Abstract  A new kind of milli-sized sorbent-calcium alginate supporting a weak acidic pink red B (APRB)-calcium fluoride nano-sized hybrid-was prepared. The micro-structure of the hybrid and adsorbent were characterized, and its adsorption capacity for organic contaminants, e.g. dyes, PCBs and microcystin (MC)-LR, was investigated. Cationic dyes were adsorbed selectively via charge attraction, with a saturation capacity of 188 mg of cationic red 3R per gram of the milli-sized adsorbent. However, the adsorptions of PCBs and MC-LR corresponded to the octanol-water partition law, and their partition coefficients were calculated to be 7788.6 mg kg(-1) for PCB029, 13325 mg kg(-1) for PCB101, 434.6 mg kg(-1) for PCB180, and 369.2 mg kg(-1) for MC-LR. When the milli-sized adsorbent was used in the treatment of two concentrated dye wastewaters and two polluted ground waters, the removal of the colored substances, chemical oxygen demand (COD), and concentration of PCBs and MC-LR were satisfactory. In the synthesis of the materials, all of the reactants are easily available and harmless to the environment, and APRB may be obtained from concentrated APRB-containing wastewater instead. The development of the milli-sized hybrid adsorbent provided liquid-solid separation, for favorable use in engineering. It will play an important role in the treatment of concentrated wastewater and the remediation of ground water contamination.

Abstract  A single set of conditions consisting of a palladium catalyst, a commercially available ligand, and a base, allow for several types of C-N bond constructions to be conducted in water with the aid of a commercially available "designer" surfactant (TPGS-750-M). Products containing a protected NH2 group in the form of a carbamate, sulfonamide, or urea can be fashioned starting with aryl or heteroaryl bromides, iodides, and in some cases, chlorides, as substrates. Reaction temperatures are in the range of room temperature to, at most, 50 degrees C, and result in essentially full conversion and good isolated yields.

Abstract  No phytoplankton should be present in treated drinking water because of its potential for bad odor and toxins that may pose hazards to animals and humans upon consumption. This study describes the efficiency of alum and lime-alum treatments for removing phytoplankton from the Nile river water used as a source of drinking water in Egypt. The results showed that alum could not precipitate all phosphate nor coagulate bloom forming cyanobacteria present in the water sample. On the other hand, lime-alum treatment precipitated much more phosphate than alum, and coagulated all phytoplankton present in the water samples including those that could not be coagulated by alum. Furthermore, lime-alum treatment did not change the pH of the water during all the experiment period. Hence, it is suggested that lime-alum be used instead of alum during water treatment processes in Egypt.

Abstract  The drug metabolism studies in which we have been engaging for about 40 years since 1952 are briefly reviewed in this paper. Our main efforts were initially made to elucidate the metabolic fates of various abused drugs including barbiturates, carbamates, opioids, amphetamines and cannabinoids in mammals from pharmacological and toxicological points of view. Among the interesting findings obtained from these studies, the most remarkable one was that morphine-6-glucuronide, a minor metabolite of morphine, has much stronger analgesic activity than morphine. Recently we have also been interested in clarifying the enzyme system involved in the metabolic pathways of the above drugs. Several cytochrome P-450 isozymes were thus purified from the liver microsomes of mammals and their role in oxygenation of amphetamines and cannabinoids were elucidated. The finding that MALDO (microsomal aldehyde oxygenase), a purified P-450 isozyme, could catalyze an oxidation of lipid-soluble aldehydes to the corresponding carboxylic acids was most noticeable. Metabolic and toxicologic studies on furylfuramide (AF-2) and polychlorinated biphenyl (PCB) have also been performed using rats and other animal species, and some interesting results were obtained.

