Vehicular air pollution, playgrounds, and youth athletic fields

In spite of epidemiological evidence concerning vehicular air pollution and adverse respiratory/cardiovascular health, many athletic fields and school playgrounds are adjacent to high traffic roadways and could present long-term health risks for exercising children and young adults. Particulate matter (PM(1),0.02-1.0 microm diameter) number counts were taken serially at four elementary school athletic/playground fields and at one university soccer field. Elementary school PM1 measurements were taken over 17 days; measurements at the university soccer field were taken over 62 days. The high-traffic-location elementary school field demonstrated higher 17-day [PM1] than the moderate and 2 low traffic elementary school fields (48,890 +/- 34,260, 16,730 +/- 10,550, 11,960 +/- 6680, 10,030 +/- 6280, respective mean counts; p < .05). The 62-day mean PM1 values at the university soccer field ranged from 115,000 to 134,000 particles cm(-3). Lowest mean values were recorded at measurement sites furthest from the highway (approximately 34,000 particles cm(-3)) and followed a second-order logarithmic decay (R2 = .999) with distance away from the highway. Mean NO2 and SO2 levels were below 100 ppb, mean CO was 0.33 +/- 1.87 ppm, and mean O3 was 106 +/- 47 ppb. Ozone increased with rising temperature and was highest in the warmer afternoon hours (R = .61). Although the consequence of daily recess play and athletic activities by school children and young athletes in high ambient [PM1] conditions has not yet been clearly defined, this study is a critical component to evaluating functional effects of chronic combustion-derived PM exposure on these exercising schoolchildren and young adults. Future studies should examine threshold limits and mechanistic actions of real-world particle exposure.     

Bronchoconstriction Provoked by Exercise in a High-Particulate-Matter Environment is Attenuated by Montelukast

Abstract

Airborne ultrafine and fine particulate matter (PM₁ from fossil-fueled internal combustion engines may cause abnormal airway narrowing. Because of high PM₁ exposure from ice resurfacing machines, the ice-rink athlete is especially vulnerable to PM₁ toxicity. The purpose of this study was to evaluate protection by a single dose of montelukast in college ice hockey players following PM₁ exposure exercise. Nine male ice hockey players (age 19.3 ± 1.22 yr) performed 4 randomized, double-blinded, high-intensity, 6-min cycle ergometer trials in low [PM₁] (2260 ± 500 particles/cm³) and high [PM₁] (348,600 ± 121,600 particles/cm³) after placebo or montelukast. Pre- and postspirometry showed similar peak FEV₁ (forced expiratory volume in 1 s) falls between placebo and montelukast after low [PM₁] trials (14.5 ± 18.06 vs. 9.5 ± 11.75% of baseline, respectively). Peak FEV₁ falls after high [PM₁] trials were greater for placebo than for montelukast (17.3 ± 9.79% vs. 1.7 ± 5.77% of baseline; p < .0001). High [PM₁] FEV₁ fall after exercise following montelukast ingestion was less than after exercise following placebo ingestion under high and low [PM₁] conditions and after exercise following montelukast ingestion under low [PM₁] conditions at 5, 10, and 15 min postchallenge (p < .004, .0006, .009, respectively). Montelukast provided greater protection against bronchoconstriction after exercise during high [PM₁] than low [PM₁] exposure (～90% vs. ～35%), suggesting that bronchoconstriction from PM₁ exposure is predominately leukotriene mediated. The precise mechanism of airborne PM₁-induced leukotriene-mediated airway narrowing remains unclear.     

Pulmonary Function Decay In Women Ice Hockey Players: Is There a Relationship to Ice Rink Air Quality?

