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PubMed1989

Lipid peroxidation: a possible mechanism of trichloroethylene-induced nephrotoxicity.

The purpose of this study was to investigate whether lipid peroxidation plays a role in (TCE) trichloroethylene-induced nephrotoxicity in mice at different oxygen concentrations. Male NMRI mice (25-30 g) were treated i.p. with TCE in a dosage of 125-1000 mg/kg in sesame oil. To determine the TCE-induced depletion of reduced glutathione (GSH) in the kidney cortex and liver tissue, mice were given 1000 mg/kg TCE i.p., then killed between 0 and 6 h after TCE administration and GSH was measured was non-protein sulfhydryls. In another series of experiments, mice were administered 125 to 1000 mg/kg TCE i.p. with or without a 2 h i.p. pretreatment with 1500 mg/kg L-buthionine-S-R-sulfoximine (BSO). Mice were then exposed to a 10, 15, 20 or 100% oxygen atmosphere for 3 h and lipid peroxidation in vivo was measured as exhalation of ethane. Subsequently, mice were killed and malondialdehyde (MDA) generation was measured in the liver and kidney cortex. Ethane evolution was estimated by gas chromatography and MDA was determined as thiobarbituric acid reactive substances. In a further series of experiments mice were treated in the same manner as for ethane and MDA determination and the changes in blood urea nitrogen (BUN) and accumulation of the organic ion p-aminohippurate (PAH) were determined. PAH accumulation by renal cortical slices were measured as the slice to medium (S/M) ratio. Six hours after administration of 1000 mg/kg TCE to mice, GSH was significantly depleted to about 60% of control in the kidney cortex but not in the liver. Three hours after TCE administration, MDA content in the kidney cortex and ethane exhalation increased in a dose-dependent manner only under a 10% oxygen atmosphere. Under the same experimental conditions, MDA content remained unchanged in the liver. BSO depletion of GSH prior TCE administration induced an increase of the MDA content in the kidney cortex and an increase of the ethane exhalation in vivo. At 10% oxygen concentration, TCE induced a dose-dependent increase in BUN and a dose-dependent decrease of PAH accumulation by the renal cortical slices. Thus, the results of the present study suggest that, under hypoxic conditions, lipid peroxidation plays a role in TCE nephrotoxicity.

Animals↗
PubMed1994

Ivanov-Smolensky conditioning: relationship between CR and UR form and intensity.

The Ivanov-Smolensky conditioning procedure involves a CS followed by a command (US). There are two URs--an instructed UR and a reflexive UR such as an autonomic reaction. Anticipatory responses during the CS, of either the instructed or reflexive UR, provide a measure of conditioning. We examined whether the reflexive CR and UR are similar in form, and whether larger reflexive CRs and URs are associated with larger instructed URs. Subjects were asked to exhale "quickly and powerfully" (exhalation was thus the instructed UR) either following (Forward) or prior to (Backward) a light CS; a change in heart rate to the CS (reflexive CR) alone was the index of conditioning. The heart rate CR and UR were both deceleratory in nature, although the onset of the CR was faster than the UR. In addition, Backward-conditioned subjects demonstrated some degree of inhibitory control by the CS. Finally, the CR intensity was inversely related to exhalation magnitude.

Adult↗
PubMed2004

Impact of breathing motion on whole breast radiotherapy: a dosimetric analysis using active breathing control.

PURPOSE: The active breathing control (ABC) apparatus was used to quantify the effect of breathing motion on whole breast radiotherapy (RT) with standard wedges and intensity-modulated RT (IMRT). METHODS AND MATERIALS: Ten patients with early-stage breast cancer underwent routine free-breathing (FB) CT simulations for whole breast RT. An ABC apparatus was used to obtain two additional CT scans with the breath held at the end of normal inhalation and normal exhalation. The FB scan was used to develop both a standard treatment plan using wedged coplanar tangents and an IMRT plan using multiple static multileaf collimator segments. To simulate breathing, each plan was copied and applied to the normal inhalation and normal exhalation CT scans. RESULTS: The medial field border (defined by a radiopaque catheter) for the normal inhalation and normal exhalation scans moved an average of 0.6 cm anteriorly and 0.3 cm posteriorly compared with the FB position, respectively. The corresponding movement of the lateral field border was an average of 0.4 cm anteriorly and 0.2 cm posteriorly compared with the FB position. For both the wedged and the IMRT techniques, the dose delivered to breast tissue, biopsy cavity, and ipsilateral lung was similar for each of the three CT scan positions. However, the internal mammary node dose varied significantly with breathing. CONCLUSIONS: The dose delivered to breast using standard wedges or step-and-shoot IMRT is relatively insensitive to the effects of breast motion during normal breathing. However, an appreciable portion of the internal mammary nodes are irradiated during normal inhalation, contributing to the uncertainty in the analysis of the efficacy of internal mammary nodal RT in breast treatment.