Abstract  Dietary intake is the most important source of exposure to dioxins for the general population. This pathway contributes more than 90% of the daily intake for the general population of Korea. The objective of this study was to assess current exposure to dioxin-like compounds in fish and shellfish consumed by the general population in Korea. Residues of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and dioxin-like, non-, and mono-substituted polychlorinated biphenyls (co-planar PCBs) were quantified in 32 fish and shellfish collected from domestic fisheries markets. The contributions of individual DL-PCB congeners to the total 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TEQ) were greater than 50%. Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents based on the TCDD equivalency factors (TEFs) developed by the World Health Organization (TEQ(WHO)) were compared to guidelines suggested for the protection of human health by the World Health Organization (WHO). The greatest TEQ concentration was observed in herring, followed by that in dried anchovy and Sailfin sandfish. The exposure to dioxin-like compounds from current fish consumption patterns was estimated to be 72 pg TEQ(WHO)/day, which is equal to 1.2 pg TEQ(WHO)/kg, bw/d, a value that is less than the current tolerable daily intake (TDI) guideline in Korea, which is 4 pg TEQ(WHO)/kg, bw/d. The relatively great exposure was determined to be due to greater fish consumption rate in Korea, rather than greater concentrations of residues in food.

Abstract  Developing polymer chemistries capable of on-demand, controlled depolymerization is an important tool in a broad variety of applications in science, technology, and industry. We report functionalized poly(caprolactone)s (PCL)s designed to allow on-demand and complete depolymerization through incorporation of pendant protected amino groups that, on deprotection, trigger nucleophilic attack and yield a single cyclic product. Two cleavable protecting groups were used to cap PCL: light sensititve o-nitrobenzyl alcohol (ONB) and tert-butyl carbamate (Boc) (for proof of concept). NMR confirmed that PCL-Boc degrades completely into the designed intramolecular cyclization products within a day upon deprotection. TEM visualization of particles made from PCL-ONB encapsulating iron oxide nanoparticles reveals complete disruption of nanoparticles and release of payload. This work demonstrates that intramolecular cyclization within the polymer backbone is an excellent route to accelerate polymer degradation by backbiting reactions into small fragments that should be easily cleared from the circulation.

Abstract  A novel method based on ultrasound-assisted surfactant-enhanced emulsification microextraction (UASEME) has been developed for the preconcentration of cobalt prior to its determination by graphite furnace atomic absorption spectrometry. In the UASEME technique, chloroform was used as the extraction solvent, sodium dodecyl sulfate was adopted as emulsifier, and ultrasound was applied to assist emulsification. There is no need of using organic dispersive solvent which is typically required in conventional dispersive liquid-liquid microextraction method. Several parameters that affect the extraction efficiency, such as the kind and volume of the extraction solvent, the type and concentration of the surfactant, pH of sample solution, concentration of the chelating agent, and extraction time and temperature were investigated and optimized. Under the optimal conditions, the linearity of calibration curve was in the range of 0.1-5 ng mL(-1) with a correlation coefficient (R (2)) of 0.9992. An enrichment factor of 58 was achieved with a sample volume of 5.0 mL. The detection limit of this method for Co was 15.6 ng L-1, and the relative standard deviation (RSD) was 4.3 % at 1.0 ng mL(-1) concentration level of Co. The accuracy of the developed method was evaluated by analysis of the certified reference materials GBW07605 tea leaf and GBW10015 spinach. The method was successfully applied to determine trace cobalt in food and water samples with satisfactory results.

Abstract  HEEP COPYRIGHT: BIOL ABS. Chlorinated hydrocarbon residues were identified in the fatty tissue of roe deer from 2 populations, inhabiting forest and field, and an attempt was made to define carbaryl levels in samples taken from the brain, lungs and testes. In samples of fatty tissue the combined concentration of DDD and metabolites, and of different metabolites, was many times higher in roe deer living in fields. No significant differences were found in the total concentration of DDT, metabolites and DDE in the fatty tissue of individuals of different sex originating from the same habitat. There was a significantly higher concentration of gamma-BHC in the fatty tissue of field-living roe deer. The accumulation of gammaBHC in the organ of field-living roe deer was manifestation of the general use of this pesticide for plant protection. Traces of DMDT (2,2-di-(p-methoxyphenyl)-1,1,1-trichloroethane) residue were found in certain tissues examined from field- and forest-living roe deer. Despite the general use of preparations containing carbaryl for plant protection, no residue of this insecticide was found. All concentrations of insecticide residues found in roe tissue were below the levels proscribed by FAO requirements for food substances.