Fossil-fueled ice rink resurfacing machines emit high levels of ultrafine and fine particulate matter (PM₁) and may be related to asthmalike symptoms in skaters. We examined PM₁ exposure and airway status in elite women ice hockey players over 4 training years. Lung function, asthma symptoms, and rink PM₁ were evaluated. Pre- and postexercise spirometry was performed on 14 female hockey players and 9 female control nordic skiers 4 times over 4 yr. Baseline lung functions were normalized to height cubed (Ht³) and recalculated to subject mean height (1.69 m) to evaluate change. Venue CO, NO₂, and PM₁ were measured. Training history for hockey players included 2 yr in a low-[PM₁] rink, followed by transition to high-[PM₁] fossil fuel machine resurfaced rinks; [PM₁] for control ski venue was low. [CO] and [NO₂] were acceptable at all venues. Controls showed no baseline function change over 4 yr. For hockey players, 1997 lung function values at the low-[PM₁] venue were significantly higher than 2001 high-[PM₁] venue values (p < .05); decay per year between 1997 and 2001 was greater for FEF_25?75 (251 ± 185, 83 ± 40, 109 ± 58, 109 ± 187 ml yr^?1, mean ± SD for FEF_25?75, FVC, FEV1, PEF, respectively; p < .05). No relationships between baseline lung functions and airway hyperresponsiveness or symptoms were identified. Five of 9 controls had symptoms, and 10 of 14 subjects had symptoms. This preliminary study suggests [PM₁] is related to airway function decay in ice rink athletes.     

Effects of Concentrated Ambient Particles on Heart Rate,Blood Pressure,and Cardiac Contractility in Spontaneously Hypertensive Rats

Epidemiological studies have shown that particulate matter (PM) air pollution is associated with cardiovascular mortality and morbidity, especially for particles with aerodynamic diameters under 2.5 μm (PM_2.5). Recent studies have revealed an association between PM pollution and autonomic functions including heart rate (HR), blood pressure (BP), and heart-rate variability. However, the association and linking mechanisms have not been clearly demonstrated in animal studies. Utilizing a novel approach that employs a mixed-effects model to overcome the problems of variations in diseased animals and circadian cycles, we have previously demonstrated an association between concentrated PM_2.5 and changes of HR and BP in pulmonary hypertensive rats. The objective of this study is to test the plausibility of this methodology and to demonstrate the particle effects under different pathophysiology. The feasibility of cardiac contractility (measured as QA interval, QAI) as an indicator for PM toxicology was also explored. Four spontaneously hypertensive (SH) rats were repeatedly exposed to concentrated PM_2.5 during spring and summer. The mass concentration of particles during the 5 h of exposure was 202.0 ± 68.8 (mean ± SE) and 141.0 ± 54.9 μg/m³ for spring and summer experiments, respectively. During spring exposures, the maximum increase of HR and mean BP noted at the end of exposure were 51.6 bpm (p < .001) and 8.7 mm Hg (p = .002), respectively. The maximum decrease of QAI noted at the same time was 1.6 ms (p = .001). Though a similar pattern was demonstrated during summer exposures, the responses were less prominent. We conclude that concentrated PM_2.5 may increase HR and mean BP and decrease QAI in SH rats. Our results also show that QAI may be used as an indicator in PM toxicology.     

Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans

Context: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants.

Objectives: Determine if simultaneous exposure to PM and NO₂ results in synergistic interactions.

Materials and methods: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO₂, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM_2.5CAPs, 89.5?±?10.7 µg/m³), or NO₂+PM_2.5CAPs for 2?h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18?h after exposure. Bronchoalveolar lavage (BAL) was performed 18?h after exposure.

Results: NO₂ exposure alone increased cholesterol and HDL 18?h after exposure, decreased high frequency component of HRV one and 18?h after exposure, decreased QT variability index 1?h after exposure, and increased LDH in BAL fluid. The only significant change with PM_2.5CAPs was an increase in HDL 1?h after exposure, likely due to the low concentrations of PM_2.5CAPs in the exposure chamber. Exposure to both NO₂ and PM_2.5CAPs increased BAL α1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO₂ or PM_2.5CAPs alone, suggesting possible interactions between the two pollutants.

