Unrecognized volatile and semi-volatile organic compounds from brake wear.

Motor vehicles are among the major sources of pollutants and greenhouse gases in urban areas and a transition to "zero emission vehicles" is underway worldwide. However, emissions associated with brake and tire wear will remain. We show here that previously unrecognized volatile and semi-volatile organic compounds, which have a similarity to biomass burning emissions are emitted during braking. These include greenhouse gases or, these classified as Hazardous Air Pollutants, as well as nitrogen-containing organics, nitrogen oxides and ammonia. The distribution and reactivity of these gaseous emissions are such that they can react in air to form ozone and other secondary pollutants with adverse health and climate consequences. Some of the compounds may prove to be unique markers of brake emissions. At higher temperatures, nucleation and growth of nanoparticles is also observed. Regions with high traffic, which are often disadvantaged communities, as well as commuters can be impacted by these emissions even after combustion-powered vehicles are phased out.

Effect of dimethylamine on the gas phase sulfuric acid concentration measured by Chemical Ionization Mass Spectrometry.

Sulfuric acid is widely recognized as a very important substance driving atmospheric aerosol nucleation. Based on quantum chemical calculations it has been suggested that the quantitative detection of gas phase sulfuric acid (H2SO4) by use of Chemical Ionization Mass Spectrometry (CIMS) could be biased in the presence of gas phase amines such as dimethylamine (DMA). An experiment (CLOUD7 campaign) was set up at the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber to investigate the quantitative detection of H2SO4 in the presence of dimethylamine by CIMS at atmospherically relevant concentrations. For the first time in the CLOUD experiment, the monomer sulfuric acid concentration was measured by a CIMS and by two CI-APi-TOF (Chemical Ionization-Atmospheric Pressure interface-Time Of Flight) mass spectrometers. In addition, neutral sulfuric acid clusters were measured with the CI-APi-TOFs. The CLOUD7 measurements show that in the presence of dimethylamine (<5 to 70 pptv) the sulfuric acid monomer measured by the CIMS represents only a fraction of the total H2SO4, contained in the monomer and the clusters that is available for particle growth. Although it was found that the addition of dimethylamine dramatically changes the H2SO4 cluster distribution compared to binary (H2SO4-H2O) conditions, the CIMS detection efficiency does not seem to depend substantially on whether an individual H2SO4 monomer is clustered with a DMA molecule. The experimental observations are supported by numerical simulations based on A Self-contained Atmospheric chemistry coDe coupled with a molecular process model (Sulfuric Acid Water NUCleation) operated in the kinetic limit.

Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans.

A physiologically based pharmacokinetic (PBPK) model was developed and applied to a metabolic series approach for the ethyl series (i.e., ethyl acetate, ethanol, acetaldehyde, and acetate). This approach bases toxicity information on dosimetry analyses for metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for parent or individual compounds. In vivo pharmacokinetic studies of ethyl acetate and ethanol were conducted in rats following IV and inhalation exposure. Regardless of route, ethyl acetate was rapidly converted to ethanol. Blood concentrations of ethyl acetate and ethanol following both IV bolus and infusion suggested linear kinetics across blood concentrations from 0.1 to 10 mM ethyl acetate and 0.01-0.8 mM ethanol. Metabolic parameters were optimized and evaluated based on available pharmacokinetic data. The respiratory bioavailability of ethyl acetate and ethanol were estimated from closed chamber inhalation studies and measured ventilation rates. The resulting ethyl series model successfully reproduces blood ethyl acetate and ethanol kinetics following IV administration and inhalation exposure in rats, and blood ethanol kinetics following inhalation exposure to ethanol in humans. The extrapolated human model was used to derive human equivalent concentrations for the occupational setting of 257-2120 ppm ethyl acetate and 72-517 ppm ethyl acetate for continuous exposure, corresponding to rat LOAELs of 350 and 1500 ppm.

New insights on the role of sea ice in intercepting atmospheric pollutants using (129)I.

Measurements of (129)I carried out on sea ice samples collected in the central Arctic Ocean in 2007 revealed relatively high levels in the range of 100-1400×10(7) at L(-1) that are comparable to levels measured in the surface mixed layer of the ocean at the same time. The (129)I/(127)I ratio in sea ice is much greater than that in the underlying water, indicating that the (129)I inventory in sea ice cannot be supported by direct uptake from seawater or by iodine volatilization from proximal (nearby) oceanic regimes. Instead, it is proposed that most of the (129)I inventory in the sea ice is derived from direct atmospheric transport from European nuclear fuel reprocessing plants at Sellafield and Cap La Hague. This hypothesis is supported by back trajectory simulations indicating that volume elements of air originating in the Sellafield/La Hague regions would have been present at arctic sampling stations coincident with sampling collection.

