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PubMed2006

In Vitro Comparison of Output and Particle Size Distribution of Budesonide from Metered-Dose Inhaler with Three Spacer Devices during Pediatric Tidal Breathing.

OBJECTIVES: The aim of this in vitro study was to determine the delivered dose of budesonide 200mug via a chlorofluorocarbon-free pressurized metered dose inhaler (pMDI) when administered through different spacers in tidal breathing patterns of young children. METHODS: Tidal breathing was simulated for toddlers and children. Spacers tested were Babyhaler((R)), AeroChamber((R)) Plus small and medium; the pMDI was Budiair((R)) 200microg. Output was measured after one actuation and five inhalations in primed and unprimed spacers. Cumulated output was evaluated after each of five simulated inhalations. Aerosol characteristics - i.e. particle size distribution of the output - were determined in primed spacers with a cascade impactor using high-performance liquid chromatography and UV detection. RESULTS: Total output from primed spacers after five inhalations was determined between 37.9microg and 40.9microg with little differences between spacers and breathing patterns. About 58-79% of this total output was inhaled with the first breath from the AeroChamber((R)) Plus and about 26% from the Babyhaler((R)). The fine particles <5mum ranged between 87% and 92% of the delivered dose for all three spacers. DISCUSSION AND CONCLUSION: The nominal dose (200microg) of the Budiair((R)) 200microg inhaler is reduced to 40microg delivered dose or less by using Babyhaler((R)) and AeroChamber((R)) Plus spacers taking five breaths. With a single breath the delivered dose can be reduced further to a minimum of 10microg using the Babyhaler((R)). Clinical studies are warranted in the future for decisions on 'clinical efficacy', safety, and exact dose adjustment.

Administration, Inhalation↗
PubMed2006

Esophageal candidiasis as a side effect of inhaled fluticasone propionate dry powder: recovery by switching over to hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP).

BACKGROUND: Esophageal candidiasis is one of the local side effects of inhaled corticosteroid treatment, and it is difficult to prevent this condition. Our previous report indicated that the prevalence of esophageal candidiasis among patients treated with inhaled fluticasone propionate dry powder (FP-dp) reached up to 37% in Japanese patients. Although a reduction in the daily dose of inhaled FP-dp can eliminate this infection, it may lead to asthma not being well-controlled in these patients. OBJECTIVE: The aim of this study was to estimate whether switching to an equal daily dose of inhaled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP), the oropharyngeal deposition of which is very low, can eliminate the infection without deterioration of asthma. METHODS: A total of 10 stable asthmatic patients with esophageal candidiasis, induced by inhaled FP-dp treatment (400 or 800 microg/ day), were enrolled in this study. A second upper GI endoscopy was performed, more than 1 month but less than 3 months after switching to an equal dose of inhaled HFA-BDP with a tube spacer device, Duopacer. The patients' medications were not changed during the study. RESULTS: Esophageal candidiasis was eliminated in 9 of the 10 patients. The degree of candidiasis reduced in another patient. The forced expiratory volume in 1 sec (FEV1.0) did not worsen during the study. CONCLUSION: Switching from FP-dp to HFA-BDP with Duopacer is useful in preventing esophageal candidiasis.

Administration, Inhalation↗
PubMed1998

[Inhalation of nitric oxide in severe lung failure].

Despite intensive therapeutic efforts, adult respiratory distress syndrome (ARDS) is still associated with a lethality ranging from 50 to 80%. Besides hypoxemia, fatal outcome is caused by myocardial insufficiency due to a progressive decrease in pulmonary vascular conductance. Inhalation of NO can selectively dilate pulmonary vessels in ventilated lung regions, thus increasing mean pulmonary artery conductance and decreasing venous admixture. This study determines the effects of NO inhalation in patients with severe ARDS on pulmonary gas exchange, haemodynamics and mortality. Twenty surgical patients (mean age 50.3 +/- 9.25 years) with severe ARDS (Murray score 3.4 +/- 0.3) were treated with variable concentrations of NO during mechanical ventilation with continuous positive pressure. Pulmonary artery catheters were used to measure pressures, flow and venous admixture. Mortality with NO inhalation was compared with that of previous ARDS patients (n = 20) who had not received NO. Mean duration of NO inhalation was 120.1 +/- 33.12 hours (n = 20) (range 40 to 254 hours). Mean NO concentration during the first hour of delivery was 18.5 +/- 3.88 ppm. Sixteen patients had FiO2 of 1.0 when NO was started. Within the first hour of NO inhalation, the PaO2/FiO2 ratio increased from 82.1 +/- 10.28 to 124.6 +/- 28.18. Eighteen patients were responders. Mean ventilatory pressure was lowered. Oxygenation improvement was most marked during the first 36 hours and then gradually declined. Despite the significant increase in NO related oxygenation, pulmonary artery pressures did not consistently decrease. Sixteen patients in the NO group died. In the group without NO 15 patients died. Compared with ARDS patients of similar severity not receiving NO, the NO-treated patients had the same lethality. In severe ARDS, oxygenation significantly improves with the initiation of NO inhalation, but this effect declines over time. With NO, FiO2 and ventilatory pressures can be lowered. Whether the theoretically reduced oxygen toxicity and the reduced invasiveness of mechanical ventilation with NO reduces patient mortality must be determined in larger patient groups.

