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(1/20240) The urinary elimination profiles of diazepam and its metabolites, nordiazepam, temazepam, and oxazepam, in the equine after a 10-mg intramuscular dose.

A method for the extraction of diazepam and its metabolites (nordiazepam, temazepam, and oxazepam) from equine urine and serum and their quantitation and confirmation by liquid chromatography-tandem mass spectrometry is presented. Valium, a formulation of diazepam, was administered at a dose of 10 mg intramuscularly to four standard-bred mares. Diazepam is extensively metabolized in the horse to nordiazepam, temazepam, and oxazepam. Diazepam urinary concentrations were found to be less than 6 ng/mL. Nordiazepam was found to be mainly in its glucuronide-conjugated form and was measured out to a collection time of 53-55 h. Oxazepam and temazepam were entirely conjugated, and their urinary concentrations were measured out to collection times of 121 h and 77-79 h, respectively. Diazepam and nordiazepam were measured in equine postadministration serum out to collection times of 6 and 54 h, respectively. Oxazepam and temazepam were not detected in postadministration serum.  (+info)

(2/20240) A single membrane-embedded negative charge is critical for recognizing positively charged drugs by the Escherichia coli multidrug resistance protein MdfA.

The nature of the broad substrate specificity phenomenon, as manifested by multidrug resistance proteins, is not yet understood. In the Escherichia coli multidrug transporter, MdfA, the hydrophobicity profile and PhoA fusion analysis have so far identified only one membrane-embedded charged amino acid residue (E26). In order to determine whether this negatively charged residue may play a role in multidrug recognition, we evaluated the expression and function of MdfA constructs mutated at this position. Replacing E26 with the positively charged residue lysine abolished the multidrug resistance activity against positively charged drugs, but retained chloramphenicol efflux and resistance. In contrast, when the negative charge was preserved in a mutant with aspartate instead of E26, chloramphenicol recognition and transport were drastically inhibited; however, the mutant exhibited almost wild-type multidrug resistance activity against lipophilic cations. These results suggest that although the negative charge at position 26 is not essential for active transport, it dictates the multidrug resistance character of MdfA. We show that such a negative charge is also found in other drug resistance transporters, and its possible significance regarding multidrug resistance is discussed.  (+info)

(3/20240) Stabilization of poly-L-lysine/DNA polyplexes for in vivo gene delivery to the liver.

We are developing a self-assembling non-viral in vivo gene delivery vehicle based on poly-l-lysine and plasmid DNA. We have characterized poly-l-lysines of different chain lengths for DNA condensation and strength of DNA binding. Poly-l-lysine chains >20 residues bound DNA efficiently in physiological saline, while shorter chains did not. Attachment of asialoorosomucoid to PLL increased the PLL chain length required for efficient DNA binding in saline and for efficient DNA condensation. By electron microscopy, poly-l-lysine/DNA polyplexes appeared as toroids 25-50 nm in diameter or rods 40-80 nm long; conjugation of asialoorosomucoid to the polylysine component increased the size of resulting polyplexes to 50-90 nm. In water, poly-l-lysine and asialoorosomucoid-PLL polyplexes have effective diameters of 46 and 87.6 nm, respectively. Polyplexes containing only poly-l-lysine and DNA aggregated in physiological saline at all charge ratios and aggregated at neutral charge ratios in water. Attachment of asialoorosomucoid lessened, but did not eliminate, the aggregation of PLL polyplexes, and did not result in efficient delivery of polyplexes to hepatocytes. Conjugation of polyethylene glycol to poly-l-lysine sterically stabilized resulting polyplexes at neutral charge ratios by shielding the surfaces. For efficient in vivo gene delivery, polyplexes will need to be sterically stabilized to prevent aggregation and interaction with serum components.  (+info)

(4/20240) Isolation of SMTP-3, 4, 5 and -6, novel analogs of staplabin, and their effects on plasminogen activation and fibrinolysis.

Four novel triprenyl phenol metabolites, designated SMTP-3, -4, -5, and -6, have been isolated from cultures of Stachybotrys microspora IFO 30018 by solvent extraction and successive chromatographic fractionation using silica gel and silica ODS columns. A combination of spectroscopic analyses showed that SMTP-3, -4, -5, and -6 are staplabin analogs, containing a serine, a phenylalanine, a leucine or a tryptophan moiety in respective molecules in place of the N-carboxybutyl portion of the staplabin molecule. SMTP-4, -5, and -6 were active at 0.15 to 0.3 mM in enhancing urokinase-catalyzed plasminogen activation and plasminogen binding to fibrin, as well as plasminogen- and urokinase-mediated fibrinolysis. On the other hand, the concentration of staplabin required to exert such effects was 0.4 to 0.6 mM, and SMTP-3 was inactive at concentrations up to 0.45 mM.  (+info)

(5/20240) Novel selective inhibitors for human topoisomerase I, BM2419-1 and -2 derived from saintopin.

Compounds BM2419-1 and -2 were isolated from a culture broth of a fungus Paecilomyces sp. BM2419. It was shown that these novel compounds were artifacts derived from saintopin, a dual inhibitor of topoisomerase I and II by independent processes. In the human topoisomerase I inhibition assay using the recombinant Saccharomyces cerevisiae, BM2419-1 and -2 inhibited selectively the yeast growth dependent on human topoisomerase I induction with IC50 values of 0.3 ng/ml and 6.0 ng/ml, respectively.  (+info)

(6/20240) Apicularens A and B, new cytostatic macrolides from Chondromyces species (myxobacteria): production, physico-chemical and biological properties.

A novel macrolide, apicularen A, was produced by several species of the genus Chondromyces. Initially it was discovered by bioassay-guided RP-HPLC-fractionation of culture extracts of Chondromyces robustus, strain Cm a13. Apicularen A showed no antimicrobial activity, but was highly cytotoxic for cultivated human and animal cells, with IC50 values ranging between 0.1 and 3 ng/ml. A cometabolite of apicularen A, the N-acetylglucosamine glycoside apicularen B, was distinctly less cytotoxic with IC50 values between 0.2 and 1.2 microg/ml, and showed weak activity against a few Gram-positive bacteria. Apicularen A is chemically closely related to the salicylihalamides A and B from the marine sponge Haliclona sp.  (+info)

(7/20240) BE-31405, a new antifungal antibiotic produced by Penicillium minioluteum. I. Description of producing organism, fermentation, isolation, physico-chemical and biological properties.

A new antifungal antibiotic, BE-31405, was isolated from the culture broth of a fungal strain, Penicillium minioluteum F31405. BE-31405 was isolated by adsorption on high porous polymer resin (Diaion HP-20), followed by solvent extraction, precipitation and crystallization. BE-31405 showed potent growth inhibitory activity against pathogenic fungal strains such as Candida albicans, Candida glabrata and Cryptococcus neoformans, but did not show cytotoxic activity against mammalian cells such as P388 mouse leukemia. The mechanism studies indicated that BE-31405 inhibited the protein synthesis of C. albicans but not of mammalian cells.  (+info)

(8/20240) Structure of actinotetraose hexatiglate, a unique glucotetraose from an actinomycete bacterium.

An Actinomycete strain A499 belonging to the genera Amycolatopsis or Amycolata isolated from a Western Australian soil sample produced the cyclic decapeptide antibiotic quinaldopeptin (1), together with the actinotetraose hexatiglate (2), the hexa-ester of a novel non-reducing glucotetraose.  (+info)