Discussion and conclusions: NO₂ exposure may produce and enhance acute cardiovascular effects of PM_2.5CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants.     

Outdoor wood furnaces create significant indoor particulate pollution in neighboring homes

Abstract

Context: The use of outdoor wood furnaces (OWFs) is common in many parts of the United States. Little published information exists on the concentrations of outdoor and indoor fine particulates found near OWFs.

Objective: To compare PM_2.5 (cts) and PM_0.5 (cts) particle concentrations inside four Connecticut homes located 30.5–259?m from OWFs, and inside six Connecticut control homes located more than 2?km from the nearest OWF.

Materials and methods: PM_2.5 (cts) and PM_0.5 (cts) measurements were made with a Dylos light-scattering particulate counter.

Results: Mean PM_2.5 (cts) concentrations were 4.21 times as great in the four OWF exposed homes than the six control homes (0.302?×?10⁶ counts/m³ versus 0.0718 counts?×?10⁶/m³ p?<?0.001). The mean PM_2.5 (cts) concentrations inside the four OWF exposed homes roughly corresponds to a mass PM_2.5 of 37?µg/m³, which is above the US EPA 24-h PM_2.5 limit of 35?µg/m³. Mean PM_0.5 (cts) concentrations were 3.44 times as great in the four OWF exposed homes than in the six control homes (0.657 versus 0.191?×?10⁶/m³ p?<?0.001). Mean PM_2.5 (cts) and PM_0.5 (cts) concentrations were significantly higher in the house 259?m from an OWF as compared with the mean of the six control homes.

Conclusion: Existing regulations, such as the present Connecticut law requiring a 61 meter distance between an OWF and neighboring homes, are not adequate to protect the health of neighboring residents.     

Sulphation of resveratrol,a natural compound present in wine,and its inhibition by natural flavonoids

1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. Resveratrol is sulphated, and the hepatic and duodenal sulphation might limit the bioavailability of this compound. The aim of this study was to see whether natural flavonoids present in wine, fruits and vegetables inhibit the sulphation of resveratrol in the human liver and duodenum. 2. In the liver, IC₅₀ for the inhibition of resveratrol sulphation was 12 ± 2 pM (quercetin), 1.0 ± 0.04 μM (fisetin), 1.4 ± 0.1 μM (myricetin), 2.2 ± 0.1 μM (kaempferol) and 2.8 ± 0.2 μM (apigenin). Similarly, in the duodenum, IC₅₀ was 15 ± 2 pM (quercetin), 1.3 ± 0.1 μM (apigenin), 1.3 ± 0.5 μM (fisetin), 2.3 ± 0.1 μM (kaempferol) and 2.5 ± 0.3 μM (myricetin). 3. The type of inhibition of quercetin on resveratrol sulphation was studied in three liver samples and was determined to be non-competitive and mixed in nature. K_m (mean ± SD; μM) was 0.23 ± 0.07 (control), 0.40 ± 0.08 (5 pM quercetin) and 0.56 ± 0.09 (10 pM quercetin). V_max (mean ± SD; pmol·min^?1·mg^?1) was 99 ± 11 (control), 73 ± 15 (5 pM quercetin) and 57 ± 10 (10 pM quercetin). K₁ and K_1es estimates (mean ± SD) were 3.7 ± 1.8 pM and 12.1 ± 1.7 pM respectively (p = 0.010). 4. Chrysin was a substrate for the sulphotransferase(s) and an assay was developed for measuring the chrysin sulphation rate in human liver. The enzyme followed Michaelis‐Menten kinetics and K_m and V_max (mean ± SD) measured in four livers were 0.29 ± 0.07 μM and 43.1 ± 1.9 pmol·min^?1·mg^?1 respectively. 5. Catechin was neither an inhibitor of resveratrol sulphation nor a substrate of sulphotransferase. 6. These results are consistent with the view that many, but not all, flavonoids inhibit the hepatic and duodenal sulphation of resveratrol, and such inhibition might improve the bioavailability of this compound.     

