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Biomedical subjects

W D Bennett

Publications and source records attributed to W D Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis.

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Adolescent↗
PubMed1994

Effect of enhanced supramaximal flows on cough clearance.

Efficiency of cough for clearing mucus from the lungs is believed to be a function of peak airflow velocities in the airways. Initial transient supramaximal flows are characteristic of cough, and these peak flow rates can be enhanced by placing a triggered shutter at the mouth, serving the role of the epiglottis. Using radiolabeled monodispersed aerosols (99mTc-iron oxide) and gamma camera analysis, we measured over a 2-h period the efficacy of 60 voluntary vs. shutter coughs for clearing mucus from the airways of patients (n = 15) with chronic airway obstruction (mean ratio of forced expired volume in 1 s to forced vital capacity = 0.55). In a subset of patients (n = 9), we also measured the efficacy of forced expirations, or huffs, without glottis closure. Peak flow rate was greater for shutter than voluntary coughs [9.4 +/- 2.0 (SD) vs. 4.1 +/- 1.9 l/s; P < 0.001]. Retention at 60 min (as a fraction of initial deposition) was significantly different for the 3 study days (control, 0.83 +/- 0.17; voluntary cough, 0.69 +/- 0.18; shutter cough, 0.75 +/- 0.19; P = 0.01), but only control vs. voluntary cough values were significantly different from each other (P = 0.01). In contrast, retention at 120 min was significantly different for the 3 days, but both voluntary and shutter coughs were significantly different from control (P = 0.01 and P = 0.02, respectively) (control, 0.73 +/- 0.16; voluntary cough, 0.61 +/- 0.20; shutter cough, 0.65 +/- 0.20). Patients studied with buffs showed a clearance rate faster than control and similar to that associated with voluntary cough.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Mucociliary clearance of inhaled particles measured at 2 h after ozone exposure in humans.

Acute exposure of humans to ozone is known to acutely cause pulmonary function decrements, inflammation, and increased permeability of pulmonary epithelium. A single study in humans has also shown that mucociliary transport increases during acute ozone exposure. Because different responses have shown a different time course of recovery after exposure, it was important to examine mucociliary transport at a different time after the cessation of ozone exposure. We exposed 15 healthy male and female nonsmoking subjects, on different occasions, to clean air and 0.4 ppm ozone for 1 h while they exercised continuously. Pulmonary function was measured immediately before and after exposure and 90 min and 24 h after exposure. Between 2 and 5 h after each exposure, retention of inhaled 5-microns mass median aerodynamic diameter 99mTc-labeled Fe2O3 particles was measured. Each subject returned the next day for a final particle retention measurement. Despite significant changes in pulmonary function, there was no difference in mean whole lung retention time of particles between clean air [77.9 +/- 0.8 (SE) min] and ozone (78.0 +/- 0.8 min) exposures, indicating that mucociliary transport is unaffected by ozone exposure when it is measured 2 h after exposure.

Adolescent↗
PubMed1993

The acute effect of ipratropium bromide bronchodilator therapy on cough clearance in COPD.

Using radiolabeled, monodispersed aerosols (99mTc-iron oxide) and gamma camera analysis, we measured the efficacy of cough for clearing mucus from the airways of the lung following inhalation of the bronchodilator ipratropium bromide (IB) (Atrovent, Boehringer Ingelheim, Inc), a drug that has been shown to have no effect on mucociliary clearance in COPD. Clearance of radiolabeled aerosol was studied over a 2.5-h period on three separate days, a control day with no coughing, and two study days during which the patient performed controlled cough maneuvers over the course of clearance measurements following IB or placebo therapy (double blind, crossover). Fifteen patients, age > 45 years, with stable moderate-to-severe airway obstruction (mean FEV1/FVC = 0.45) were studied. IB diminished the effectiveness of cough for clearing the radiolabeled particles from the airways. This effect of IB on cough clearance may be due to (1) changes in the airflow dynamics induced by bronchodilation or (2) altered rheology or depth of airway secretions.

Aged↗
PubMed1992

Ineffectiveness of cough for enhancing mucus clearance in asymptomatic smokers.

Using monodisperse aerosols radiolabeled with 99mTc, we studied the effectiveness of cough and rapid inhalations for clearing mucus in ten asymptomatic smokers. On three separate study days, each subject breathed 5 microns (MMAD) 99mTc-iron oxide particles under controlled breathing conditions. While seated in front of a gamma camera, retention (R) of lung activity (measured as a percent of initial activity) was measured over the initial 2 h and again at 24 h following particle inhalation. On the control day the subject sat quietly in front of the camera, while on the cough day each subject performed 60 controlled coughs during the first hour of retention measurements, and on the rapid inhalation study day each subject performed 90 rapid inhalations during the first hour of retention measurements. Because breathing patterns were controlled during particle inhalation, initial lung deposition patterns were matched on control, cough, and rapid inhalation study days. By paired analysis, retentions at both 1 and 2 h (R1 and R2) for the cough and rapid inhalation measurements were not significantly different from control (mean control R1 = 69 percent; mean cough R1 = 66 percent; mean rapid inhalation R1 = 66 percent, NS; and mean control R2 = 59 percent, mean cough R2 = 55 percent; mean rapid inhalation R2 = 54 percent, NS). Retention at 24 h (R24) was not significantly different between cough, rapid inhalation, and control measurements (mean cough R24 = 15 percent, mean rapid inhalation R24 = 14 percent, mean control R24 = 17 percent). In other words, these young smokers with normal pulmonary function were unable to enhance their rate of mucus clearance by coughing. The inability of these young smokers to enhance their mucus clearance by cough suggests a change in the mucociliary apparatus from normal.

