectrometry for this purpose. Exploiting the sensitivity of the method, we demonstrated that a substantial portion of triclocarban forms adducts with keratinocyte protein under the P450 inducing conditions employed.
... After repeated oral administration of 3,4,4'-trichlorocarbanilide (TCC) ... the biliary metabolites ... were isolated and identified. The major TCC biliary metabolite was found to be 2'-hydroxy-TCC. This compound was isolated mainly from the nonconjugated and the glucuronide fractions. Other metabolites present in substantial quantities were 6-hydroxy-TCC and 2',6-dihydroxy-TCC mainly as glucuronides and 3'-hydroxy-TCC mainly as the sulfate conjugate. Small amounts of 3',6-dihydroxy-TCC were isolated from each of the fractions. No unchanged TCC was found in the bile. Only traces of other metabolites were found, and no N-hydroxylated products were observed. ...
IDENTIFICATION AND USE: Triclocarban (TCC) is a solid. It has anti-microbial activity and is used globally in a wide range of personal cleansing products that include deodorant soaps, detergents, cleansing lotions, and wipes. In North America, TCC is used exclusively as an antimicrobial and preservative in bar and liquid soaps and body washes. HUMAN STUDIES: Studies in humans indicate no evidence of skin sensitization or severe irritation. Petrolatum (0.1mL) containing 0, 1, 3, 6, and 9% TCC was applied continuously for 21 days on ten males. Minimal skin irritation was observed with the 9% concentration. There was no evidence of skin sensitization in volunteers tested with TCC (1.5% and 10%). The potential impact of exposure to TCC on fetal abnormalities was studied in 39 pregnant women diagnosed with fetal or post-birth abnormalities. Significantly increased levels of TCC were detected in maternal sera from mothers with abnormal births. TCC was also studied for its endocrine-disrupting effects. TCC exerted estrogenic activities by inducing luciferase activities in an ER reporter gene assay, promoting the proliferation of the MCF-7 cells, up-regulating the expression of pS2 and down-regulating ERalpha expression at both the mRNA and protein levels in the MCF-7 cells. In prostate cancer-derived LNCaP and C4-2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. ANIMAL STUDIES: TCC was non-irritating to guinea pig and rabbit skin. TCC did not cause skin sensitization in guinea pigs. At a concentration of 4% TCC did not exhibit a photoallergic activity in guinea pigs. In rabbit eyes, TCC caused no discernable irritation in the rinsed group and was only mildly irritating in the un-rinsed group. TCC was tested in groups of 80 Sprague Dawley rats per sex in a two year chronic feeding study at dose levels of 0, 25, 75 and 250 mg/kg bw/day. Mean body weight of males at 250 mg/kg bw/day and females at 75 and 250 mg/kg bw/day were slightly reduced compared to controls during most of the study. Anemia was seen in males at 75 and 250 mg/kg bw/day and females at 250 mg/kg bw/day. Blood chemistry analysis showed a slight increase in alkaline phosphatase, blood urea nitrogen, glucose and total bilirubin at various time points for the high-dose males. There was no evidence for dose-related increases in tumor incidence at any site. The long-term effect to rats of TCC was also tested in a three-generation reproduction study. At the highest TCC dose level, the mean number of live pups at birth was lower than controls in the litters for the F0 generation. A similar trend was not observed in the F1 and F2 generation. TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. TCC was negative for the induction of structural and numerical chromosome aberrations in CHO cells. TCC was considered not to be mutagenic with and without metabolic activation in the Ames test (Salmonella typhimurium strains TA98, TA100, TA1535 and TA 1537). ECOTOXICITY STUDIES: TCC has been detected in aquatic ecosystems and the results of toxicity studies indicate a potential risk to the environment. TCC induced systemic toxic effects in nematode Caenorhabditis elegans. TCC was also reproductively toxic to fish at concentrations at or near those that have been measured in surface water. The effects of TCC on mortality, population growth, lifespan, and fecundity were examined in the monogonont rotifer (Brachionus koreanus) using cellular ROS levels, GST enzymatic activity, and gene expression of defensomes. In TCC-exposed B. koreanus, growth retardation and reduced fecundity were observed and were shown to have a potentially deleterious effect on the life cycle of B. koreanus. In addition, time-dependent increases in ROS contents and GST enzymatic activity were shown in response to TCC exposure. In the reproduction test with the New Zealand mudsnail Potamopyrgus antipodarum TCC caused significantly increased embryo numbers at all tested concentrations, except in the group of 0.170 ug/L. TCC inhibited the growth of T. thermophila and the impairment of plasma membrane was observed after 2 hr exposure of TCC. Furthermore, it is noticeable that at environmentally relevant concentrations (1.0 ug/L), TCC can lead to statistically significant DNA damage in Tetrahymena thermophila, while the inhibition of growth and change of cell viability cannot be observed. In the freshwater mudsnail Potamopyrgus antipodarum after four weeks, environmentally relevant TCC concentrations of 1.6 to 10.5 ug/L resulted in significant increases in the number of unshelled embryos, whereas 0.2, 1.6, and 10.5 ug/L exposures significantly increased numbers of shelled embryos.