Meat intake in Britain in relation to other dietary components and to demographic and risk factor variables: analyses based on the National Diet and Nutrition Survey of 2000/2001.

BACKGROUND: Red and processed meat intakes have been positively associated with the risk of several major chronic diseases. Understanding population intakes is important when formulating dietary recommendations. The present study investigated the dispersion of intakes of red and processed meat and associations with dietary, socio-demographic and risk factors. METHODS: The present study comprised a secondary analysis of the British National Diet and Nutrition Survey 2000/1, including 7-day dietary records, from 766 male and 958 female respondents aged 19-64 years. Composite dishes were disaggregated into primary ingredients. Self-reported vegetarians (V) were grouped into one stratum and other respondents were stratified into five groups (F1-F5) according to energy-adjusted red plus processed meat (RPM) intake, to give six strata. 7-day RPM intakes were adjusted to estimate 'usual' habitual intakes, using ratios of between-person to total variance in daily intakes. RESULTS: Mean recorded intakes of red, processed, white and total meat were 48, 41, 40 and 129 g day(-1) , respectively, in males and 30, 22, 30 and 82 g day(-1) in females. Estimated habitual intakes of RPM standardised to sex-specific energy intakes across the six strata were: 12 (V), 56, 76, 90, 105 and 137 g day(-1) in males and 5 (V), 34, 46, 55, 65 and 88 g day(-1) in females. Lower RPM consumers tended to be of higher social class and educational level and to have more favourable levels of some risk factors. CONCLUSIONS: Mean intakes of red, processed and white meat were of similar magnitude. Habitual intakes of RPM showed wide dispersion with one-quarter of males < 55 g day(-1) and one-quarter of females < 27 g day(-1) . Lowering overall RPM consumption could be achieved by seeking greater reductions among current high consumers.

Effect of ribavirin on junin virus infection in guinea pigs.

Junin virus (JUNV) is the aetiological agent of Argentine haemorrhagic fever. The pathogenesis of the infection is not well understood, no licensed vaccines exist and no specific antiviral therapy is available. Previous studies have demonstrated the ability of ribavirin to delay and reduce JUNV disease and virus burden in guinea pigs without preventing death. Based on available data, we performed three different studies to determine the efficacy of ribavirin against JUNV in the guinea pig model with a focus on survival. Different doses and treatment schedules of ribavirin were tested in a lethal model of JUNV infection. Our results show that prolonged treatment with high doses of ribavirin significantly reduces the mortality in guinea pigs infected with JUNV. These results may be useful in future experimental studies or clinical testing.

Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.

Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 ± 13 and 66 ± 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no apparent additional exacerbating effects due to ethanol coexposure.

Salmonella SdiA recognizes N-acyl homoserine lactone signals from Pectobacterium carotovorum in vitro, but not in a bacterial soft rot.

Genomes of Salmonella enterica isolates, including those linked to outbreaks of produce-associated gastroenteritis, contain sdiA, which encodes a receptor of N-acyl homoserine lactones (AHL). AHL are the quorum-sensing signals used by bacteria to coordinately regulate gene expression within -their populations. Because S. enterica does not produce its own AHL, SdiA is hypothesized to function in the interspecies cross-talk with AHL-producing bacteria. Under laboratory conditions, S. enterica responded to AHL from phytobacteria by upregulating expression of srgE. AHL-dependent expression of srgE required a functional sdiA. Essentially, no sdiA-dependent resolution of the srgE recombinase-based (RIVET) reporter was observed inside a soft rot formed on a tomato by an AHL-producing strain of Pectobacterium carotovorum. The results of the control experiments suggest that sdiA is not expressed inside tomato, pepper, green onion, or carrot affected by the soft rot, and the lack of sdiA expression in planta prevents Salmonella spp. from responding to AHL. Despite its inability to detect and respond to AHL during colonization of soft rots, S. enterica reached higher final cell numbers inside a tomato soft rot compared with its growth in intact tomato fruit. The synergistic effect was the strongest under the conditions that are typical for the Florida fall/winter production season.

Natural rates of sediment containment of PAH, PCB and metal inventories in Sydney Harbour, Nova Scotia.