Abstract  Dinoflagellates are microalgae that are associated with the production of many marine toxins. These toxins poison fish, other wildlife and humans. Dinoflagellate-associated human poisonings include paralytic shellfish poisoning, diarrhetic shellfish poisoning, neurotoxic shellfish poisoning, and ciguatera fish poisoning. Dinotlagellate toxins and bioactives are of increasing interest because of their commercial impact, influence on safety of seafood, and potential medical and other applications. This review discusses biotechnological methods of identifying toxic dinoflagellates and detecting their toxins. Potential applications of the toxins are discussed. A lack of sufficient quantities of toxins for investigational purposes remains a significant limitation. Producing quantities of dinoflagellate bioactives requires an ability to mass culture them. Considerations relating to bioreactor culture of generally fragile and slow-growing dinoflagellates are discussed. Production and processing of dinoflagellates to extract bioactives, require attention to biosafety considerations as outlined in this review. (c) 2006 Elsevier Inc. All rights reserved.

Abstract  The Juan de Fuca eddy is a toxic "hot spot." Domoic acid (DA) was detected in the eddy during each of six cruises over a 4-yr study, although Pseudo-nitzschia abundance and toxin concentrations were highly variable. During the September 2004 eddy bloom, Pseudo-nitzschia spp. exceeded 13 X 10(6) cells L(-1), and particulate DA reached 80 nmol L(-1). Of the >10 species of Pseudo-nitzschia identified in this region, those coincident with the most toxic blooms are P. cf. pseudodelicatissima, P. cuspidata, P. multiseries, and P. australis. However, the presence of any particular species could not be used as an indicator of toxicity because of the high level of variability in intracellular DA in field assemblages. Pseudo-nitzschia cells were typically associated with blooms of other diatom taxa but also were coincident with blooms of euglenoids and dinoflagellates in the eddy region. Pseudo-nitzschia always comprised <17% of the total carbon biomass, thereby rendering remote sensing an unsuitable means for predicting toxigenic Pseudo-nitzschia blooms in this region. Our results support the hypothesis that the Juan de Fuca eddy region and not the nearshore zone is the primary initiation site for toxic blooms of Pseudo-nitzschia affecting the Washington coast. Although particulate DA was observed near the edges of the Columbia River plume, whether toxin can be produced in situ in plume water is not resolved. No first-order predictive relationships were found for either Pseudo-nitzschia abundance or DA concentration and environmental data from all six cruises.

Abstract  Sericostoma vittatum is a caddisfly species, endemic to the Iberian Peninsula, proposed as a biomonitor species for lotic ecosystems. Since inhibition of choliriesterases' (ChE) activity has been used to evaluate the exposure of macroinvertebrates to organophosphates and carbamate pesticides, this work intended to characterize the ChE present in this species so their activity can be used as a potential biomarker of exposure. Biochemical and pharmacological properties of ChE were characterized in this caddisfly species using different substrates (acetylthiocholine iodide, propionylthiocholine iodide, and butyrylthiocholine iodide) and selective inhibitors (eserine sulfate, BW284c51, and iso-OMPA). Also, the in vitro effects of two insecticides (carbaryl and chlorantraniliprole) and two psychiatric drugs (fluoxetine and carbamazepine) on ChE activity were investigated. The results suggest that S. vittatum possess mainly AChE able to hydrolyze both substrates acetylthiocholine and propionylthiocholine since: (1) it hydrolyzes the substrate acetylthiocholine and propionylcholine at similar rates and butyrylthiocholine at a much lower rate; (2) it is highly sensitive to eserine sulfate and BW284c51, but not to iso-OMPA; and (3) its activity is inhibited by excess of substrate, a characteristic of typical AChE. in vitro inhibitions were observed only for carbaryl exposure while exposure to chlorantraniliprole and to relevant environmental concentrations of psychiatric drugs did not cause any significant effect on AChE activity. This study suggests that AChE activity in caddisflies can indeed be used to discriminate the effects of specific insecticides in monitoring programs. The use of non-target species such as caddisflies in ecotoxicological research in lotic ecosystems is also discussed. (C) 2014 Elsevier Inc. All rights reserved.