Breast Neoplasms↗
PubMed2003

Alterations in normal liver doses due to organ motion.

PURPOSE: To assess the clinical significance of differences between treatment planning calculations based on static computed tomography (CT) and more realistic predictions of the actual delivered dose to intrahepatic lesions by a geometric convolution approach that accounts for random setup variations and breathing-induced organ motion. MATERIALS AND METHODS: We recalculated target and normal liver doses for 40 patients previously treated on a conformal therapy dose escalation protocol to include the effect of setup uncertainties and liver motion due to patient breathing. Initial three-dimensional (3D) dose calculations based on pretreatment CT scans taken with voluntary breath-hold at normal exhalation were convolved with 3D anisotropic probability distribution functions reflecting population measurements of position setup variation. The convolution also included a distribution function (one-dimensional, inferior-superior direction only) representing the asymmetric temporal pattern (biased toward exhalation, based on population measurements) of a typical breathing cycle, scaled in amplitude for each patient. RESULTS: After convolution, the minimum clinical target volume (CTV) dose met or exceeded the minimum planning target volume (PTV) dose from the static plan in all but one case, indicating adequate PTV design. However, clinically relevant and statistically significant increases (decreases) in liver normal tissue complication probability (NTCP) from values computed for the static cases occurred for tumors located toward the bottom (top) of the liver, as predicted for these patients scanned at exhalation. The change in liver NTCP (from a nominal 20%) ranged from +12.0% to -11.7% (average magnitude change 3.9% [sigma = 3.3%]). Changes in prescription dose required to restore the original 20% NTCP ranged from -3.7 Gy to +7.9 Gy (average magnitude change 1.9 Gy [sigma = 1.9 Gy]). CONCLUSIONS: Although the PTV concept can ensure adequate CTV coverage, the doses to normal liver are incorrectly modeled without including patient-related geometric uncertainties.

Algorithms↗
PubMed2004

Evaluation of the influence of breathing on the movement and modeling of lung tumors.

PURPOSE: Respiration causes movement and potential shape change in lung tumors that are not fully appreciated using conventional free-breathing CT models for radiotherapy planning. Although target expansion has the potential to ensure proper tumor coverage in the face of motion on a free-breathing CT scan, large variations in how individual patients' tumors move may make such expansions difficult to uniformly define. In addition, excessive expansion may result in the unnecessary inclusion of normal lung in the treated volume. This study was designed to evaluate the influence of breathing movement on tumors and to assess the validity of the free-breathing CT scan for target delineation in the lung. METHODS AND MATERIALS: Data from 16 consecutive lung cancer patients who underwent treatment planning CT scans at inhale and exhale and during free breathing on a fast helical CT scanner were analyzed. Gross tumor volumes (GTV) were defined on each scan. A composite GTV was created by combining the inhale and exhale GTVs (COMP). Two methods of expansion were used to compare COMP to the free-breathing GTV (FREE). First the free-breathing data set was expanded uniformly by 1 cm (FREE + 1). Next, a nonuniform expansion was generated in all 6 directions to ensure complete coverage of COMP with the minimal subtended volume (FREE + EXP). The amount of excess normal lung treated with these 2 expansions was compared. The volume of the COMP missed using the 1-cm expansion was determined. RESULTS: There was a significant amount of excess normal lung tissue treated with the uniform 1-cm (FREE + 1) expansion, as well as with the nonuniform (FREE + EXP) expansion. In addition, there were also cases where this technique led to marginal miss of the tumor, including one case where 47% of the overall tumor was missed with this 1-cm (FREE + 1) expansion. An attempt to create a systematic model for expansion was not successful. Although the mean expansions in the anterior-posterior, superior-inferior, and right-left directions were reasonable (0.9, 1.0, and 0.8 cm, respectively), the large intrapatient variations (sigma 0.6 cm anterior-posterior, 0.7 cm superior-inferior, and 0.5 cm right-left) suggest difficulty in assigning a simple rule for population target expansion. Some extension of FREE outside of the borders of COMP was observed, suggesting the need for evaluation of reproducibility over multiple breathing states. CONCLUSIONS: Traditional methods of expanding the GTV to CTV by 1 cm are less than ideal. This method tends to include more normal lung than necessary and may lead to marginal miss. Interpatient tumor movement variations further prohibit defining a simple rule for nonuniform expansion that would minimize the volume of normal lung in the target. Although the development of target volumes by combining information from breath-hold CT scans at inhale and exhale states shows some promise in minimizing excess lung irradiated while maintaining adequate tumor coverage, further tests of breathing reproducibility need to be performed to provide a confident baseline for defining target expansions by this technique.