Analyses of metal and organic contaminants were carried out on 41 sediment cores, dated using (210)Pb and (137)Cs, from the heavily industrialized region of Sydney Harbour, N.S. to evaluate the history of contamination and to predict the rates of natural containment of the harbour by sediment burial. Geochronologies for metals (eg. Pb, As) and polycyclic aromatic hydrocarbons (PAHs) are correlated with the development of the steel and coke industries in the Sydney region while polychlorinated biphenyl (PCB) geochronologies reflect the disposal of electrical equipment used in the steel mill/coking operations. Pb was derived mainly from atmospheric emissions and its concentration has declined exponentially with time in harbour sediments since the closure of the steel mill/coke ovens in the 1980s with a time constant of about 15 years. This represents the time scale for the circulation of this particle-associated contaminant in transient catchment basins prior to permanent deposition in the sediments. PAH and PCB sediment concentrations have also declined exponentially with time since the 1980s, but with a smaller time constant of 10 years owing to the fact that they enter the harbour directly with steel mill and coke oven effluent rather than through atmospheric pathways. Since the time dependence for the burial of metal and organic inventories can be modeled by first order processes, future contaminant levels can be predicted for surface sediments in Sydney Harbour. Mean sediment concentrations of metal and organic contaminants in the upper 5 cm throughout most of the harbour are predicted to decline to levels below the effects range-medium (above which organisms are very likely to be negatively affected by the presence of a contaminant) by 2030.

Variability of platelet aggregate dispersal with glycoprotein IIb-IIIa antagonists eptifibatide and abciximab.

BACKGROUND: Utilization of glycoprotein IIb-IIIa (GPIIb-IIIa) inhibitors improves outcomes of patients with acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention (PCI). These results may be related to the ability of the inhibitors to destabilize coronary thrombi, reduce microembolization, and restore vessel patency. OBJECTIVE: To evaluate in vitro the ability of GPIIb-IIIa antagonists, abciximab and eptifibatide, to promote the disaggregation of platelet-rich thrombus. METHODS: Antagonist-induced disaggregation was assayed in plasma by aggregometry, as well as in whole blood by point of care and capillary perfusion systems. Fibrinogen dissociation from the platelet surface was quantified by flow cytometry. RESULTS: Significant disaggregation of 5 microm ADP-induced aggregates was observed after addition of either agent. The maximum extent and rate of disaggregation were significantly higher with eptifibatide than with abciximab. Both antagonists also dispersed 2 microg mL(-1) collagen-induced aggregates, again with eptifibatide having a greater effect. Eptifibatide, but not abciximab (up to 10 microg mL(-1)), was efficient at dissociating aggregates to single platelets in whole blood and dispersing aggregates that had been aged for 30 min before treatment. Eptifibatide also reduced existing thrombus burden in the perfusion model under arterial flow conditions. A key mechanism of aggregate dispersal was antagonist-induced displacement of platelet-bound fibrinogen, which was greater with eptifibatide, a competitive inhibitor of fibrinogen binding, than with the noncompetitive inhibitor, abciximab. CONCLUSIONS: These results suggest that drug concentration and residence time, along with thrombus extent and age, may be critical determinants in promoting timely recanalization.

Thermal inactivation D- and z-values of Salmonella serotypes and listeria innocua in chicken patties, chicken tenders, franks, beef patties, and blended beef and turkey patties.

Commercially formulated meat products, including chicken patties, chicken tenders, franks, beef patties, and blended beef and turkey patties, were obtained from processors. Each product was inoculated with 7 to 8 logs of Salmonella (Senftenberg, Typhimurium, Heidelberg, Mission, Montevideo, and California) or Listeria innocua. The inoculated meat samples were heat treated at 55 to 70 degrees C. At each temperature, the decimal reduction time (D) was obtained by linear regression of survival curves. Values of D and the temperature difference required for the thermal inactivation curve to drop a logarithmic cycle (z) were determined for the Salmonella serotypes and L. innocua in each product. At 55 to 70 degrees C. for the five tested products, the D-values for the Salmonella serotypes and L. innocua were 26.97 to 0.25 min and 191.94 to 0.18 min, respectively, and their z-values were 7.60 to 9.83 degrees C and 4.86 to 8.67 degrees C, respectively. Significant differences were found for the D- and z-values among the five products. This study will better enable processors to determine the process lethality of pathogens in commercial meat products.