Administration, Inhalation↗
PubMed2005

The inhalation of drugs: advantages and problems.

Inhalation is a very old method of drug delivery, and in the 20th century it became a mainstay of respiratory care, known as aerosol therapy. Use of inhaled epinephrine for relief of asthma was reported as early as 1929, in England. An early version of a dry powder inhaler (DPI) was the Aerohalor, used to administer penicillin dust to treat respiratory infections. In the 1950s, the Wright nebulizer was the precursor of the modern hand-held jet-venturi nebulizer. In 1956, the first metered-dose inhaler (MDI) was approved for clinical use, followed by the SpinHaler DPI for cromolyn sodium in 1971. The scientific basis for aerosol therapy developed relatively late, following the 1974 Sugarloaf Conference on the scientific basis of respiratory therapy. Early data on the drug-delivery efficiency of the common aerosol delivery devices (MDI, DPI, and nebulizer) showed lung deposition of approximately 10-15% of the total, nominal dose. Despite problems with low lung deposition with all of the early devices, evidence accumulated that supported the advantages of the inhalation route over other drug-administration routes. Inhaled drugs are localized to the target organ, which generally allows for a lower dose than is necessary with systemic delivery (oral or injection), and thus fewer and less severe adverse effects. The 3 types of aerosol device (MDI, DPI, and nebulizer) can be clinically equivalent. It may be necessary to increase the number of MDI puffs to achieve results equivalent to the larger nominal dose from a nebulizer. Design and lung-deposition improvement of MDIs, DPIs, and nebulizers are exemplified by the new hydrofluoroalkane-propelled MDI formulation of beclomethasone, the metered-dose liquid-spray Respimat, and the DPI system of the Spiros. Differences among aerosol delivery devices create challenges to patient use and caregiver instruction. Potential improvements in aerosol delivery include better standardization of function and patient use, greater reliability, and reduction of drug loss.

Administration, Inhalation↗
PubMed1993

Inhaled nitric oxide in the adult respiratory distress syndrome and other lung diseases.

In 1987, nitric oxide was reported to be an endothelium-dependent relaxing factor. When inhaled as a gas at low levels, nitric oxide selectively dilates the pulmonary circulation. Significant systemic vasodilation does not occur because nitric oxide is inactivated by rapidly binding to hemoglobin. In an injured lung with pulmonary hypertension, inhaled nitric oxide produces local vasodilation of well-ventilated lung units and may "steal" blood flow away from unventilated regions. This reduces intrapulmonary shunting and may improve systemic arterial oxygenation. In patients with adult respiratory distress syndrome, inhaled nitric oxide reduces pulmonary hypertension and improves arterial oxygenation without reducing systemic arterial pressure. Tachyphylaxis to nitric oxide inhalation has not been observed. While additional chronic toxicology studies need to be performed, significant pulmonary toxicity has not been observed at low inhaled concentrations (< 80 parts per million by volume). Potentially, inhaled nitric oxide may be a valuable therapy in patients with adult respiratory distress syndrome.

Administration, Inhalation↗
PubMed1993

Inhalation injury.

Inhalation injury remains a primary determinant of patient survival, with 60% to 70% of burn center fatalities attributed to the pulmonary complications of inhalation injury. Substantial airway damage and pulmonary complications can result from the inhalation of toxic fumes and gases found in smoke. Partial to complete airway obstruction, pulmonary edema, pneumonia, and progressive pulmonary failure may occur. Early diagnosis of inhalation injury and vigorous pulmonary care and support are vitally important to patient survival. Bronchoscopy and xenon 133 ventilation-perfusion scans are two of the newer diagnostic tools used to identify burn patients with inhalation injury. Treatment measures for patients with inhalation injury and recommendations for nursing practice are discussed.