Abstract  A global dataset was compiled to examine relations between the total nitrogen to total phosphorus ratio (TN:TP) and microcystin concentration in lakes and reservoirs. Microcystin concentration decreased as TN:TP ratios increased, suggesting that manipulation of the TN:TP ratio may reduce microcystin concentrations. This relationship was experimentally tested by adding ammonium nitrate to increase the TN:TP ratio in large-scale (70m(3)), in situ mesocosms located in a eutrophic reservoir that routinely experiences toxic blooms of cyanobacteria. At a TN:TP ratio >75:1, chlorophytes dominated the phytoplankton community in the mesocosms, while cyanobacterial biovolume was significantly reduced and microcystin was not detected. In contrast, the unmanipulated reservoir was dominated by cyanobacteria, and microcystin was detected. Secchi depths were 1.1 to 1.8times greater in the mesocosms relative to the reservoir. Cladoceran zooplankton had a larger body size (0.14mm on average) in the mesocosms compared to conspecifics in the reservoir, which was likely related to the higher quality food. Combined, these empirical and experimental data indicate that although nutrient addition is counterintuitive to current cyanobacteria management practices, increasing the TN:TP ratio by adding nitrogen may be a potential short-term management strategy to reduce cyanobacteria and cyanotoxins when other alternatives (e.g., phosphorus reduction) are not possible. Additional experimental studies with careful controls are needed to define best management practices and identify any potential unintended consequences before nitrogen addition is implemented as a lake and reservoir management practice.

Abstract  Cyanobacteria can form blooms and in these situations they dominate the phytoplanktonic community, reaching extremely high densities. In the domain Bacteria, high population densities can stimulate a phenomenon known as quorum sensing, which may produce several modifications in the cell physiology. Very little is known about quorum sensing in Cyanobacteria. Because of their planktonic way of life, quorum sensing should be more evident during a bloom event. In this work, we tested whether cell density could shape the production of bioactive compounds produced by Cyanobacteria. The experiments consisted of two treatments, where cultures of Cyanobacteria were maintained at low and high cellular densities through a semi-continuous set-up. Analyses were performed by HPLC-PDA and MALDI-TOF MS. Seventeen peptides were detected and 14 identified, including microcystins, aeruginosins, cyanopeptolins and microviridins. The results showed that cellular density seems to have a significant effect on the peptides production. Most of the compounds had significantly higher cellular quotas in the higher-density treatment, although microviridins and an unknown peptide were produced only at low density. These results may hint at a possible role for quorum sensing in triggering the production of several cyanobacterial peptides.

Abstract  In vivo and/or in vitro mammalian cell systems were used to evaluate sister chromatid exchange (SCE) induction and gene mutagenesis effects following exposure to ethyl carbamate (urethane), vinyl carbamate, ethyl N-hydroxycarbamate, and 2-hydroxyethyl carbamate. Although ethyl carbamate caused dose-dependent increases in SCE when injected into mice, it was ineffective for inducing SCE and gene mutation (6-thio-guanine resistance) in Chinese hamster V-79 cells cultured with or without the addition of S9 enzyme mix during treatment. Chemical-specific patterns of genotoxicity were evident for the known or suspect metabolites under test: only vinyl carbamate consistently (in vivo and in vitro) revealed strong activity for the genetic endpoints. SCE induction levels of 5-8 times baseline were observed after animal or cell culture exposures to vinyl carbamate. Doses required to produce this effect in V-79 cells in the presence of S9 mix were approximately 100 times lower than those needed when S9 was absent. The extensive gene mutagenesis (approaching 600 mutants/10(6) survivors) noted was completely dependent upon the presence of S9 mix. These observations are consistent with current theory holding that vinyl carbamate is a metabolic intermediate of ethyl carbamate, and is converted to the ultimately reactive species (presumably, vinyl carbamate epoxide) which is responsible for ethyl carbamate carcinogenesis.

Abstract  The potent bacterial mutagen 2-chloroacrolein is formed from the carcinogenic herbicide S-2,3-dichloroallyl diisopropylthiocarbamate (diallate) on incubation with hepatic microsomal monooxygenases or on reaction with m-chloroperbenzoic acid. A proposed activation mechanism for this promutagen involves sulfoxidation followed by [2,3] sigmatropic rearrangement and 1,2-elimination reactions. A portion of the highly reactive intermediate, diallate sulfoxide (proximate mutagen), is attacked by glutathione in a reaction which competes with its transformation to the ultimate mutagen, 2-chloroacrolein.