Mechanisms of nitric oxide release from nitrovasodilators in aqueous solution: reaction of the nitroprusside ion ([Fe(CN)5NO]2-) with L-ascorbic acid.

Nitric Oxide (NO) is a very diverse endogenous molecule and is responsible for a number of mammalian physiological activities. Sodium nitroprusside (SNP) is a long known hypotensive agent due to its ability to produce NO in situ. In this study, we have carried out a detailed investigation on the kinetics and mechanism of the decomposition of SNP by L-ascorbic acid to afford NO in aqueous medium. Spectrophotometric and electrochemical methods were employed in these studies. Experiments were performed under an argon atmosphere and reaction rates were strongly pH dependent and increases with pH. NO release increases up to about pH 7 after which it decreases at higher pHs. The two ionized forms of ascorbate present in aqueous solution reduce SNP in the order A2->>HA->>H2A (H2A=L-ascorbic acid) to release NO. The outer-sphere reduction of SNP by ascorbate involved three clear stages with NO being released in the last stage. Our kinetic results also show catalysis by group 1 alkali metal ions to increase down the group from Li+ to Cs+. A detail study presented here, strongly illustrate the possibility of the biological antioxidant, L-ascorbic acid, to play a vital role in the in situ metabolism of nitrosocompounds such as SNP to produce NO.

SdiA of Salmonella enterica is a LuxR homolog that detects mixed microbial communities.

Proteins of the LuxR family detect the presence of N-acylhomoserine lactones (AHLs) and regulate transcription accordingly. When AHLs are synthesized by the same species that detects them, the system allows a bacterium to measure the population density of its own species, a phenomenon known as quorum sensing. The sdiA genes of Escherichia coli and Salmonella enterica serovar Typhimurium are predicted to encode LuxR homologs. However, these species do not appear to synthesize AHLs or any other molecule detected by SdiA. It has previously been demonstrated that overexpression of sdiA results in the activation of the ftsQAZ locus in E. coli and four other loci in Salmonella serovar Typhimurium. Here we report that transcriptional fusions to these five loci fall into two classes. The first class requires overexpression of sdiA for activation. The second class responds to sdiA expressed from its natural position in the chromosome if the appropriate AHLs are added to the culture. The only member of the second class is a series of Prck-luxCDABE fusions in Salmonella serovar Typhimurium. SdiA responds with highest sensitivity to AHLs that have a keto modification at the third carbon and an acyl chain length of 6 or 8 (half-maximal response between 1 and 5 nM). Growth of Salmonella in proximity to species known to synthesize these AHLs results in sdiA-dependent activation of the Prck-luxCDABE fusions. SdiA appears to be the first AHL receptor discovered that detects signals emanating exclusively from other species.

Atlantic water flow pathways revealed by lead contamination in Arctic basin sediments.

Contaminant lead in sediments underlying boundary currents in the Arctic Ocean provides an image of current organization and stability during the past 50 years. The sediment distributions of lead, stable lead isotope ratios, and lead-210 in the major Arctic Ocean basins reveal close coupling of the Eurasian Basin with the North Atlantic during the 20th century. They indicate that the Atlantic water boundary current in the Eurasian Basin has been a prominent pathway, that contaminant lead from the Laptev Sea supplies surface water in the transpolar drift, and that the Canadian and Eurasian basins have been historically decoupled.

Immigration and the ephemerality of a natural population bottleneck: evidence from molecular markers.

Population bottlenecks are often invoked to explain low levels of genetic variation in natural populations, yet few studies have documented the direct genetic consequences of known bottlenecks in the wild. Empirical studies of natural population bottlenecks are therefore needed, because key assumptions of theoretical and laboratory studies of bottlenecks may not hold in the wild. Here we present microsatellite data from a severe bottleneck (95% mortality) in an insular population of song sparrows (Melospiza melodia). The major findings of our study are as follows: (i) The bottleneck reduced heterozygosity and allelic diversity nearly to neutral expectations, despite non-random survival of birds with respect to inbreeding and wing length. (ii) All measures of genetic diversity regained pre-bottleneck levels within two to three years of the crash. This rapid recovery was due to low levels of immigration. (iii) The rapid recovery occurred despite a coincident, strong increase in average inbreeding. These results show that immigration at levels that are hard to measure in most field studies can lead to qualitatively very different genetic outcomes from those expected from mutations only. We suggest that future theoretical and empirical work on bottlenecks and metapopulations should address the impact of immigration.