Airway Obstruction↗
PubMed2002

Low-dose inhaled corticosteroid therapy and risk of emergency department visits for asthma.

BACKGROUND: Patients who visit the emergency department (ED) because of asthma frequently have a relapse. While the use of inhaled corticosteroids has been demonstrated to improve asthma symptoms and lung function, it is not clear whether their use after discharge from the ED reduces asthma relapse rates. OBJECTIVE: To determine whether inhaled corticosteroid therapy reduces ED asthma relapse rates. METHODS: We analyzed ED visit and medication data on patients 5 to 60 years of age who were enrolled in a government-sponsored drug plan and who visited an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta, Canada (N = 1293). Using a Cox proportional hazards model, we determined the relative risk (RR) of relapse ED visits among users and nonusers of inhaled corticosteroids after discharge from the ED. We also compared the RR of relapse ED visits across different dose categories. RESULTS: Users of inhaled corticosteroids after ED discharge had 45% fewer relapse ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI], 0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95% CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose therapy (RR, 0.67; 95% CI, 0.47-0.94). CONCLUSIONS: Inhaled corticosteroid therapy after ED discharge is associated with a significant reduction in the risk of subsequent ED visits. Low-dose therapy appears to be as effective as high-dose therapy. However, further studies are needed to determine the optimal dosing regimen for inhaled corticosteroid therapy for asthma.

Administration, Inhalation↗
PubMed2000

Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma.

We studied the effect of inhaled corticosteroids on the increase in bone mineral content in prepubertal children with asthma. Forty-eight asthmatic, prepubertal children receiving either inhaled beclomethasone dipropionate or budesonide were evaluated. Nine children of similar age not receiving inhaled steroids served as controls. The average age of corticosteroid-treated children was 7.8 +/- 2.4 years, and of control children, 8.4 +/- 2.1 years (NS). The average dose of inhaled corticosteroids in the treated children was 0.67 +/- 0.48 mg/m(2)/day, and they were followed over a 9-20-month period. Total bone mineral content (TBMC) was measured at baseline and after 9-20 months. A derived value for 12 months' TBMC was calculated, assuming that changes in TBMC were linear with the passage of time. The change in TBMC over a 12-month period was 264 +/- 68 mg for the corticosteroid-treated children and 330 +/- 84 mg for control children (P < 0.025). In a multiple regression analysis in which adjustments were made for the effects of age, height, and weight, the change in TBMC in corticosteroid-treated children was inversely related to the inhaled steroid dose/m(2)/day (P = 0.016). The increase in the lumbar vertebral bone mineral density in control children was also significantly greater than in the corticosteroid-treated children (P < 0.025). We conclude that inhaled steroids, at an average dose of 0.67 mg/m(2)/day, when used in the treatment of asthma reduce the acquisition of bone mineral in prepubertal children.

Absorptiometry, Photon↗
PubMed2004

Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma.

BACKGROUND: Anti-leukotriene (AL) agents are being considered as 'add-on' therapy to inhaled corticosteroids (ICS), in chronic asthma. OBJECTIVES: To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL (until August 2003), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and looked at American Thoracic Society and European Respiratory Society meeting abstracts (1998 to 2003). SELECTION CRITERIA: Randomised placebo-controlled trials of asthmatics aged two years and older with at least one month intervention. DATA COLLECTION AND ANALYSIS: Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double). MAIN RESULTS: Of 587 citations, 27 (25 adult and 2 paediatric) trials met inclusion criteria. Sixteen trials were published in full-text and 16 trials reported data in a way that allowed meta-analysis. In symptomatic patients, addition of licensed doses of anti-leukotrienes to ICS resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids: Relative Risk (RR) 0.64; 95% Confidence Interval (CI) 0.38 to 1.07). A modest improvement group difference in PEF was seen (Weighted Mean Difference (WMD) 7.7 L/min; 95% CI 3.6 to 11.8 L/min) together with decrease in use of rescue short-acting beta2-agonist use (WMD 1 puff/week; 95%CI 0.5 to 2). With only 3 trials comparing the use of licensed doses of anti-leukotrienes with increasing the dose of inhaled glucocorticoids, no firm conclusion can be drawn about the equivalence of both treatment options. In ICS-sparing studies of patients who were well controlled at baseline, addition of anti-leukotrienes produced no overall difference in dose of inhaled glucocorticoids (WMD -21 mcg/d, 95%CI -65, 23 mcg/d), but it was associated with fewer withdrawals due to poor asthma control (RR 0.63, 95% CI 0.42 to 0.95). REVIEWERS' CONCLUSIONS: The addition of licensed doses of anti-leukotrienes to add-on therapy to inhaled glucocorticoids brings modest improvement in lung function. Although addition of anti-leukotrienes to inhaled glucocorticoids appears comparable to increasing the dose of inhaled steroids, the power of the review is insufficient to confirm the equivalence of both treatment options. Addition of anti-leukotrienes is associated with superior asthma control after glucocorticoid tapering; although the glucocorticoid-sparing effect cannot be quantified at present, it appears modest.