Air Pollution and Postneonatal Mortality in a Tropical City: Kaohsiung,Taiwan

With growing evidence of the association between daily mortality and air pollution in adults, it is important to investigate whether infants are also susceptible to the adverse health effects of ambient air pollutants. The purpose of this study is to examine the relationship between air pollution and postneonatal mortality in Kaohsiung, Taiwan, a large industrial city with a tropical climate, during the period 1994–2000, using a case-crossover analysis. Case–crossover analysis provides an alternative to Poisson time-series regression for studying the short-term adverse health effects of air pollution. The air pollutants examined included particulate matter (PM₁₀), sulfur dioxide (SO₂), ozone (O₃), nitrogen dioxide (NO₂), and carbon monoxide (CO). The risk of postneonatal deaths was estimated to increase by 4.0% per 67 μg/m³ (the interquartile range in daily ambient concentration of PM₁₀) for PM₁₀, 1.8% per 17.84 ppb for NO₂, 5.1% per 0.31 ppm for CO, and 4.6% per 19.20 ppb for O₃. Although positive, none of these associations achieved statistical significance. The established link between air pollution levels and infant mortality may not be as strong in cities with tropical climates, although other factors such as differences in pollutant mix or the underlying health of the postneonates may explain the lack of a strong association in this study. Further studies of this type in cities with varying climates and cultures are needed.     

Chemical partitioning of fine particle-bound As,Cd, Cr,Ni, Co,Pb and assessment of associated cancer risk due to inhalation,ingestion and dermal exposure

The bioavailability and human health risks of As, Pb, Ni, Co, Cr and Cd in fine particulate matter (PM_2.5) at an urban site on a National highway in Agra, India were investigated. Inductively coupled plasma-optical emission spectrometer was used for metal analysis in sequentially extracted samples to ascertain the highly mobile, reducible, bioavailable and immobile fractions of the metals. Cancer risk resulting from inhalation, dermal and ingestion exposure to each metal in these fractions was calculated according to US EPA models. The average mass concentration of PM_2.5 was 87.16?±?62.51?μg/m³. Cr, Ni and Pb were the most abundant metals. The results showed that Pb and Cr were higher in the mobile fraction. Cd and Co had high bioavailability. Ingestion is the major exposure pathway for all heavy metals except Cr to infants, children and adults followed by inhalation and dermal contact. The cumulative risk for Cr(VI) due to dermal and inhalation routes exceed the maximum acceptable limit for children of age 1–7?years, 8–15?years and adults when total concentration is considered, but the estimated risks are within the acceptable limit when the bioavailable, water soluble and mobile fraction are taken into account. Hence the study shows that children and adults living in the vicinity of this site are more susceptible, hence more attention should be paid to protect them from pollution hazards. The study indicates the importance of metal speciation in assessing associated human health risks.     

Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers

Objective: Amisulpride is a substituted benzamide neuroleptic, which binds selectively to dopamine D₂ and D₃ receptors, mainly in the limbic structures. States of delusion and agitation occur frequently in the population aged more than 65 years, especially in demented patients and this sometimes requires the use of neuroleptics. The objectives of this study were to determine the safety and the pharmacokinetic profile of 50 mg of amisulpride administered orally as a single dose to elderly volunteers. Methods: Twenty healthy volunteers (10 men and 10 women) aged 65–79 years were included in this open trial. Frequent measurements of blood pressure and heart rate were made and ECG and blood samples were performed up to 72 h after drug intake. Results: The overall clinical and cardiovascular safety was satisfactory. The mean C_max of the racemate amisulpride in elderly people was 64.1 ± 6.7 ng · ml⁻¹, and was not different from the value of 56 ± 4.1 ng · ml⁻¹ in young subjects. As with the C_max, the mean values of t_1/2 and AUC in elderly people (15.6 ± 1.3 h and 667 ± 51 ng · ml⁻¹· h, respectively) were not different to values observed in young subject (respectively 11.7 ± 0.5 h and 603 ± 25 ng · ml⁻¹· h). Conclusions: A single oral dose of amisulpride was well tolerated and showed a similar pharmacokinetic profile in healthy elderly and young subjects. However, these findings should be confirmed after multiple dosing in a larger population in order to establish the lack of need of dosage adjustment in this elderly population. Received: 13 October 1997 / Accepted in revised form: 11 March 1998     