Triclocarban (TCC) is an antimicrobial agent routinely detected in surface waters that has been hypothesized to interact with the vertebrate endocrine system. The present study examined the effects of TCC alone and in combination with the model endocrine disruptor 17beta-trenbolone (TRB) on fish reproductive function. Adult Pimephales promelas were continuously exposed to either 1 ug TCC/L or 5 ug TCC/L, to 0.5 ug TRB/L, or to a mixture (MIX) of 5 ug TCC/L and 0.5 ug TRB/L for 22 d, and a variety of reproductive and endocrine-related endpoints were examined. Cumulative fecundity was significantly reduced in fathead minnows exposed to TRB, MIX, or 5 ug TCC/L. Exposure to 1 ug TCC/L had no effect on reproduction. In general, both TRB and MIX treatments caused similar physiological effects, evoking significant reductions in female plasma vitellogenin, estradiol, and testosterone, and significant increases in male plasma estradiol. Based on analysis of the ovarian transcriptome, there were potential pathway impacts that were common to both TRB- and TCC-containing treatment groups. In most cases, however, those pathways were more plausibly linked to differences in reproductive status than to androgen-specific functions. Overall, TCC was reproductively toxic to fish at concentrations at or near those that have been measured in surface water. There was little evidence that TCC elicits reproductive toxicity through a specific mode of endocrine or reproductive action, nor that it could augment the androgenic effects of TRB. Nonetheless, the relatively small margin of safety between some measured environmental concentrations and effect concentrations suggests that concern is warranted.
Many widely used healthcare products contain antiseptics, whose persistence in aquatic environments, soils, and sediments leads to the contamination of ecosystems and adversely affects wildlife. Recently, the impact not only of high but also low doses of contaminants and mixtures of several chemicals has become a focus of concern. In this study, toxicity tests of the antiseptics triclosan (TCS) and triclocarban (TCC) were performed in an aquatic test medium using the nematode Caenorhabditis elegans. Nominal concentrations of TCS and TCC were tested in separate single-substance toxicity tests (96-hr-exposure), focusing on growth and reproduction endpoints. Median effective concentrations (EC50s) from the single-substance tests were subsequently used to set up five different ratios of TCS:TCC mixtures leading to the same toxicity. Six dilutions of each mixture ratio were tested for effon reproduction of C. elegans. In the single-substance tests, TCC was about 30 times more toxic than TCS when considering effects on growth and concerning reproduction, TCC was about 50 times more toxic than TCS. For both substances, the toxic effect on reproduction was more pronounced than the one on growth. Low doses of TCS (1-10 umol/L) stimulated reproduction by up to 301% compared to the control, which might be due to endocrine disruption or other stress-related compensation responses (hormesis). Neither antiseptic stimulated growth. In the mixtures, increasing amounts of TCC inhibited the stimulatory effects of TCS on reproduction. In addition, the interactions of TCS and TCC were antagonistic, such that mixtures displayed lower toxicity than would have been expected when TCS and TCC mixtures adhered to the principle of concentration addition.