Administration, Inhalation↗
PubMed2005

Changes in prescribing of inhaled corticosteroids (1999-2002) in Scotland.

PURPOSE: To investigate the trend in prescribing of inhaled corticosteroids and general practitioner (GP) consultations for respiratory diseases. METHODS: A longitudinal observation study of all prescriptions, from primary care, for inhaled corticosteroids dispensed in Scotland from January 1999 to May 2002 was undertaken. The main outcome measures were the trends in prescribing of inhaled corticosteroids and GP consultations for respiratory diseases. RESULTS AND CONCLUSIONS: The prescribing of all inhaled corticosteroids has risen over the study period. The rise in prescribing of the combination product containing fluticasone and salmeterol appears not to have been at the expense of the prescribing of fluticasone alone while the prescribing of the budesonide/eformoterol combination may be at the expense of budesonide (BUD) alone. GP consultations for both asthma and chronic obstructive pulmonary disease (COPD) have declined over a similar period. The increased prescribing of inhaled corticosteroids over this period is associated with the increased use of the fluticasone/salmeterol combination rather than an increase in the use of all inhaled corticosteroids. The accompanying fall in number of consultations with GPs may be due to this increased prescribing or a move to nurse led clinics.

Administration, Inhalation↗
PubMed2003

Inhaled corticosteroids in childhood asthma: Income differences in use.

Asthma hospitalization rates in children increase with decreasing level of household income. This research was undertaken to determine whether use of inhaled corticosteroid drugs, which can prevent asthma hospitalizations, followed a similar socioeconomic gradient in children with asthma. We performed a cross-sectional study of association, using population-based prescription and healthcare data sources. Our subjects were 16,862 Manitoba children, aged 5-15 years, with prescriptions for asthma drugs during January 1995-March 1996. Our measures were adjusted for asthma severity, physician specialty, and proportion of children with an inhaled corticosteroid prescription by neighborhood income. Forty-five percent of children treated for asthma had at least one inhaled corticosteroid prescription during January 1995-March 1996. The proportion of children with inhaled corticosteroid prescriptions decreased with successive decreases in neighborhood income. The socioeconomic gradient in the likelihood of an inhaled corticosteroid prescription was most evident among children with mild-moderate asthma who were not in the care of an asthma specialist. In conclusion, a socioeconomic gradient in the use of inhaled corticosteroids prescriptions can be found among children with universal access to healthcare and drug insurance.

Administration, Inhalation↗
PubMed1995

Is there a role for inhaled nitric oxide in pediatric ARDS?

Despite advances in ventilator management and use of extracorporeal lung support, mortality related to ARDS in pediatric patients has not been reduced over the past 20 years. Progressive respiratory failure, due to evolution of the primary illness or to complications of ventilator therapy, significantly contributes to poor outcome. ARDS is characterized by severe ventilation-perfusion mismatch and by pulmonary hypertension. Because of their side effects which affect systemic hemodynamic status or worsen intrapulmonary shunting, intravenous vasodilator trials have been of limited interest. Nitric oxide (NO) has been recognized as a gas with vasodilator properties. In neonates studies have shown that inhaled NO may have an important role in the therapy of persistent pulmonary hypertension. Inhaled NO in adults with severe ARDS has been shown to reduce pulmonary hypertension without producing systemic vasodilation. This reduction of pulmonary vascular resistances may reduce pulmonary edema formation, decrease vasoconstrictor response to cardiotonic agents, and improve biventricular function. In addition, arterial oxygenation seems to be increased by improved matching of ventilation with perfusion. Improvement of oxygenation with inhaled NO suggests that use of lower tidal volumes and FIO2 may be more successful. Until now, there are no published studies regarding NO administration in ARDS affecting nonneonatal pediatric patients. However, the results obtained in adults and newborns suggest that inhaled NO may be a useful adjuvant therapy of ARDS in children, possibly in association with other therapies. Even in adults it remains unclear whether therapy with inhaled NO can reduce morbidity and mortality. Prospectives and randomized studies are essential to assess the real utility of inhaled NO in ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1997