Pharmacokinetics of the 5-hydroxytryptamine1A agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OHDPAT) in the rat after intravenous and oral administration

1. Plasma levels of ³H and unchanged drug were measured in the non-anaesthetized male rat after intravenous (i.v.) or oral administration of (±)-(R,S)-[propyl-³H]-8-OHD-PAT, at three dose levels per route of administration. The excretion of conjugated metabolites in bile was also studied following i.v. administration.

2. For unchanged 8-OHDPAT following i.v. administration, terminal t_1/2 was 1.56 ± 0.01?h (mean ± SD, n±4), k_elim 0.45 ± 0.01 h^?1, volume of distribution 0.14 ± 0.02 litres and clearance 1.10 ± 0.17 ml min^?1. After oral administration, terminal t_1/2, k_elim apparent volume of distribution and clearance were essentially the same when bioavailability was taken into account. Neither dose size nor route of administration had any significant effect on either terminal t_1/2 or k_elim. Comparison of AUCs following i.v. and oral administration yielded a mean for absolute oral bioavailabiltty of 2.60 ± 0.24%.

3. Comparison of AUCs for total plasma ³H showed that the extent of absorption was 80.1%, indicating that the low oral bioavailability of 8-OHDPAT is due to first-pass metabolism, rather than poor absorption from the GI tract.

4. Following i.v. administration, irrespective of dose, some 10% of the ³H dose was excreted in the bile in 6h, 8.5% as 8-OHDPAT-glucuronide and 1.5% as the glucuronide of the N-despropylated metabolite, 8-OHDPAT. The majority of the biliary excretion occurred within 3?h of dosing.     

Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg^?1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half-life (t_1/2β) was the same after the three doses (3.4±0.15h) and the mean half-lives of the distribution phase (t_1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg^?1 respectively). The mean AUC_0-∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL^?1, respectively, showing a linear increase. The individual values of AUC_0-∞ corrected for the administered dose (AUC_0-∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL^?1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (V_ss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg^?1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min^?1 kg^?1) showed significant differences between doses. The values of V_ss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC_0-∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.     

Pharmacokinetic study of a tripeptide HIV-1 protease inhibitor,KNI-174, in rats after intravenous and intraduodenal administrations

Recently, as a new type of anti-AIDS drug, an HIV-1 protease inhibitor, KNI-174, has been synthesized; it shows a potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-174 in rat plasma and examined the pharmacokinetics of KNI-174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti-AIDS drug. This HPLC assay method is specific to KNI-174 and the standard curve was linear from 0.02 to 30 μg ml^?1 plasma. After i.v. administration, 10.0 mg kg^?1, KNI-174 disappeared from the rats' plasma in a three-exponential decay. The mean terminal elimination half-life, t_1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CL_tot, was 9.53 ± 1.08 ml min^?1 and the distribution volume at steady state, V_{d, ss}′ was 7070 ± 960 ml kg^?1. In the case of the i.d. administration, 10.0 mg kg^?1, the mean peak plasma concentration, C_max, and the peak time, t_max, were 0.196 ± 0.076 μg ml^?1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI-174 till infinity, BA^(0-infinity), was 5.37 per cent. Because the IC₅₀ of KNI-174 against HIV-1 in PHA-PBM was 138 ng ml^?1, the time needed for maintaining the concentrations above IC₅₀ after a single i.d. administration of KNI-174 is estimated to be 0.350 ± 0.184 h.     

Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor,KNI-272, in rats after intravenous administration

The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg^?1 KNI-272, the mean terminal elimination half-life, t_1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL_tot, was 15.1 ± 1.2 mL min^?1 and the distribution volume at steady state, V_d,ss, was 3790±280 mL kg^?1. On the other hand, after 1.0mg kg^?1 IV administration, t_d,ss, was 3.04±0.11 h, CL_tot was 15.9±0.2mL min^?1, and V_d,ss was 6950±600 mL kg^?1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg^?1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL^?1, 0.888 ± 0.008 μg mL^?1, and 0.470±0.55 μg mL^?1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg^?1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg^?1 dose, respectively. The renal clearance (CL_R) and the biliary clearance (CL_B) were calculated to be 0.191 and 0.256mL min^?1 for 1.0mg kg^?1, and 0.0248 and 0.215 mL min^?1 for 10.0 mg kg^?1, respectively. When comparing these values with the CL_tot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.     

Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method

Twenty-four young healthy volunteers received a single dose of metformin 500 mg (Glucophage®, Nordic Laboratories, Canada) in tablet form. Plasma concentrations were determined by HPLC in samples collected prior to and 0.33, 0.66, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18, 24, and 30 h after dosing. Mean (± SD) C_max was 682.1 (160.6) ng ml^?1 at a mean (± SD) t_max of 2.4 (0.93) h. Overall elimination was monoexponential with a mean (± SD) half-life of 3.16 (0.47) h. We conclude that metformin is rapidly absorbed from this formulation and is also rapidly eliminated. Extrapolation to steady state predicts that equilibrium will be reached within 24 h.     

Stability and pharmacokinetic studies of a new immunosuppressant,mycophenolate mofetil (RS-61443), in rats

Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non-enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg^?1, the terminal elimination half-life,-t_1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL^?1. After intraduodenal (ID) administration of MPM at 16.7 mg kg^?1, t_1/2β was 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL^?1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a new oral immunosuppressant.     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.     

Glucuronidation of resveratrol,a natural product present in grape and wine,in the human liver

1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. It has been shown that the compound is sulphated in human liver and the aims of the present investigation were to study resveratrol glucuronidation in human liver microsomes and to determine whether flavonoids inhibit resveratrol glucuronidation. 2. A simple and reproducible radiometric assay for resveratrol glucuronidation was developed. The assay employed uridine-5′-diphosphoglucuronic acid-[¹⁴C] and unlabelled resveratrol. Resveratrol-glucuronide was isolated by TLC. The intra- and interassays variabilities were 1 and 1.5%, respectively. 3. The rate of resveratrol glucuronidation was measured in 10 liver samples. The mean ± SD and median of resveratrol glucuronidation rate were 0.69 ± 0.34 and 0.80 nmol/min/mg, respectively. Resveratrol glucuronosyl transferase followed Michaelis-Menten kinetics and the K_m and V_max (mean ± SD; n = 5) were 0.15 ± 0.09?mm and 1.3 ± 0.3 nmol/min/mg, respectively. The intrinsic clearance was 11 ± 4 × 10^?3 ml/min.mg. 4. The flavonoid quercetin inhibited resveratrol glucuronidation and its IC₅₀ (mean ± SD; n = 3) was 10 ± 1 μM. Myricetin, catechin, kaempferol, fisetin and apigenin (all at 20 μM) inhibited resveratrol glucuronidation and the percent of control ranged between 46% (catechin) to 72% (apigenin). 5. The present results show that resveratrol is glucuronated in the human liver. Glucuronidation may reduce the bioavailability of this compound however, flavonoids inhibit resveratrol glucuronidation and such an inhibition might improve the bioavailability of resveratrol.     