Adult↗
PubMed2004

Both inflammation and remodeling influence nitric oxide output in children with refractory asthma.

BACKGROUND: Exhaled nitric oxide can be used to monitor airway inflammation in asthma. We hypothesized that the strong link between nitric oxide and inflammation may obscure a weaker link with airway remodeling. OBJECTIVE: The aim of this study was to determine whether airway remodeling influenced exhaled nitric oxide in 28 asthmatic children (median age [25th-75th], 11 [10-14] years old) with refractory asthma defined as airflow limitation and/or exacerbations despite high-dose inhaled steroids. METHODS: Multiple-flow analysis of exhaled nitric oxide was used to correlate alveolar nitric oxide concentration and maximal conducting airway nitric oxide output to pulmonary function tests, bronchoalveolar lavage, and bronchial biopsy findings. RESULTS: Nitric oxide measurements were related to inflammation and T(H)1/T(H)2 balance, that is, subepithelial eosinophilic infiltration and eosinophilic cationic protein and IFN-gamma/IL-4 ratio in bronchoalveolar lavage fluids. Nitric oxide measurements were also correlated with several parameters of airway remodeling: alveolar nitric oxide concentration with TGF-beta in bronchoalveolar lavage fluid (r = 0.42, P =.03) and maximal conducting airway nitric oxide output with reticular basement membrane thickness (r = 0.61, P =.0007) and tissue inhibitor of matrix metalloproteinases 1/matrix metalloproteinase 9 ratio in bronchoalveolar lavage fluid (r = 0.43, P =.04). Moreover, alveolar nitric oxide concentration was correlated with MEF(25-75) (r = 0.60, P =.02). CONCLUSIONS: These findings suggest that both subacute inflammation and remodeling influence nitric oxide output in refractory asthma.

Adolescent↗
PubMed2005

Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma.

BACKGROUND: Very late antigen (VLA-4) antagonists have been proposed as potential therapies for diseases in which cell recruitment and accumulation are causative. Asthma, which is characterized by airway inflammation involving the accumulation of eosinophils and mononuclear cells, is one such disease. OBJECTIVE: We sought to assess the effect of IVL745, a VLA-4 antagonist, on the early and late asthmatic response (LAR) and on markers of airway inflammation after allergen inhalation. METHODS: The study was of a placebo-controlled, double-blind, randomized, 2-way crossover design. Sixteen subjects with mild-to-moderate asthma controlled with short-acting beta2-agonists only and with a LAR to inhaled allergen participated in the study. At one treatment period they took 20 mg of IVL745 and one treatment period placebo. Both treatments were taken twice daily for 7 days, with a single dose on day 8. Treatments were separated by a washout period of at least 2 weeks. On day 7 of each treatment period, sputum was induced and collected, and exhaled nitric oxide (NO) was measured. On day 8, an inhaled bolus allergen challenge was performed, and blood was taken for pharmacokinetics. On day 9, exhaled NO was measured, and a methacholine challenge was done. On day 10, sputum was induced and collected. Adverse events, peak expiratory flow (PEF), use of short-acting beta2-agonists, and asthma symptoms were recorded daily throughout the study. RESULTS: There was no statistically significant difference between IVL745 and placebo in the effect on the LAR after allergen challenge, as measured by the area under the curve of the percentage change in FEV1 from the prechallenge baseline (mean [SEM], -81.99 [18.80] after IVL745 and -72.58 [21.29] after placebo; 95% CI of difference, -36 to 16.8; P = .46) or by the maximum percentage change from the prechallenge baseline (mean [SEM], -23.44 [4.73] after IVL745 and -21.30 [5.17] after placebo; 95% CI of difference, -11 to 6.29; P = .60). There was a statistically significant decrease in the percentage of eosinophils in sputum on day 7 of treatment with IVL745 (mean [SEM], 7.32 [1.46]) compared with placebo (mean [SEM], 15.00 [1.92]; 95% CI of difference, -13 to -1.2; P = .02). There was no statistically significant difference between IVL745 and placebo with respect to the early asthmatic response, methacholine hyperresponsiveness, exhaled NO, postallergen sputum, symptoms, inhaled beta2-agonist use, or PEF. CONCLUSION: In patients with mild-to-moderate atopic asthma, IVL745 did not affect the early and late response to inhaled allergen or markers of airway inflammation, except for a modest reduction in sputum eosinophils.

