Effects of an antibacterial soap on the ecology of aerobic bacterial flora of human skin. (1/48)

The effects of ad lib use of an antibacterial soap containing 1.0% trichlorocarbanilide and 0.5% trifluoromethyldichlorocarbanilide on the bacterial flora of six skin sites of 132 subjects were measured by comparison with the flora of 93 control subjects who avoided the use of topical antibacterials. Each subject was examined once. The test soap produced significant reductions in geometric mean counts of the total aerobic flora on the back, chest, forearm, calf, and foot; counts were also reduced in the axilla, but not to a significant extent. The overall reduction by the test soap on all sites was 62% (P less than 0.001). Neither age nor sex influenced the effect of the soap on the flora. The antibacterial soap also reduced the prevalence of Staphylococcus aureus on the skin, mostly by virtually eliminating it from areas other than the axilla. Partial inhibition of the gram-positive flora was not accompanied by an increase in gram-negative species. The latter were found principally in the axilla; Klebsiella pneumoniae and Enterobacter aerogenes were the species most frequently found.  (+info)

New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. (2/48)

Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins from Plasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II and P. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a K(i) of 1 to 6 microM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (K(i) greater than 280 microM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 microg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, with K(i) values ranging from 0.05 to 0.68 microM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.  (+info)

Acute depigmentation of fertile brown eggs in a commercial layer operation. (3/48)

Rapid depigmentation of brown eggs is an infrequent but startling event in the commercial egg industry that can result in significant economic losses. Loss of shell pigment in brown-shelled eggs is caused by various factors. In many cases, the exact cause of flock-wide pigment loss remains undetermined. A rapid decline in shell pigmentation was observed in 2 flocks of Hyline brown layers. The lack of evidence of an infectious disease process suggested a feed or management problem. On the basis of a small-scale, "in-house" feeding trial, the feed was identified as the cause of depigmentation. Feed analysis by liquid chromatography with mass spectrometry confirmed the presence of 4,4'-dinitrocarbanilide, a major component of nicarbazin (NCZ). There was no evidence of increased mortality, and only a slight but transient drop in the egg production was observed. Depigmentation effects were rapidly reversed after replacing the feed with NCZ-free feed.  (+info)

Partitioning, persistence, and accumulation in digested sludge of the topical antiseptic triclocarban during wastewater treatment. (4/48)

The topical antiseptic agent triclocarban (TCC) is a common additive in many antimicrobial household consumables, including soaps and other personal care products. Long-term usage of the mass-produced compound and a lack of understanding of its fate during sewage treatment motivated the present mass balance analysis conducted at a typical U.S. activated sludge wastewater treatment plant featuring a design capacity of 680 million liters per day. Using automated samplers and grab sampling, the mass of TCC contained in influent, effluent, and digested sludge was monitored by isotope dilution liquid chromatography (tandem) mass spectrometry. The average mass of TCC (mean +/- standard deviation) entering and exiting the plant in influent (6.1 +/- 2.0 microg/L) and effluent (0.17 +/- 0.03 microg/ L) was 3737 +/- 694 and 127 +/- 6 g/d, respectively, indicating an aqueous-phase removal efficiency of 97 +/- 1%. Tertiary treatment by chlorination and sand filtration provided no detectable benefit to the overall removal. Due to strong sorption of TCC to wastewater particulate matter (78 +/- 11% sorbed), the majority of the TCC mass was sequestered into sludge in the primary and secondary clarifiers of the plant. Anaerobic digestion for 19 days did not promote TCC transformation, resulting in an accumulation of the antiseptic compound in dewatered, digested municipal sludge to levels of 51 +/- 15 mg/kg dry weight (2815 +/- 917 g/d). In addition to the biocide mass passing through the plant contained in the effluent (3 +/- 1%), 76 +/- 30% of the TCC input entering the plant underwent no net transformation and instead partitioned into and accumulated in municipal sludge. Based on the rate of beneficial reuse of sludge produced by this facility (95%), which exceeds the national average (63%), study results suggest that approximately three-quarters of the mass of TCC disposed of by consumers in the sewershed of the plant ultimately is released into the environment by application of municipal sludge (biosolids) on land used in part for agriculture.  (+info)

Identification of a Bis-guanylhydrazone [4,4'-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase. (5/48)

Chk2 is a protein kinase involved in the ATM-dependent checkpoint pathway (http://discover.nci.nih.gov/mim). This pathway is activated by genomic instability and DNA damage and results in either cell cycle arrest, to allow DNA repair to occur, or cell death (apoptosis). Chk2 is activated by ATM-mediated phosphorylation and autophosphorylation and in turn phosphorylates its downstream targets (Cdc25A, Cdc25C, BRCA1, p53, Hdmx, E2F1, PP2A, and PML). Inhibition of Chk2 has been proposed to sensitize p53-deficient cells as well as protect normal tissue after exposure to DNA-damaging agents. We have developed a drug-screening program for specific Chk2 inhibitors using a fluorescence polarization assay, immobilized metal ion affinity-based fluorescence polarization (IMAP). This assay detects the degree of phosphorylation of a fluorescently linked substrate by Chk2. From a screen of over 100,000 compounds from the NCI Developmental Therapeutics Program, we identified a bis-guanylhydrazone [4,4'-diacetyldiphenylureabis(guanylhydrazone); NSC 109555] as a lead compound. In vitro data show the specific inhibition of Chk2 kinase activity by NSC 109555 using in vitro kinase assays and kinase-profiling experiments. NSC 109555 was shown to be a competitive inhibitor of Chk2 with respect to ATP, which was supported by docking of NSC 109555 into the ATP binding pocket of the Chk2 catalytic domain. The potency of NSC 109555 was comparable with that of other known Chk2 inhibitors, such as debromohymenialdisine and 2-arylbenzimidazole. These data define a novel chemotype for the development of potent and selective inhibitors of Chk2. This class of drugs may ultimately be useful in combination with current DNA-damaging agents used in the clinic.  (+info)

The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. (6/48)

The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.  (+info)

Triclocarban enhances testosterone action: a new type of endocrine disruptor? (7/48)

Many xenobiotics have been associated with endocrine effects in a wide range of biological systems. These associations are usually between small nonsteroid molecules and steroid receptor signaling systems. In this report, triclocarban (TCC; 3,4,4'-trichlorocarbanilide), a common ingredient in personal care products that is used as an antimicrobial agent was evaluated and found to represent a new category of endocrine-disrupting substance. A cell-based androgen receptor-mediated bioassay was used to demonstrate that TCC and other urea compounds with a similar structure, which have little or no endocrine activity when tested alone, act to enhance testosterone (T)-induced androgen receptor-mediated transcriptional activity in vitro. This amplification effect of TCC was also apparent in vivo when 0.25% TCC was added to the diet of castrated male rats that were supported by exogenous testosterone treatment for 10 d. All male sex accessory organs increased significantly in size after the T+TCC treatment, compared with T or TCC treatments alone. The data presented here suggest that the bioactivity of endogenous hormones may be amplified by exposure to commercial personal care products containing sufficient levels of TCC.  (+info)

Inhibitors of bacterial multidrug efflux pumps potentiate antimicrobial photoinactivation. (8/48)

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