Effects of Concentrated Fine Ambient Particles on Rat Plasma Levels of Asymmetric Dimethylarginine

The health effects of ambient fine particulate matter (PM_2.5) and its potential impact on vascular endothelial function have not been thoroughly investigated. As endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis and its complications, we examined the effects of concentrated fine ambient particles (CAPs) on the plasma level of asymmetric dimethylarginine (ADMA) in a pilot study. ADMA is a circulating endogenous inhibitor of nitric oxide synthase (NOS) that is associated with impaired vascular function and increased risk for cardiovascular events. A mobile air research laboratory (AirCARE 1) was used to provide “real-world” CAPs exposures for this study conducted in Detroit, MI. Fourteen Brown Norway rats were exposed to filtered air (FA) (n = 7) or CAPs (0.1–2.5 μm) (n = 7) for 3 consecutive days (8 h/day) in July 2002. Rats were exposed during these periods to average particle mass concentrations of 354 μg/m³. Rat plasma samples were collected 24 h postexposure. Plasma concentrations of ADMA were significantly elevated in rats exposed to CAPs versus those exposed to FA (mean ± standard deviation = 1.49 ± 0.18 vs. 1.29 ± 0.26 μM, p = .05 by one-tailed t-test). Analyses of meteorological data and CAPs trace element composition suggest thatlocal particle emission sources contributed largely to overall mass of CAPs. Results of this pilot study suggest that exposure to PM_2.5 at high concentrations may trigger an acute increase in circulating ADMA level. This finding has implications for the regulation of vasomotor tone by particulate pollutants and the propensity for adverse cardiovascular events.     

Inhibition of phenol sulfotransferase (SULT1A1) by quercetin in human adult and foetal livers

1. Quercetin is one of the most abundant flavonoids in edible vegetables, fruit and wine. The aim was to study the type of inhibition of SULT1A1 by quercetin in the human adult and foetal livers. 2. The activity of SULT1A1 was measured with 4 µM 4-nitrophenol and 0.4 µM 3'-phosphoadenosine-5'-phosphosulphate-[³⁵S], and its mean (± SD) and median were 769 ± 311 and 740 pmol min^?1 mg^?1, respectively (adult liver, n = 10), and 185 ± 98 and 201 pmol min^?1 mg^?1, respectively (foetal liver, n = 8, p < 0.0001). 3. In non-inhibited samples, K_m for SULT1A1 (mean ± SD) was 0.31 ± 0.14 µM (adult liver) and 0.49 ± 0.17 µM (foetal liver, n.s.). V_max for SULT1A1 (mean ± SD) was 885 ± 135 pmol min^?1 mg^?1 (adult liver) and 267 ± 93 pmol min^?1 mg^?1 (foetal liver, p = 0.007). 4. The IC₅₀ of quercetin for SULT1A1 was measured in three samples of adult and foetal livers and was 13 ± 2.1 and 12 ± 1.4 nM, respectively. 5. The type of inhibition was mixed non-competitive in adult and foetal livers and K_i was 4.7 ± 2.5 nM (adult liver) and 4.8 ± 1.6 nM (foetal liver). 6. In the adult liver, the intrinsic clearance (mean ± SD) was 3.3 ± 1.5 ml min^?1 mg^?1 (non-inhibited samples), 0.9 ± 0.4 ml min^?1 mg^?1 (12.5 nM quercetin) and 0.5 ± 0.06 ml min^?1 mg^?1 (25 nM quercetin). In the foetal liver, the intrinsic clearance (mean ± SD) was 0.5 ± 0.2 ml min^?1 mg^?1 (non-inhibited samples), 0.12 ± 0.01 ml min^?1 mg^?1 (12.5 nM quercetin) and 0.2 ± 0.09ml min^?1 mg^?1 (25nM quercetin). 7. In conclusion, quercetin is a potent inhibitor of human adult and foetal liver SULT1A1. It reduces the sulphation rate and intrinsic clearance of 4-nitrophenol in both human adult and foetal livers. This suggests that quercetin may inhibit the sulfation rate of those drugs sulphated by SULT1A1. The inhibition of SULT1A1 is complex and not due solely to competition at the catalytic site of SULT1A1.