Adult↗
PubMed2006

Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma.

BACKGROUND: Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. OBJECTIVE: To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. METHODS: Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. RESULTS: After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a -0.18 doubling dilution shift (95% CI, -1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction (P < .005) of total and low-density lipoprotein cholesterol. CONCLUSION: There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. CLINICAL IMPLICATIONS: Simvastatin is not useful for the treatment of asthma.

Adult↗
PubMed2005

A pilot study of oral L-arginine in cystic fibrosis.

Exhaled nitric oxide has previously been found to be low in cystic fibrosis. The aim of this study was to determine whether exhaled nitric oxide levels would increase in response to oral L-arginine supplementation administered daily for 4 weeks. Exhaled and nasal nitric oxide was measured weekly. Plasma L-arginine levels increased in response to supplementation but this was not reflected in an increase in eNO levels.

Administration, Oral↗
PubMed2005

Spatial and time variations of radon-222 concentration in the atmosphere of a dead-end horizontal tunnel.

The concentration of radon-222 has been monitored since 1995 in the atmosphere of a 2 m transverse dimension, 128 m long, dead-end horizontal tunnel located in the French Alps, at an altitude of 1600 m. Most of the time, the radon concentration is stable, with an average value ranging from 200 Bq m(-3) near the entrance to about 1000 Bq m(-3) in the most confined section, with an equilibrium factor between radon and its short-lived decay products varying from 0.61 to 0.78. However, radon bursts are repeatedly observed, with amplitudes reaching up to 36 x 10(3) Bq m(-3) and durations varying from one to several weeks, with similar spatial variations along the tunnel as the background concentration. These spatial variations are qualitatively interpreted in terms of natural ventilation. Comparing the radon background concentration with the measured radon exhalation flux at the wall yields an estimate of 8+/-2 x 10(-6) s(-1) (0.03+/-0.007 h(-1)) for the ventilation rate. The hypothesis that the bursts could be due to transient changes in ventilation can be ruled out. Thus, the bursts are the results of transient increased radon exhalation at the walls, that could be due to meteorological effects or possibly combined hydrological and mechanical forcing associated with the water level variations of the nearby Roselend reservoir lake. Such studies are of interest for radiation protection in poorly ventilated underground settings, and, ultimately, for a better understanding of radon exhalation associated with tectonic or volcanic processes.

Air Movements↗
PubMed2004

Aerodynamic characteristics of laryngectomees breathing quietly and speaking with the electrolarynx.

The primary purpose of this study was to investigate the aerodynamic characteristics of laryngectomees under two conditions: breathing quietly and speaking with electrolarynx. Twenty male adult subjects, 8 normal speakers, and 12 laryngectomees participated the experiment. Airflow, pressure, and speech data were obtained simultaneously. The acceptability of electrolarynx speech under different conditions was also evaluated by 20 listeners (14 men, 6 women). Results indicated a higher peak expiration airflow and pressure among the laryngectomees as compared with the normal during breathing. Three different breathing patterns appeared among the laryngectomees when speaking with the electrolarynx: holding breath, exhaling, and breathing. Four long-time electrolarynx users held breath during speaking. Seven of 12 laryngectomees kept exhaling, whereas only 1 could breathe during speech production. In addition, (1) the acceptability of electrolarynx speech was the highest when speaking breathlessly; (2) no significant difference was found in the acceptability between the patterns of exhaling and breathing smoothly; and (3) the acceptability decreased if breathing quickly during phonation with the electrolarynx. It also suggests that the laryngectomees who can breathe during speaking may be more appropriate to use the new electrolarynx controlling the pitch by expiration pressure.