Abstract  Microcystins (MCs) comprise a family of more than 80 related cyclic hepatotoxic heptapeptides. Oxidation of MCs causes cleavage of the chemically unique C20 beta-amino acid (2S, 3S, 8S, 9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid (Adda) amino to form 2-methyl-3-methoxy-4-phenylbutanoic acid (MMPB), which has been exploited to enable analysis of the entire family. In the present study, the reaction conditions (e.g. concentration of the reactants, temperature and pH) used in the production of MMPB by oxidation of cyanobacterial samples with permanganate-periodate were optimized through a series of well-controlled batch experiments. The oxidation product (MMPB) was then directly analyzed by high-performance liquid chromatography with diode array detection. The results of this study provided insight into the influence of reaction conditions on the yield of MMPB. Specifically, the optimal conditions, including a high dose of permanganate (> or = 50 mM) in saturated periodate solution at ambient temperature under alkaline conditions (pH approximately 9) over 1-4 h were proposed, as indicated by a MMPB yield of greater than 85%. The technique developed here was applied to determine the total concentration of MCs in cyanobacterial bloom samples, and indicated that the MMPB technique was a highly sensitive and accurate method of quantifying total MCs. Additionally, these results will aid in development of a highly effective analytical method for detection of MMPB as an oxidation product for evaluation of total MCs in a wide range of environmental sample matrices, including natural waters, soils (sediments) and animal tissues.

Abstract  We measured microcystins in blood from people at risk for swallowing water or inhaling spray while swimming, water skiing, jet skiing, or boating during an algal bloom. We monitored water samples from a small lake as a Microcystis aeruginosa bloom developed. We recruited 97 people planning recreational activities in that lake and seven others who volunteered to recreate in a nearby bloom-free lake. We conducted our field study within a week of finding a 10-mu g/L microcystin concentration. We analyzed water, air, and human blood samples for water quality, potential human pathogens, algal taxonomy, and microcystin concentrations. We interviewed study participants for demographic and current health symptom information. Water samples were assayed for potential respiratory viruses (adenoviruses and enteroviruses), but none were detected. We did find low concentrations of Escherichia coli, indicating fecal contamination. We found low levels of microcystins (2 mu g/L to 5 mu g/L) in the water and (< 0.1 ng/m(3)) in the aerosol samples. Blood levels of microcystins for all participants were below the limit of detection(0.147 mu g/L). Given this low exposure level, study participants reported no symptom increases following recreational exposure to microcystins. This is the first study to report that water-based recreational activities can expose people to very low concentrations of aerosol-borne microcystins; we recently conducted another field study to assess exposures to higher concentrations of these algal toxins.

Abstract  Occurrence and spatial distributions of microcystins (MCs; MC-RR, -YR, -LR, -LA, -LF, -LW) in Poyang Lake were studied during the period from July 6 to July 18, 2012, by using ultra-high-performance liquid chromatography-electrospray ionization tandem triple quadrupole/mass spectrometry (UPLC-MS/MS). MC-RR was the most dominant variant (94.70 and 84.73 % for intracellular (cellular MCs) and extracellular (dissolved MCs) MCs, respectively) in Poyang Lake, followed by MC-LR (4.65 and 13.17 %, respectively), MC-YR (0.8 and 2.63 %, respectively), and MC-LA (0.02 and 0.00 %), while MC-LW and MC-LF were not detected. Total MCs concentrations (intracellular +extracellular MCs) ranged between 0.0036 and 7.97 μg/L, with an average of 0.79 μg/L, and only two sampling stations with the total MCs concentrations exceeded the drinking water guideline level of 1 μg/L for MC-LR proposed by World Health Organization. The overall spatial pattern of intracellular and extracellular MCs in Poyang Lake demonstrates decreasing trends from east to west, and the south part higher than the north part. Intracellular MCs content was negatively correlated with total nitrogen (r = -0.34, p < 0.01) and NO3 (r = -0.35, p < 0.01), while no significant correlation was found between intracellular MCs concentration and total phosphorus, NH4, and NO2 (p > 0.05), suggesting that NO3 might be a regulating factor for MCs production in Poyang Lake. In addition, intracellular MCs concentrations were positively correlated with wind speed, Microcystis and Cyanobacteria biomass (r = 0.34-0.51, p < 0.05), indicating that wind speed plays an important role in the spatial distributions of MCs, and NO3, toxic cyanobacteria (mainly Microcystis), and wind speed seem to be the important forcing factors driving MCs spatial distributions in Poyang Lake.

