Combination of the Silver-Ethylene Interaction and 3D Printing To Develop Antibacterial Superporous Hydrogels for Wound Management.

Due to insufficient biomedical functions of hydrogels for wound management, the exploitation of available methods to expand the biomedical functions of hydrogels always becomes the cutting-edge research. Here, we report on the use of the silver-ethylene interaction and 3D printing technique to develop the antibacterial superporous polyacrylamide (PAM)/hydroxypropyl methylcellulose (HPMC) hydrogel dressings. Experiments demonstrated that the silver-ethylene interaction played significant roles in mediating the formation, dispersion, and cross-linking of silver nanoparticles (AgNPs) in the hydrogel matrix as well as the cross-linking of the PAM networks. At the same time, such organometallic complexes also controlled the release of AgNPs to balance the cytocompatibility and antibacterial activity of the AgNP-cross-linked hydrogels. On the other hand, the use of 3D printed templates and HPMC as the pore-making materials demonstrated could tailor hydrogels into 91.4% porosity and the formed pores into open channels, endowing hydrogels with rapid water uptake rate and 14 times dead-weight of uptake capacity. Furthermore, experiments showed that the regular large pores arisen from 3D printed templates could buffer the swelling of superporous hydrogel dressings, thus decreasing the detachment risk of dressings from wounds. In vivo experiments demonstrated that the AgNP-cross-linked superporous hydrogel dressings could promote the healing of the infected wounds and restrain scar tissue formation.

A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.

Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in-wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.

Effect of Ethephon as an Ethylene-Releasing Compound on the Metabolic Profile of Chlorella vulgaris.

In this study, Chlorella vulgaris (C. vulgaris) was treated with ethephon at low (50 µM) and high (200 µM) concentrations in medium and harvested at 0, 7, and 14 days, respectively. The presence of ethephon led to significant metabolic changes in C. vulgaris, with significantly higher levels of α-tocopherol, γ-aminobutyric acid (GABA), asparagine, and proline, but lower levels of glycine, citrate, and galactose relative to control. Ethephon induced increases in saturated fatty acids but decreases in unsaturated fatty acids. The levels of highly saturated sulfoquinovosyldiacylglycerol species and palmitic acid bound phospholipids were increased on day 7 of ethephon treatment. Among the metabolites, the productivities of α-tocopherol (0.70 µg/L/day) and GABA (1.90 µg/L/day) were highest for 50 and 200 µM ethephon on day 7, respectively. We propose that ethephon treatment involves various metabolic processes in C. vulgaris and can be an efficient way to enrich the contents of α-tocopherol and GABA.

Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans.

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

Kinetics of ethylene and ethylene oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and of human livers.

Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST). Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ET-exposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of V(max) [nmol/(min·mg protein)] and of the apparent Michaelis constant (K(m) [mmol/l ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, V(max) values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly. By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as V(max)/K(m) [µl/(min·mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO.

The role of vinyl sulfonic acid homopolymer in calcium oxalate crystallization.

In this study, the effect of water soluble homopolymer of vinylsulfonic acid on spontaneous crystallization of calcium oxalate (CaOx) was investigated. CaOx crystals exhibiting different shapes and phase structures were produced in the presence of polymer. While the crystal growth of calcium oxalate was inhibited by homopolymer, the morphology of calcium oxalate transformed from monohydrate to dihydrate. Inhibition of calcium oxalate crystallization was provided by adsorption of homopolymer onto the active growth sites of crystals on account of the charge and hydrophilic effects. Polyelectrolyte effects were interpreted in terms of the adsorption of inhibitors onto the active growth sites on the crystal surface.

Exposición al óxido de etileno del personal auxiliar en odontología / Exposure to ethylene oxide in dental auxiliary staff

El riesgo que representa el uso del óxido de etileno durante los procesos de esterilización, se magnifica en la medida en la cual el personal encargado de su manipulación desconoce sus efectos y por encima de estos las medidas preventivas que se deben adoptar para el desarrollo de un ejercicio profesional dentro de la Salud y Seguridad en el Trabajo

The risk of use ethylene oxide during sterilization process is increased at time that the personnel uncknoked its effects and preventions norms

A new method for estimating the retention of selected smoke constituents in the respiratory tract of smokers during cigarette smoking.