Effects of chemical mixtures at environmentally relevant concentrations on endocrine systems of aquatic organisms are of concern. Triclocarban (TCC) and inorganic mercury (Hg2+) are ubiquitous in aquatic environments, and are known to interfere with endocrine pathways via different mechanisms of toxic action. However, effects of mixtures of the two pollutants on aquatic organisms and associated molecular mechanisms were unknown. This study examined effects of binary mixtures of TCC and Hg2+ on histopathological and biochemical alteration of reproductive organs in zebrafish (Danio rerio) after 21 d exposure. The results showed that: 1) At concentrations studied, TCC alone caused little effect on hepatic tissues, but it aggravated lesions in liver caused by Hg2+via indirect mechanisms of disturbing homeostasis and altering concentrations of hormones; 2) Histological lesions were more severe in gonads of individuals, especially males, exposed to the binary mixture. Exposure to TCC alone (2.5 or 5 ug/L) (measured concentration 140 or 310 ng/L) or Hg2+ alone (5 ug/L or 10 ug/L (measured concentration 367 or 557 ng/L) slightly retarded development of oocytes, whereas co-exposure to nominal concentrations of 5 ug/L TCC and 10 ug /L Hg2+ promoted maturation of oocytes. In males, maturation of sperm was slightly delayed by exposure to either TCC or Hg2+, while their combinations caused testes to be smaller and sperm to be fewer compared with fish exposed to either of the contaminants individually; 3) Lesions observed in fish exposed to binary mixtures might be due to altered transcription of genes involved in steroidogenesis, such as cyp19a, 3beta-HSD, cyp17, 17beta-HSD and modulated concentrations of testosterone and estradiol in blood plasma. The observed results further support the complexity of toxic responses of fish exposed to lesser concentrations of binary chemical mixtures. Since it is impossible to collect empirical information in controlled studies of all possible combinations of toxicants, the application of omics methods might improve the predictive capabilities of results of single classes of chemicals.
A human exposure study in a small group of subjects demonstrated that a portion of the TCC present in bar soaps is absorbed through the skin and is excreted in urine as N-glucuronides. Because they are produced and used in large quantities in various products, they are absorbed into the human body of the general population. The absorption of triclocarban during a human pharmacokinetic study was estimated at 0.6% of the 70 + or - 15 mg of triclocarban in the soap used. The triclocarban-N-glucuronide urine concentration varied considerably among the study subjects, and continuous daily use of the soap led to steady-state levels of excretion.
The metabolism of (14)C-TCC (3,4,4'-trichlorocarbanilide) has been investigated in humans following oral exposure to 2.2 mumol/kg. Fecal elimination (70% of dose) was complete at the 120 hour point after administration and the urinary excretion (27% of dose) was complete after 80 hours post-administration. Urinary glucuronides appear to be valuable biomarkers of triclocarban exposure.
After a pharmacokinetic study in man, radioactivity was rapidly cleared from blood after intravenous administrations of (14)C-triclocarban in propylene glycol with a blood clearance half-life measured to be 8.6 hours.
/MILK/ ... Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. ... The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure.
The antibacterial triclocarban (TCC) concentrates in the cellular fraction of blood. Consequently, plasma levels are at least two-fold lower than the TCC amount present in blood. Utilizing whole blood sampling, a low but significant absorption of TCC from soap during showering is demonstrated for a small group of human subjects.
Kappa agonist compounds and pharmaceutical formulations thereof
申请人：——
公开号：US20030144272A1
公开（公告）日：2003-07-31
Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.
The compounds of formulae I, II, IIA, III, IIIA, IIIB, IIIB-i, IV and IVA have the structure:
1
2
wherein
R
1
, R
2
, R
3
, R
4
; and
X, X
4
, X
5
, X
7
, X
9
;
Y, Z and n are as described in the specification.
in over-the-counter consumer antiseptic wash products, due to their toxicity. Withdrawal of TCC has prompted efforts to search for new antimicrobial compounds. In this paper, we present the synthesis and biologicalevaluation, as antibiotic and non-cytotoxic agents, of a series of diarylureas, analogues of TCC. These compounds are characterized by an intriguingly simple chemistry and can be easily synthesized
[EN] COMPOSITIONS AND METHODS OF MODULATING SHORT-CHAIN DEHYDROGENASE ACTIVITY<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE MODULATION DE L'ACTIVITÉ DE LA DÉSHYDROGÉNASE À CHAÎNE COURTE
申请人：UNIV CASE WESTERN RESERVE
公开号：WO2018218251A1
公开（公告）日：2018-11-29
Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors described herein.
Carboxamide and amino derivatives and methods of their use
申请人：Dolle E. Roland
公开号：US20050113294A1
公开（公告）日：2005-05-26
Carboxamide and amino derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the carboxamide derivatives are ligands of the δ opioid receptor and are useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ opioid receptor-mediated conditions.