Abstract  A predictive model integrating adsorption kinetics and competitive isotherm models (Homogeneous Surface Diffusion Model, Freundlich-type and Fritz & Schlunder isotherms) was developed to describe and understand the competing mechanism(s) and the ionic strength (IS) role on microcystins (MC) and tannic acid (TA) competitive adsorption. The developed model showed good agreement with the experimental data obtained from batch adsorption tests and isotherms conducted with MC extracts and TA model solutions (single-solute and multicomponent, IS presence and absence) using a mesoporous powdered activated carbon (PAC). Results confirm that similar size molecules such as MC and TA are strong competitors and tannin-rich waters may severely affect MC residuals in the treated water. Unlike usually considered, both direct site and pore blockage mechanisms seem relevant. Competition effects appear to be more dependent on the competitor/contaminant molar ratio than on the initial concentrations. The IS affects the extent and the mechanisms of MC-TA competitive adsorption, reducing PAC dose for safe control of MC residuals. The developed model, including a D-s analysis, is an important tool to understand the competitive adsorption of similar size adsorbates. (C) 2013 Elsevier Ltd. All rights reserved.

Abstract  The effects of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, on the voltage-sensitive sodium channels (VSSC) were examined in the rat brain and cardiac myocytes. NS-7 inhibited [3H]batrachotoxinin A 20 alpha-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 microM, while the compound was less effective in the cardiac myocytes (Ki = 13 microM). Aconitine, on the other hand, inhibited [3H]BTX binding to brain membranes and cardiac myocytes with the same potency. In contrast. NS-7 had no affinity for [3H]saxitoxin binding in brain (neurotoxin receptor site 1). In superfused slices of the rat cerebral cortex, NS-7 inhibited the veratridine (5 microM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 microM, whereas the compound showed a weak and not significant suppression of KCl-evoked glutamate release. The tissue concentrations of NS-7 in the rat cerebral cortex and heart were 89 and 28 nmole/g tissue, respectively, 5 min after its intravenous injection (8 mg/kg). Furthermore, in the cerebral cortex, NS-7 distributed preferentially to the membrane-enriched synaptosomal fraction. Since neurotoxin receptor site 2 is located in the transmembrane region of the VSSC moiety, the channel function may be substantially inhibited by a peripheral administration of NS-7. These results suggest that the blockade of neurotoxin receptor site 2 of VSSC in the brain contributes to the neuroprotective action of NS-7.

Abstract  Red-Al was used to selectively remove the C-2 benzoate of 7,13-bisTES baccatin (8). Derivatization of the resulting C-2 hydroxy compound provided the corresponding p-nitrophenyl carbamate, the p-methoxy and p-nitrobenzoates, and cyclohexyl ester. Attachment of the taxol side chain to the above four analogs via lactam (15) followed by desilylation provided five analogs of taxol modified at the C-2 position, including a C-1,C-2 cyclic carbonate. These five analogs were less potent than taxol in a tubulin polymerization assay and a cytotoxicity assay against human colon cancer cell line.