This report describes a new method for estimating the retention of selected mainstream smoke constituents in the respiratory tract of adult smokers during cigarette smoking. Both particulate-phase (PP) constituents including nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N'-nitrosonornicotine (NNN), two tobacco-specific nitrosamines (TSNA), and gas-vapor-phase (GVP) constituents including carbon monoxide (CO), isoprene (IP), acetaldehyde (AA), and ethylene, were studied. To estimate the amounts of smoke constituents delivered during smoking, we used predetermined linear relationships between the measured cigarette filter solanesol content and machine-generated mainstream deliveries of these selected compounds. To determine the amounts of smoke constituents exhaled, the expired breath was directed through a Cambridge filter pad (CFP) attached to an infrared spectrometer. PP compounds were trapped on the CFP for later analysis and GVP compounds were analyzed in near real time. The smokers' respiratory parameters during smoking, such as inhalation/exhalation volume and time, were monitored using LifeShirt(R), a respiratory inductive plethysmography (RIP) device. The retention of each smoke constituent, expressed as a percentage, was then calculated as the difference between the amount delivered (estimated) and the amount exhaled relative to the amount delivered. We studied 16 adult male smokers who smoked cigarettes according to 3 predefined smoking patterns: no inhalation (pattern A), normal inhalation (pattern B), and deep inhalation (pattern C). For the three PP constituents, the mean retentions for pattern A ranged between 10 and 20%; and while the mean retentions of the two TSNAs were significantly higher for pattern C (84% for NNK and 97% for NNN) than those for pattern B (63% for NNK and 84% for NNN), the mean retentions of nicotine were basically the same between patterns B and C, which were both greater than 98%. For the GVP constituents, the retentions were similar between pattern B and pattern C, although different constituents were retained to different degrees (average values of 33%, 52%, 79%, and 99% for ethylene, IP, CO, and AA, respectively). The differences in the retention between different constituents could be interpreted in terms of each constituent's physical properties such as volatility and solubility. In conclusion, the method described is suitable for studying the retention of selected mainstream smoke constituents in the respiratory tract of smokers.

New insights on the stereodynamics of ethylene adsorption on an oxygen-precovered silver surface.

The control of spatial orientation of molecules has a great influence on the stereodynamics of elementary processes occurring both in homogeneous and heterogeneous phases. Nonpolar molecules have so far escaped direct experimental investigations because of their poor sensitivity to several external constraints. Recently, it has been shown that the collisional alignment produced in supersonic expansions coupled with molecular-beam velocity selection can help solve such problems. Here we show that the sticking probability of ethylene, a nonpolar molecule prototypical of unsaturated hydrocarbons, on an O(2)-precovered Ag(001) surface is larger for molecules approaching in a helicopter-like motion than for those cartwheeling. A mechanism involving a weakly bound precursor state is suggested, with helicopter molecules having a lower chance of being scattered back into the gas phase than cartwheels when colliding with preadsorbed ethylene.

Pharmacokinetics of ethylene in man by on-line laser photoacoustic detection.

The pharmacokinetics of ethylene are determined using laser-based photoacoustic detection and a closed chamber setup. Concentration-time data are analyzed using a two-compartment and a physiologically based pharmacokinetic (PBPK) model. Endogenous production was 92 +/- 13 pmol/h/kg for the two-compartment model and 75 +/- 10 pmol/h/kg for the PBPK model. These values agree with previous work at our department but are significantly lower than published values based on gas chromatography. The blood:air partition coefficient in the PBPK model was determined by curve fitting, because simulations based on published values did not agree well with data. Curve fitting gave a value of 0.092 +/- 0.029. The real-time nature and high sensitivity of photoacoustic detection make it a useful addition to gas chromatography in closed chamber studies.

Effect of the combined treatment of insecticides and an attractant for the control of Phloeotribus scarabaeoides, a pest of Olea europea.

Different insecticides have been tested for the control of the olive bark beetle, Phloeotribus scarabaeoides Bern. This scolytid can be managed at two points in its biological cycle: in pruned logs, where it excavates reproduction galleries, or in living trees, after emergence from the logs, where it digs feeding galleries. In mortality laboratory bioassays, the efficiency of organophosphorus insecticides has been ranked as follows: chlorpyrifos + dimethoate < formothion < methidathion. Formothion and methidathion, the two most efficient, were sprayed on olive logs together with a pyrethroid insecticide, deltamethrin, and a formulation which combined an organophosphorus (fenitrothion) and a pyrethroid (cypermethrin) insecticide. Deltamethrin inhibited the excavation of new reproduction galleries and induced a repellent effect on the olive pest. In contrast, none of the organophosphorus insecticides or the combination, fenitrothion + cypermethrin, were able to control the olive bark beetle. In olive trees, deltamethrin controlled this olive pest without showing the repellent effect observed for logs. Ethylene, a plant hormone, has been reported as an attractant for the olive bark beetle. The use of dispensers which released ethylene increased the number of P. scarabaeoides approaching the treated olive trees, thus favouring its use in a lure-and-trap control system.