Concentration-time relationships for the effects of inhaled trichloroethylene on signal detection behavior in rats.

The risk from inhaled volatile organic compounds (VOCs) is presently assessed on the basis of lifetime exposure to average concentrations of the vapor. This strategy yields rational predictions of risk if the product of concentration (C) and the duration of exposure (t) yields constant effects on health (Haber's Rule). The validity of this assumption was evaluated by assessing the acute behavioral effects of inhaled trichloroethylene (TCE) vapor at various values of C and t. Adult male Long-Evans rats (n = 11) were trained to perform a signal detection task in which a press on one lever produced food on trials containing a signal (a brief, unpredictable light flash); a press on a second lever produced food on trials lacking a signal. Response time (RT) and indices of sensitivity (SI) and bias (RI) derived from the theory of signal detection were calculated at three times during repeated daily 60-min tests conducted in air containing 0, 400, 800, 1200, 1600, 2000, or 2400 ppm TCE. Behavior remained stable during tests in air. In TCE, SI declined and RT increased as functions of both C and t. RI was not affected by TCE. Effects on SI and RT were not predictable from the C x t product: both endpoints were more affected by C than by t. To quantify the change in the effect of TCE across exposure times, concentration-effect relationships for inhaled TCE on SI and RT were modeled with cubic polynomial functions at each of the three exposure durations. Concentrations of inhaled TCE associated with preselected changes in SI and RT were then estimated for each animal from these functions. Criterion concentrations, SI0.1 and RT100, were defined as the concentration of TCE associated with a 0.1-unit decrease in SI or a 100-msec increase in RT, respectively. Both SI0. 1 and RT100 increased as exposure duration decreased, but did so more slowly than would be predicted by Haber's Rule. This pattern indicates that application of Haber's Rule overestimates the concentration of inhaled TCE associated with changes in signal detection and thus underestimates the risk of behavior change from short-term exposures to TCE. On the other hand, the fact that SI0.1 and RT100 did increase with shorter exposure times indicates that the converse assumption, that the toxicity of inhaled TCE is independent of the duration of exposure, yields an overly conservative estimate of risk.

Administration, Inhalation↗
PubMed1997

Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices.

Poor inhalation technique is prevalent in asthmatics using standard metered dose inhalers (MDI). Both dry powder inhalers (DPI) and breath activated MDIs offer a solution to this problem. Our aim was to compare the lung delivery of salbutamol from two DPIs, Diskhaler and Diskus (Accuhaler), and the Easi-Breathe breath activated MDI. Ten healthy volunteers mean (SEM) age 24.0 years (1.7) were studied in a randomized single (investigator) blind crossover design. Single 1200 micrograms nominal doses of salbutamol via Diskhaler and Diskus (6 sequential 200 micrograms puffs) and Easi-Breathe (12 sequential 100 micrograms puffs) were given over 6 min. Mouth rinsing was performed after every inhalation sequence. Lung delivery was evaluated by measuring the early lung absorption profile of salbutamol at 5, 10, 15 and 20 min after inhalation, with calculation of peak (Cmax) and average over 20 min (Cav) concentration (ng/ml). Both the Diskhaler and the Easi-Breathe produced significantly greater salbutamol Cmax and Cav than Diskus (as mean and 96% CI for difference vs. Diskus): [Cmax] Diskus 3.22 vs. Diskhaler 4.35 (95% CI 0.19 to 2.08), vs. Easi-Breathe 3.98 (95% CI -0.18 to 1.71). [Cav] Diskus 2.62 vs. Diskhaler 3.95 (95% CI 0.52 to 2.14), vs. Easi-Breathe 3.52 (95% CI 0.09 to 1.71). For Cav this amounted to a 1.51-fold difference (95% CI 1.35 to 1.68) between Diskhaler vs. Diskus, and a 1.36-fold difference (95% CI 1.03 to 1.69) for Easi-Breathe vs. Diskus. In conclusion we found that, in vivo, the Diskus DPI produced significantly lower lung delivery for the same nominal dose of salbutamol than either Diskhaler DPI or the Easi-Breathe pressurised aerosol. This shows that breath activated inhaler devices may have different in vivo deposition characteristics for delivering the same drug.