Adult↗
PubMed2005

Assessment of smoking status in patients with peripheral arterial disease.

OBJECTIVE: To assess the utility of a novel rapid urinary cotinine assay to detect and quantify the level of smoking in patients with peripheral arterial disease. METHODS: This was a cross-sectional study in a vascular surgical outpatient department of a large teaching hospital. Participants were 100 consecutive subjects presenting to a hospital outpatient clinic with a diagnosis of intermittent claudication confirmed by a positive Edinburgh claudication questionnaire and an ankle-brachial pressure index of less than 0.9. Main outcome measures were patient-offered smoking history, exhaled breath carbon monoxide levels, urinary cotinine levels as measured by a novel rapid assay, and laboratory-measured creatinine-adjusted urinary cotinine levels. Results Fifty-five subjects declared that they were current smokers, 40 declared that they were ex-smokers, and 5 declared that they were never-smokers. Of the 40 ex-smokers, 6 subjects (15%) had urinary cotinine levels greater than 500 ng/mL (regular smokers), and a further 2 (5%) had urinary cotinine levels between 100 and 500 ng/mL (light, irregular, or passive smokers). The rapid urinary cotinine assay had a sensitivity and specificity of 100% and 98%, respectively, in its ability to detect active smoking, and the degree of smoking correlated well with laboratory creatinine-corrected urinary cotinine levels (Spearman coefficient, 0.805; P < .001). By contrast, exhaled carbon monoxide had a sensitivity and specificity of 95% and 89%, respectively, and although it correlated well with urinary cotinine (Spearman coefficient, 0.782; P < .001), it was found on linear regression analysis to be unreliable in differentiating light smokers from nonsmokers. CONCLUSIONS: Patient-offered smoking history is unreliable because there is no correlation between the patient-reported number of cigarettes smoked per day and urinary cotinine levels. The novel rapid assay for urinary cotinine described here is superior to exhaled carbon monoxide measurement in detecting the level of smoking exposure among patients with intermittent claudication, and its results correlate well with laboratory-measured cotinine.

Aged↗
PubMed2006

Morphological and functional determinants of fluoxetine (Prozac)-induced pulmonary disease in an experimental model.

Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.

Airway Resistance↗
PubMed2004

Adenosine 5'-monophosphate increases levels of leukotrienes in breath condensate in asthma.

Hyperresponsiveness (AHR) is a key physiological abnormality in asthma. In clinical and research studies AHR is measured bronchial challenge, with methacholine (MCh), but more recently with adenosine-5'-monophosphate (AMP). In the search for markers of airway inflammation in asthmatic patients, we measured the concentrations of histamine and cysteinyl-leukotrienes (cys-LTs) before and after MCh and AMP challenges in the exhaled breath condensate of 13 patients with mild asthma (FEV1 78.5%pred) and nine healthy non-smokers, using specific enzyme immunoassays. With methacholine challenge we did not find any differences between asthmatics and normal subjects in the pre- and post-challenge concentrations of cys-LTs: 27.2+/-1.4 vs. 29.2+/-1.2 pg/ml and 26.3+/-2.2 vs. 27.5+/-4.2 pg/ml, respectively or histamine: 5.1+/-0.4 vs. 5.1+/-0.6 nM and 4.5+/-0.4 vs. 4.4+/-0.3 nM; P>0.05). In asthmatic patients cys-LT levels were significantly higher after AMP challenge (56.2+/-9.7 vs. 31.7+/-6.9 pg/ml; P<0.05); but there was no difference in healthy subjects (27.2+/-4.6 vs. 30.3+/-4.7 pg/ml). There was no difference in histamine concentrations in asthmatic (5.9+/-1.8 vs. 4.5+/-0.5 nM), or healthy subjects (5.5+/-0.4 vs.5.7+/-0.9 nM) after AMP challenge. In conclusion, our results show that the cys-LTs are increased in exhaled breath condensate after AMP challenge, which may indicate that the AMP acts indirectly by releasing cys-LTs from primed mast cells. The detection of LTs and histamine in exhaled breath condensate may be useful in monitoring asthma.