Contaminants in the Canadian Arctic: 5 years of progress in understanding sources, occurrence and pathways.

Recent studies of contaminants under the Canadian Northern Contaminants Program (NCP) have substantially enhanced our understanding of the pathways by which contaminants enter Canada's Arctic and move through terrestrial and marine ecosystems there. Building on a previous review (Barrie et al., Arctic contaminants: sources, occurrence and pathways. Sci Total Environ 1992:1-74), we highlight new knowledge developed under the NCP on the sources, occurrence and pathways of contaminants (organochlorines, Hg, Pb and Cd, PAHs, artificial radionuclides). Starting from the global scale, we examine emission histories and sources for selected contaminants focussing especially on the organochlorines. Physical and chemical properties, transport processes in the environment (e.g. winds, currents, partitioning), and models are then used to identify, understand and illustrate the connection between the contaminant sources in industrial and agricultural regions to the south and the eventual arrival of contaminants in remote regions of the Arctic. Within the Arctic, we examine how contaminants impinge on marine and terrestrial pathways and how they are subsequently either removed to sinks or remain where they can enter the biosphere. As a way to focus this synthesis on key concerns of northern residents, a number of special topics are examined including: a mass balance for HCH and toxaphene (CHBs) in the Arctic Ocean; a comparison of PCB sources within Canada's Arctic (Dew Line Sites) with PCBs imported through long-range transport; an evaluation of concerns posed by three priority metals--Hg, Pb and Cd; an evaluation of the risks from artificial radionuclides in the ocean; a review of what is known about new-generation pesticides that are replacing the organochlorines; and a comparison of natural vs. anthropogenic sources of PAH in the Arctic. The research and syntheses provide compelling evidence for close connectivity between the global emission of contaminants from industrial and agricultural activities and the Arctic. For semi-volatile compounds that partition strongly into cold water (e.g. HCH) we have seen an inevitable loading of Arctic aquatic reservoirs. Drastic HCH emission reductions have been rapidly followed by reduced atmospheric burdens with the result that the major reservoir and transport agent has become the ocean. In the Arctic, it will take decades for the upper ocean to clear itself of HCH. For compounds that partition strongly onto particles, and for which the soil reservoir is most important (e.g. PCBs), we have seen a delay in their arrival in the Arctic and some fractionation toward more volatile compounds (e.g. lower-chlorinated PCBs). Despite banning the production of PCB in the 1970s, and despite decreases of PCBs in environmental compartments in temperate regions, the Arctic presently shows little evidence of reduced PCB loadings. We anticipate a delay in PCB reductions in the Arctic and environmental lifetimes measured in decades. Although artificial radionuclides have caused great concern due to their direct disposal on Russian Shelves, they are found to pose little threat to Canadian waters and, indeed, much of the radionuclide inventory can be explained as remnant global fallout, which was sharply curtailed in the 1960s, and waste emissions released under license by the European reprocessing plants. Although Cd poses a human dietary concern both for terrestrial and marine mammals, we find little evidence that Cd in marine systems has been impacted by human activities. There is evidence of contaminant Pb in the Arctic, but loadings appear presently to be decreasing due to source controls (e.g. removal of Pb from gasoline) in Europe and North America. Of the metals, Hg provokes the greatest concern; loadings appear to be increasing in the Arctic due to global human activities, but such loadings are not evenly distributed nor are the pathways by which they enter and move within the Arctic well understood.

Estimating the time to extinction in an island population of song sparrows.

We estimated and modelled how uncertainties in stochastic population dynamics and biases in parameter estimates affect the accuracy of the projections of a small island population of song sparrows which was enumerated every spring for 24 years. The estimate of the density regulation in a theta-logistic model (theta = 1.09 suggests that the dynamics are nearly logistic, with specific growth rate r1 = 0.99 and carrying capacity K = 41.54. The song sparrow population was strongly influenced by demographic (sigma2(d) = 0.66) and environmental (sigma2(d) = 0.41) stochasticity. Bootstrap replicates of the different parameters revealed that the uncertainties in the estimates of the specific growth rate r1 and the density regulation theta were larger than the uncertainties in the environmental variance sigma2(e) and the carrying capacity K. We introduce the concept of the population prediction interval (PPI), which is a stochastic interval which includes the unknown population size with probability (1 - alpha). The width of the PPI increased rapidly with time because of uncertainties in the estimates of density regulation as well as demographic and environmental variance in the stochastic population dynamics. Accepting a 10% probability of extinction within 100 years, neglecting uncertainties in the parameters will lead to a 33% overestimation of the time it takes for the extinction barrier (population size X = 1) to be included into the PPI. This study shows that ignoring uncertainties in population dynamics produces a substantial underestimation of the extinction risk.