Mechanistic and toxicokinetic data reducing uncertainty in risk assessment.

Risk characterization comprises hazard identification describing the intrinsic toxic potential of a chemical, knowledge of dose-response-relationships, as well as of toxicokinetics describing quantitatively the relation between external and internal dose and exposure assessment. Compounds that induce reversible effects, which are repaired during and after exposure, are considered thresholded and allow definition of a NOEL. Biological reactive intermediates of chemicals have the potential to bind covalently to cellular macromolecules like proteins and DNA. Such interaction may not be repaired completely. If damage is not repaired, the effect persists and accumulates upon repeated exposure. In such cases a NOEL cannot be determined. Thus, in the risk assessment process, data on covalent binding (CB) are of qualitative and together with toxicokinetics of quantitative significance. Qualitatively, CB, especially with DNA and in correlation with this to proteins, is indicative for an irreversible and non-thresholded mutagenic and carcinogenic effect. Absence or presence of CB assists to differentiate between primarily genotoxic and thresholded non-genotoxic carcinogens. Quantitatively, toxicokinetics together with CB are used to quantify internal exposure and target dose, which is a prerequisite for species-species extrapolation, and for extrapolation from high dose to low dose. For example, the toxicokinetics of the reactive intermediates of styrene and ethylene have been determined in rodents and humans and modeled to predict dose-responses of internal exposure. It is described in this communication that such information, together with other parameters like cell proliferation as a result of cytotoxicity, is the basis for quantitative risk assessment of human exposure to these compounds. Also for chlorobenzene, the relevance of toxicokinetics for estimating the human health risk is demonstrated.

Microsomal oxidation of tribromoethylene and reactions of tribromoethylene oxide.

Halogenated olefins are of interest because of their widespread use in industry and their potential toxicity to humans. Epoxides are among the enzymatic oxidation products and have been studied in regard to their toxicity. Most of the attention has been given to chlorinated epoxides, and we have previously studied the reactions of the mono-, di-, tri-, and tetrachloroethylene oxides. To further test some hypotheses concerning the reactivity of these compounds, we prepared tribromoethylene (TBE) oxide and compared it to trichloroethylene (TCE) oxide and other chlorinated epoxides. TBE oxide reacted with H(2)O about 3 times faster than did TCE oxide. Several hydrolysis products of TBE oxide were the same as formed from TCE oxide, i.e., glyoxylic acid, CO, and HCO(2)H. Br(2)CHCO(2)H was formed from TBE oxide; the yield was higher than for Cl(2)CHCO(2)H formed in the hydrolysis of TCE oxide. The yield of tribromoacetaldehyde was < 0.4% in aqueous buffer (pH 7.4). In rat liver microsomal incubations containing TBE and NADPH, Br(2)CHCO(2)H was a major product, and tribromoacetaldehyde was a minor product. These results are consistent with schemes previously developed for halogenated epoxides, with migration of bromine being more favorable than for chlorine. Reaction of TBE oxide with lysine yielded relatively more N-dihaloacetyllysine and less N-formyllysine than in the case of TCE oxide. This same pattern was observed in the products of the reaction of TBE oxide with the lysine residues in bovine serum albumin. We conclude that the proposed scheme of hydrolysis of halogenated epoxides follows the expected halide order and that this can be used to rationalize patterns of hydrolysis and reactivity of other halogenated epoxides.

New oligoethylene ester derivatives of 5-iodo-2'-deoxyuridine as dermal prodrugs: synthesis, physicochemical properties, and skin permeation studies.

Five new oligoethylene ester derivatives (9-13) of 5-iodo-2'-deoxyuridine (IDU) were synthesized and assayed to determine their lipophilicity by both experimental lipophilicity indices (log K') and calculated partition coefficients (CLOGP). In vitro experiments were carried out to evaluate the chemical and enzymatic stability and fluxes through excised human skin of these new IDU derivatives. Esters 9-13 showed increased lipophilicity compared with the parent drug (IDU), had good stability in phosphate buffer (pH 7.4), and were readily hydrolyzed by porcine esterase. No correlation between lipophilicity and skin permeation fluxes of synthesized esters 9-13 was observed. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only esters 9 and 10 significantly increased the cumulative amount of IDU that penetrated through excised human skin compared with the parent drug (IDU).

Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide.

The purposes of the present study were: (i) to investigate the potential use of several biomarkers as quantitative indicators of the in vivo conversion of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosimetry data that might improve assessment of human risk from exogenous ET exposures. Groups (n = 7/group) of male F344 rats and B6C3F1 mice were exposed by inhalation to 0 and 3000 p. p.m. ET for 1, 2 or 4 weeks (6 h/day, 5 days/week) or to 0, 40, 1000 and 3000 p.p.m. ET for 4 weeks. N:-(2-hydroxyethyl)valine (HEV), N:7-(2-hydroxyethyl) guanine (N7-HEG) and HPRT: mutant frequencies were assessed as potential biomarkers for determining the molecular dose of EO resulting from exogenous ET exposures of rats and mice, compared with background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC-HRMS), HEV was determined by Edman degradation and GC-HRMS and HPRT: mutant frequencies were measured by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exposure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations around 1 week of exposure in most tissues evaluated (brain, liver, lung and spleen). The dose-response curves for N7-HEG and HEV were supralinear in exposed rats and mice, indicating that metabolic activation of ET was saturated at exposures >/=1000 p.p.m. ET. Exposures of mice and rats to 200 p.p.m. EO for 4 weeks (as positive treatment controls) led to significant increases in HPRT: mutant frequencies over background in splenic T cells from exposed rats and mice, however, no significant mutagenic response was observed in the HPRT: gene of ET-exposed animals. Comparisons between the biomarker data for both unexposed and ET-exposed animals, the dose-response curves for the same biomarkers in EO-exposed rats and mice and the results of the rodent carcinogenicity studies of ET and EO suggest that too little EO arises from exogenous ET exposure to produce a significant mutagenic response or a carcinogenic response under standard bioassay conditions.

A physiological toxicokinetic model for exogenous and endogenous ethylene and ethylene oxide in rat, mouse, and human: formation of 2-hydroxyethyl adducts with hemoglobin and DNA.

Ethylene (ET) is a gaseous olefin of considerable industrial importance. It is also ubiquitous in the environment and is produced in plants, mammals, and humans. Uptake of exogenous ET occurs via inhalation. ET is biotransformed to ethylene oxide (EO), which is also an important volatile industrial chemical. This epoxide forms hydroxyethyl adducts with macromolecules such as hemoglobin and DNA and is mutagenic in vivo and in vitro and carcinogenic in experimental animals. It is metabolically eliminated by epoxide hydrolase and glutathione S-transferase and a small fraction is exhaled unchanged. To estimate the body burden of EO in rodents and human resulting from exposures to EO and ET, we developed a physiological toxicokinetic model. It describes uptake of ET and EO following inhalation and intraperitoneal administration, endogenous production of ET, enzyme-mediated oxidation of ET to EO, bioavailability of EO, EO metabolism, and formation of 2-hydroxyethyl adducts of hemoglobin and DNA. The model includes compartments representing arterial, venous, and pulmonary blood, liver, muscle, fat, and richly perfused tissues. Partition coefficients and metabolic parameters were derived from experimental data or published values. Model simulations were compared with a series of data collected in rodents or humans. The model describes well the uptake, elimination, and endogenous production of ET in all three species. Simulations of EO concentrations in blood and exhaled air of rodents and humans exposed to EO or ET were in good agreement with measured data. Using published rate constants for the formation of 2-hydroxyethyl adducts with hemoglobin and DNA, adduct levels were predicted and compared with values reported. In humans, predicted hemoglobin adducts resulting from exposure to EO or ET are in agreement with measured values. In rodents, simulated and measured DNA adduct levels agreed generally well, but hemoglobin adducts were underpredicted by a factor of 2 to 3. Obviously, there are inconsistencies between measured DNA and hemoglobin adduct levels.

In vitro anti-multidrug resistance activities of acyclic and cyclic disulfonamides in murine leukemia cells.