Adenosine Monophosphate↗
PubMed2003

Sex differences in the toxicokinetics of inhaled solvent vaporsin humans 1. m-Xylene.

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of m-xylene vapor. Seventeen healthy volunteers (nine women and eight men) were exposed to m-xylene (200 mg/m3) and to clean air (control exposure) on different occasions during 2 h of light physical exercise (50 W). The chosen level corresponds to the occupational exposure limit (8-h time weighted average) in Sweden. m-Xylene was monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. m-Methylhippuric acid (a metabolite of m-xylene) was analyzed in urine by high-performance liquid chromatography. Body fat and lean body mass (LBM) were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes and/or phenotypes of cytochromes P450 2E1 and 1A1, glutathione transferases M1 and P1, and epoxide hydrolase were determined. The toxicokinetic profile in blood was analyzed using a two-compartment population model. The area under the concentration-time curve (AUC) of m-xylene in exhaled air postexposure was larger in women than in men. In addition, the excretion via exhaled air was significantly higher in women when correcting for body weight or LBM. In contrast, the men had a significantly higher volume of distribution, excretion of m-methylhippuric acid in urine, and AUC of m-xylene in urine. The toxicokinetic analyses revealed no differences between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates small sex differences in the inhalation toxicokinetics of m-xylene, which can be explained by body build.

Administration, Inhalation↗
PubMed2000

Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype.

PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta(2)-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta(2)-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta(2)-agonist (inhaled formoterol, 12 microg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype. SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV(1)]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment. RESULTS: Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo. CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta(2)-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.

Administration, Inhalation↗
PubMed1995

Influence of breathing technique on arterial blood pressure during heavy weight lifting.

Arterial hypertension occurring during heavy resistance exercise may be a risk factor for stroke in healthy young adults. Any training method that ameliorates the pressor effect of exercise should reduce the risk of stroke. The objective of this study was to observe the influence of breathing technique on arterial blood pressure (BP) generated during heavy, dynamic weight lifting. BP was recorded in 10 male athletes by radial artery catheterization. Each subject then performed double-leg press sets at 85% and 100% of maximum. Each exercise was performed twice, once with closed glottis Valsalva, and then with slow exhalation during concentric contraction. The mean BP at 100% maximum with Valsalva was 311/284. The highest pressure recorded in an individual was 370/360. With slow exhalation, the mean BP was 198/175 when the same 100% maximum was lifted (p < .005). A reduced pressor response was also noted at 85% maximal lifting with slow exhalation. Arterial hypertension produced during heavy weight lifting with Valsalva is extreme and may be dramatically reduced when the exercise is performed with an open glottis (without Valsalva). It is concluded that heavy resistance exercise is safer when performed while the subject breathes with an open glottis.

Adult↗
PubMed2001

Genetic and dietary factors affecting human metabolism of 1,3-butadiene.

The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BD to epoxy butene by monitoring exhaled breath during and after a brief exposure to BD in human volunteers. A total of 133 subjects (equal males and females; four racial groups) provided final data. Volunteers gave informed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects received a 20 min exposure to 2.0 ppm of BD, followed by a 40 min washout period. The total administered dose was 0.6 ppm*h, which is in the range of everyday exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determined by GC-FID analysis. Breathing activity (minute ventilation, breath frequency and tidal volume) was measured to estimate alveolar ventilation. After the washout period, 250 mg of chlorzoxazone were administered and urine samples collected for 6 h to measure 2E1 phenotype. The total BD uptake during exposure (inhaled BD minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate personal and population model parameters, including in-vivo BD metabolic rate. A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Earlier data analysis showed wide ranges for both total uptake BD and metabolic rate. Both varied significantly by sex and age, and showed suggestive differences by race, with Asians having the highest rates. The analyses reported here found no correlation between total BD uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype or phenotype, but the rates showed trends consistent with reported differences by genotype and phenotype for chlorzoxazone metabolism. No effects on metabolic rate were observed for long-term alcohol consumption, or consumption in the past 24 h. Overall, neither dietary factors nor genetic differences explained much of the wide variability in metabolic rates. Population characteristics, age, sex, and race, were the most important explanatory variables, but a large fraction of the total variability in metabolism remains to be explained.

Administration, Inhalation↗

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