Adult↗
PubMed2000

The inhaled administration of KF19514, a phosphodiesterase 4 and 1 inhibitor, prevents antigen-induced lung inflammation in guinea pigs.

We examined in this study the effect of KF19514, a phosphodiesterase 4 and 1 inhibitor, on antigen-induced lung inflammation by inhaled administration in guinea-pigs. It was previously reported that inhaled KF19514 prevented antigen-induced bronchoconstriction and platelet-activating factor (PAF)-induced lung inflammation. In fact, a variety of factors other than PAF are related to lung inflammation in real subjects with asthma. Guinea-pigs were actively sensitized by exposure to ovalbumin (OA). Fifteen to 20 days later, the guinea pigs were challenged by exposure to aerosols of five successively increasing concentrations of OA (0.01, 0.1, 0.5, 1 and 5 mg/ml). Bronchoalveolar lavages (BALs) were performed 24 h after the antigen challenge, and airway hyperresponsiveness to acetylcholine (ACh) was studied 24 h after the challenge by measuring lung resistance and dynamic compliance. Ovalbumin antigen challenge produced a marked and significant eosinophil accumulation in the BAL fluids and airway hyperresponsiveness to ACh 24 h after the challenge. Inhaled KF19514 (0.01-0.1%) inhibited the eosinophil accumulation significantly and dose-dependently but inhaled rolipram (0.01-0.1%) and aminophylline (0.1-1%) did not. In addition, the development of airway hyperresponsiveness was prevented by inhaled KF19514 (0.01%) but not by inhaled rolipram (0.01%) and aminophylline (0.1%). Based on these data, KF19514 was suggested to be a promising drug in the treatment of asthma by local administration to the lung.

Acetylcholine↗
PubMed1997

Uptake, distribution, and elimination of carbon tetrachloride in rat tissues following inhalation and ingestion exposures.

Carbon tetrachloride (CCl4) has been studied extensively for its hepatotoxic effects. There is a paucity of information, however, about its tissue deposition following administration by different routes and patterns of exposure. The specific objective of this study was to delineate the uptake, distribution, and elimination of CCl4 in tissues of rats subjected to equivalent oral and inhalation exposures. Male Sprague-Dawley rats (325-375 g) were exposed to 1000 ppm CCl4 for 2 hr. The total absorbed dose (179 mg CCl4/kg bw) was administered to other groups of rats as a single oral bolus or by constant gastric infusion over a period of 2 hr. Animals were terminated at selected time intervals during and postexposure and tissues (liver, kidney, lung, brain, fat, skeletal muscle, spleen, heart, and GI tract) removed for measurement of their CCl4 content by headspace gas chromatography. CCl4 levels in all tissues were much lower in the gastric infusion group than in the oral bolus and inhalation groups. Inhalation resulted in relatively high tissue CCl4 concentrations, because inhaled chemicals enter the arterial circulation and are transported directly to organs throughout the body. It seems logical that the liver should accumulate more CCl4 following ingestion than following inhalation. This did not prove to be the case when comparing liver AUC values for the gastric infusion and inhalation groups. Substantially lower CCl4 concentrations in the liver of animals in the gastric infusion group appeared to be due to very rapid metabolic clearance of the relatively small amounts of CCl4 entering the liver over the 2-hr infusion period. It was hypothesized that the capacity of first-pass hepatic and pulmonary elimination could be exceeded, if CCl4 were given as a single, large oral bolus. Indeed, deposition of CCl4 in all tissues was greater in the oral bolus group than in the gastric infusion group. The time courses of uptake and elimination of CCl4 appeared to be governed largely by a tissue's rate of blood perfusion and lipid content. CCl4 was rapidly taken up, for example, by the brain and liver. These organs' CCl4 content then diminished, as CCl4 was metabolized and redistributed to adipose tissue. CCl4 accumulated slowly, but to very high concentrations, in fat and remained elevated for a prolonged period. Thus, concentrations of CCl4 in some tissues may not be reflective of blood levels. The most appropriate measure of internal dose for CCl4 acute hepatotoxicity appears to be the area under tissue concentrations versus time curve from 0 to 30 min. Tissue time-course data sets are essential for the refinement and validation of physiological models for CCl4 and other volatile organic chemicals.