We synthesized seven acyclic ethylenedisulfonamides and twelve cyclic disulfonamides, 1, 5-bis(arenesulfonyl)-1, 3, 5-triazacycloheptanes, and compared their in vitro anti-multidrug resistance effects in P388/ADR multidrug-resistant cells which overexpress the multidrug transporter P-glycoprotein (P-gp). Acyclic disulfonamides with 4-methoxyphenyl, pyridyl, quinolyl, or isoquinolyl groups hardly influenced the sensitivity of P388/ADR cells to vinblastine (VLB), and cyclic disulfonamides with these aryl groups only slightly increased the sensitivity to VLB. Acyclic or cyclic disulfonamides with 4-chlorophenyl or naphthyl groups moderately potentiated the effect of VLB. The maximum effect was observed with 1, 5-bis(1-naphthale-nesulfonyl)-1, 3, 5-triazacycloheptan (B3). B3 enhanced the effects of vincristine, adriamycin, daunomycin and actinomycin D in P388/ADR cells, but not in sensitive P388 cells. B3 increased intracellular concentrations of VLB and adriamycin in P388/ADR cells. The expression of P-gp in P388/ADR cells was not affected by cultivation with B3 for 72 hours. These results indicated that the anti-multidrug resistance activities of B3 were dependent on its inhibitory effect on P-gp.

Quantitative determination of CGP 61755, a protease inhibitor, in plasma and urine by high-performance liquid chromatography and fluorescence detection.

A liquid chromatographic assay for the determination of CGP 61755 (I) in plasma and urine is described. A similar method for CGP 53437, another HIV-1 protease inhibitor, has been developed and reported previously. After a deproteinization step, a liquid-liquid extraction is performed. Compound I and the internal standard CGP 55749 (II) are hydrolyzed and the primary amine group derivatized using fluorescamine. Chromatography is achieved by isocratic elution with a mobile phase of 30 mM borax buffer (pH 9)-acetonitrile (58:42, v/v). The derivatives of the compounds I and II fluoresce at 480 nm, on excitation at 395 nm and the retention times under these conditions were approximately 6 and 8 min, respectively. The limit of quantitation (LOQ) which is the lowest concentration of the analyte that can be measured with a coefficient of variation and a deviation from theory of less than 20%, was 15 ng/ml plasma and 20 ng/ml urine. The analyte is stable for at least four months in human plasma and sixteen months in dog plasma samples. Different human plasma sources and three different species (rat, rabbit and dog) were tested and no interference between analyte and plasma constituents was observed.

Profile of CGP 61755: a novel and potent HIV-1 protease inhibitor that shows enhanced anti-HIV activity when combined with other antiretroviral agents in vitro.

CGP 61755 is a novel hydroxyethylene derivative produced by a high yield 10 step chemical synthesis. It is highly specific for HIV-1 protease with an IC50 of 1 nM. The ED90 in MT-2, PBLs and macrophages is infected with laboratory strains of HIV-1 or clinical isolates is 30-100 nM. In chronically infected macrophages the ED90 is 1000 nM (1000 nM for saquinavir and 10 microM for indinavir). When the antiviral activity of CGP 61755 on HIV-1 infected lymphocytes was examined using serum free medium an ED99 of 60 nM was determined, while in the presence of 10% human serum the same activity was achieved with 120 nM. When examined in combination with RT inhibitors or protease inhibitors, either in a co-culture of CEM-SS and chronically infected H9IIIB cells or in a free virus lymphocyte infection, cooperativity of the antiviral activities was observed. Dog pharmacokinetic studies comparing p.o. and i.v. data indicate that CGP 61755 has a bioavailability between 50 and 80%. Following oral administration the area under the concentration curve (AUC) values increased in a dose proportional manner. The plasma levels of the drug at 6 hours after oral administration were above the ED90. Based on these properties we believe that CGP 61755 has an attractive profile that justifies further preclinical evaluation of the drug.

Uptake and metabolism of ethene studied in a smoke-stop experiment.

Knowledge of the relationships between exposure levels and levels of hemoglobin adducts are essential when the latter are to be used for exposure monitoring or risk estimation, the hygienic control being based on measurements of exposure. These ratios are mostly very uncertain, mainly due to difficulties of determining the time-weighted average exposure concentration. A solution to this problem has been suggested involving adduct measurement before and after two consecutive periods of about 1 week, the first with absence from exposure, the second with careful measurement of exposure. This model was tested in two smokers who abstained from smoking for one week. Analysis of inhaled ethene and of adducts from ethylene oxide (EO) to N-terminal valine of hemoglobin are compatible with metabolism of 2% of inhaled ethene to EO and a detoxification rate of 1 h-1 of EO.