Kinetics and mechanism of the decomposition of S-nitrosoglutathione by l-ascorbic acid and copper ions in aqueous solution to produce nitric oxide.

S-Nitrosothiols serve as a good source of nitric oxide ((*)NO) mainly due to the ease of cleavage of the S-N bond which consequently produces (*)NO. The reductive decomposition of S-nitrosoglutathione (GSNO) by l-ascorbic acid (vitamin C) yields (*)NO which was monitored both electrochemically (using NO-probe) and spectrophotometrically. The rate of reaction and (*)NO release was found to be pH dependent in a manner which drastically increases with pH demonstrating that the l-ascorbic acid dianion (A(2-)) is by far the most reactive species of l-ascorbic acid (H(2)A). The derived rate expression (measuring the disappearance of the absorption at ca. 336 nm due to GSNO) was established as rate = -d[GSNO](t)/dt = ((k(a)[H(+)](2) + k(b)[H(+)]K(1) + k(c)K(1)K(2))/([H(+)](2) + K(1)[H(+)] + K(1)K(2)))[GSNO](t)[H(2)A](t). k(a), k(b), and k(c) are second-order rate constants via the H(2)A, HA(-), and A(2-) pathways, respectively, while K(1) and K(2) represent the first and second equilibrium dissociation constants of l-ascorbic acid. There is little or no reaction at low pH (below 5.5), where H(2)A is a predominant species, and as a result the rate constant (k(a)) via this route was found to be negligible. At 25 degrees C, k(b) = 5.23 +/- 1.47 x 10(-3) dm(3) mol(-1) s(-1) and k(c) = 1.22 +/- 0.04 x 10(3) dm(3) mol(-1) s(-1), activation parameters DeltaH(double dagger)(b) = 54.4 +/- 4.3 kJ mol(-1), DeltaS(double dagger)(b) = -106 +/- 16 J K(-1) mol(-1), DeltaH(double dagger)(c) = 80.5 +/- 7.5 kJ mol(-1), DeltaS(double dagger)(c) = 84 +/- 7 kJ mol(-1). The experimental rate and activation parameters suggest that this redox process follows an outer-sphere electron transfer mechanism. GSNO is relatively stable in the dark, aqueous medium and even in the presence of trace quantities of Cu(2+). Induced catalytic decomposition of GSNO only becomes significant above ca. 10 microM Cu(2+), but after this it shows linear dependency. To nullify any catalysis by Cu(2+) or any other transition metal ions, EDTA was added to all experimental reactions except those where catalysis by Cu(2+) was studied.

Onset of action, efficacy, and safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an environmental exposure unit.

BACKGROUND: Fexofenadine hydrochloride is the active acid metabolite of terfenadine. Fexofenadine's anti-allergic properties require confirmation in a clinical setting. OBJECTIVE: The purpose of this study was to characterize the time to onset of clinically important relief of symptoms of allergic rhinitis in subjects taking single doses of either 60 mg or 120 mg fexofenadine HCl, or placebo, after exposure to ragweed pollen in a controlled environment. Other objectives were to assess the efficacy and safety of single doses of fexofenadine HCl. METHODS: One hundred forty-six ragweed-sensitive subjects were primed in the off-season with ragweed pollen in the environmental exposure unit. One hundred thirty-six subjects who adequately responded to priming entered a single-dose placebo phase. Placebo-responders were disqualified from the study, leaving 99 subjects with adequate symptoms to be randomized and given a single dose of either fexofenadine HCl 120 mg (33), 60 mg (33) or placebo (33), after 60 minutes of allergen exposure. Exposure continued over five hours and subjects recorded symptoms every 20 minutes. This study was of a randomized, placebo-controlled, double-blind, parallel design. RESULTS: Median time to onset for relaxed criteria clinically important relief was 60 minutes for both fexofenadine treatment groups, and 100 minutes for placebo (P = .018). The proportion with relief was 82% at 60 mg, 85% at 120 mg, and 64% for placebo. Treated groups had reductions in symptom scores double that of placebo. CONCLUSIONS: Fexofenadine is safe and efficacious at single doses of 60 mg and 120 mg. Average time to onset was 60 minutes using controlled pollen exposure in an environmental exposure unit.