Adipose Tissue↗
PubMed1997

A comparison of physiologically based pharmacokinetic model predictions and experimental data for inhaled ethanol in male and female B6C3F1 mice, F344 rats, and humans.

Ethanol is added to unleaded gasoline as an oxygenate to decrease carbon monoxide automobile emissions. This introduces inhalation as a new possible route of environmental exposure to humans. Knowledge of the pharmacokinetics of inhaled ethanol is critical for adequately assessing the dosimetry of this chemical in humans. The purpose of this study was to characterize the pharmacokinetics of inhaled ethanol in male and female B6C3F1 mice and F344 rats and to develop a physiologically based pharmacokinetic (PBPK) model for inhaled ethanol in mice, rats, and humans. During exposure to 600 ppm for 6 hr, steady-state blood ethanol concentrations (BEC) were reached within 30 min in rats and within 5 min in mice. Maximum BEC ranged from 71 microM in rats to 105 microM in mice. Exposure to 200 ppm ethanol for 30 min resulted in peak BEC of approximately 25 microM in mice and approximately 15 microM in rats. Peak BEC of about 10 microM were measured following exposure to 50 ppm in female rats and male and female mice, while blood ethanol was undetectable in male rats. No sex-dependent differences in peak BEC at any exposure level were observed. Species-dependent differences were found following exposure to 200 and 600 ppm. A blood flow limited PBPK model for ethanol inhalation was developed in mice, rats, and humans which accounted for a fractional absorption of ethanol. Compartments for the model included the pulmonary blood and air, brain, liver, fat, and rapidly perfused and slowly perfused tissues. The PBPK model accurately simulated BEC in rats and mice at all exposure levels, as well as BEC reported in human males in previously published studies. Simulated peak BEC in human males following exposure to 50 and 600 ppm ranged from 7 to 23 microM and 86 and 293 microM, respectively. These results illustrate that inhalation of ethanol at or above the concentrations expected to occur upon refueling results in minimal BEC and are unlikely to result in toxicity.

Administration, Inhalation↗
PubMed1999

Physiologically based pharmacokinetic modeling of inhaled trichloroethylene and its oxidative metabolites in B6C3F1 mice.

A physiologically based pharmacokinetic (PBPK) model for inhaled trichloroethylene (TCE) was developed for B6C3F1 mice. Submodels described four P450-mediated metabolites of TCE, which included chloral hydrate (CH), free and glucuronide-bound trichloroethanol (TCOH-f and TCOH-b), trichloroacetic acid (TCA), and dichloroacetic acid (DCA). Inhalation time course studies were carried out for calibration of the model by exposing mice to TCE vapor concentrations of either 100 or 600 ppm for 4 h. At several time points, mice were euthanized and blood, liver, kidney, lung, and fat were collected and analyzed for TCE and its oxidative metabolites. Peak blood TCE concentrations were 0.86 and 7.32 microgram/mL, respectively, in mice exposed to 100 and 600 ppm TCE. The model overpredicted the mixed venous blood and tissue concentrations of TCE for mice of both exposure groups. Fractional absorption of inhaled TCE was proposed to explain the discrepancy between the model predictions and the TCE blood time course data. When fractional absorption (53%) of inhaled TCE was incorporated into the model, a comprehensive description of the uptake, distribution, and clearance of TCE in the blood was obtained. Fractional uptake of inhaled TCE was further verified by collecting TCE in exhaled breath following a 4-h constant concentration exposure to TCE and validation was provided by testing the model against TCE blood concentrations from an independent data set. The submodels adequately simulated the distribution and clearance kinetics of CH and TCOH-f in blood and the lungs, TCOH-b in the blood, and TCA and DCA, which were respectively detected for up to 43 and 14 h postexposure in blood and livers of mice exposed to 600 ppm TCE. This is the first extensive tissue time course study of the major metabolites of TCE following an inhalation exposure to TCE and the PBPK model predictions were in good general agreement with the observed kinetics of the oxidative metabolites formed in mice exposed to TCE concentrations of 100 and 600 ppm.

Adipose Tissue↗