Abstract  1. [3H]Batrachotoxinin A-20-alpha-benzoate ([3H]BTX-B) and [3H]saxitoxin ([3H]STX), radioligands that bind to distinct sites on the voltage-sensitive sodium channel, were bound specifically to saturable sites in rainbow trout (Oncorhynchus mykiss) brain synaptoneurosomes. 2. Specific [3H]BTX-B binding was temperature dependent with highest levels of specific [3H]BTX-B binding observed at 7 degrees C. Specific binding was inversely correlated with assay temperature at temperatures above 7 degrees C. 3. Saturating concentrations of scorpion (Leiurus quinquestriatus) venom (ScV) stimulated specific [3H]BTX-B binding at 27 degrees C, but not at 7 degrees C. The dihydropyrazole insecticide RH 3421 inhibited specific [3H]BTX-B binding at 7 degrees C but had no effect on specific binding at 27 degrees C. The sodium channel activators veratridine and aconitine and the local anesthetic dibucaine inhibited specific [3H]BTX-B binding at both 7 degrees C and 27 degrees C. 4. Displacement experiments in the presence of ScV at 27 degrees C gave an equilibrium dissociation constant (KD) for [3H]BTX-B of 710 nM and a maximal binding capacity (Bmax) of 11.3 pmol/mg protein. Kinetic experiments established the rates of association (1.17 x 10(5) min-1 nM-1) and dissociation (0.0514 min-1) of the ligand-receptor complex. 5. The binding of [3H]STX reached apparent saturation at 7.5 nM. Scatchard analysis of the saturation data indicated a KD of 3.8 nM and a Bmax of 1.9 pmol/mg protein. 6. These studies provide evidence for high affinity, saturable binding sites for [3H]BTX-B and [3H]STX in trout brain preparations. Whereas certain neurotoxins modified the specific binding of [3H]BTX-B in trout brain synaptoneurosomes in a predictable fashion, other compounds known to affect specific [3H]BTX-B binding in mammalian brain preparations had no effect on specific [3H]BTX-B binding in the trout.

Abstract  Compound 141W94 (Vertex VX478) (3S)-tetrahydro-3-furyl N-[((S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl- 2-hydroxypropyl] carbamate, is a potent HIV-protease inhibitor and is currently undergoing clinical trials. The purpose of this study was the rapid identification of the phase I and II in vitro metabolite of 141W94 using mass spectrometry. Four different sources of liver S9 fractions were used for studying comparative in vitro metabolism of 141W94. They were obtained from Arochlor-induced rat, normal (untreated) rat, cynomolgus monkey and human livers. Selected incubations were supplemented with uridine diphosphate glucuronic acid and the reduced form of glutathione. The predominant species seen in the incubation mixture was the parent compound 141W94. Metabolites arising from ring opening to form the diol and carboxylic acid and oxidation of the tetrahydrofurran ring (formation of dihydrofuran) were identified. In addition, of the two monohydroxylated products identified, one resulted from hydroxylation on the aniline ring and the other from hydroxylation at the benzylic position. Two different glucuronides were also observed. Comparing the three species, very little metabolism was seen in the normal (non-induced) rat. The metabolic profile and extent of metabolism with induced rat, monkey and human S9 was similar. Induced rat S9 incubation showed the formation of two unique metabolites that were not seen in non-induced rat, monkey and human S9 fractions. They were the monohydroxylated glucuronide and a carbamate cleavage product. The metabolites were identified using mass spectrometry based on their molecular masses and fragmentation patterns.

Abstract  Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs. © 2014 American Chemical Society.

Abstract  The effect of aldrin (309002) and chlordane (57749) pretreatment on the acute oral toxicity of Banol (671045) and Mobam (1079330) was studied in the rat. Female Osborne-Mendel-rats were given intraperitoneal injections of chlordane and aldrin 8 days prior to exposure by oral intubation to Banol or Mobam. The acute oral toxicity of Banol was markedly decreased and that of Mobam was slightly decreased by pretreatment of rats with chlordane or aldrin. An increase in serum and liver aliesterase (AliE) activities was caused by aldrin and chlordane but there was no change in liver and brain cholinesterase (ChE) activities. Mobam inhibited the activities of liver and brain ChE and liver and serum AliE. In aldrin pretreated rats, Banol inhibited serum AliE more, liver AliE the same, and brain and liver ChE slightly less than when administered alone. In aldrin pretreated rats Mobam did not change liver or serum AliE activities, but did decrease activities of brain and liver ChE less than when given alone. Aldrin protected against Banol as well as chlordane did, but the enzyme activities were different. Protection against Mobam was less effective, but the effects on enzyme systems were roughly paralleled by those produced by Banol.