Aerosols↗
PubMed1991

Aerosolized drug delivery: fractional deposition of inhaled particles.

Delivery of drugs by aerosol is increasingly used as a means of providing therapy to both the lungs and to the rest of the body through absorption into the pulmonary circulation. The techniques, definitions, and terminology for aerosol delivery are not standardized or necessarily understood by the increasing number of clinicians and clinical investigators involved in these studies. This paper attempts to establish some definitions and guidelines for defining and characterizing deposition of aerosols in the respiratory tract. Some of the parameters that affect deposition are discussed (e.g., particle size, breathing pattern, airway caliber). It is suggested that these parameters be controlled or measured when characterizing new aerosol delivery systems for clinical investigations. These recommendations were discussed and agreed upon during an expert meeting on definitions and standards related to aerosols in medicine at the 8th Congress of ISAM.

Administration, Inhalation↗
PubMed1991

The effect of ozone exposure on the dispersion of inhaled aerosol boluses in healthy human subjects.

Acute exposure of humans to low levels of ozone are known to cause decreases in FVC and increases in SRaw. These alterations in lung function do not, however, elucidate the potential for acute small airway responses. In this study we employed a test of aerosol dispersion to examine the potential effects of ozone on small airways in humans. Twenty-two healthy nonsmoking male volunteers were exposed to 0.4 ppm ozone for 1 h while exercising at 20 L/min/m2 body surface area. Before and immediately after exposure, tests of spirometry (FVC, FEV1, and FEF25-75) and plethysmography (Raw and SRaw) were performed. Subjects also performed an aerosol dispersion test before and after exposure. Each test involved a subject inhaling five to seven breaths of a 300-ml bolus of a 0.5 micron triphenyl phosphate aerosol injected into a 2-L tidal volume. The bolus was injected into the tidal breath at three different depths: at Depth A the bolus was injected after 1.6 L of clean air were inhaled from FRC, at Depth B after 1.2 L, and at Depth C after 1.2 L but with inhalation beginning from RV. The primary measure of bolus dispersion was the expired half-width (HW). Secondary measures were the ratio (expressed as percent) of peak exhaled aerosol concentration to peak inhaled concentration (PR), shift in the median bolus volume between inspiration and expiration (VS), and percent of total aerosol recovered (RC). Changes in pulmonary function after ozone exposure were consistent with previous findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Cough-enhanced mucus clearance in the normal lung.

We studied the effectiveness of cough for clearing mucus in 12 nonsmoking subjects with normal lung function. On 2 separate study days, each subject breathed 6-microns Mass Median Aerodynamic Diameter 99mTc-labeled iron oxide particles under controlled breathing conditions while they were seated in front of a gamma camera. Retention (R) of lung activity was measured over the initial 2 h and again at 24 h after particle inhalation. On the control day the subject sat quietly in front of the camera, while on the cough day each subject performed 60 controlled coughs during the 1st h of retention measurements. By paired analysis, retentions at both 1 and 2 h (R1 and R2, respectively) for the cough measurements were significantly less than control (mean control R1 = 85% vs. mean cough R1 = 72%, P less than 0.002; mean control R2 = 75% vs. mean cough R2 = 65%, P less than 0.02). Retention at 24 h (R24) was not significantly different between cough and control measurements (mean cough R24 = 35% and mean control R24 = 32%). Thus coughing increased the rate at which the radiolabeled particles were cleared from the bronchial airways in these individuals. Follow-up experiments with subjects performing rapid inhalations rather than cough showed similar enhanced particle clearance to that seen with cough. These results suggest that the observed enhancement of mucus clearance by cough (and rapid inhalation) in the normal lung may be due to a stimulation of the mucociliary apparatus rather than via a two-phase gas-liquid flow mechanism.

Adult↗
PubMed1989

Dual pathway clearance of 99mTc-DTPA from the bronchial mucosa.

Many studies have reported clearance rates of 99mTc-DTPA from the alveolar epithelial surface, but few have measured clearance of this solute from the bronchial mucosa. Those that have attempted such measurements have discounted the possibility that 99mTc-DTPA may be removed from the bronchial airways by mucocilliary transport as well as by absorption through the epithelium. This study was designed to better approximate the rate of 99mTc-DTPA absorption across the bronchial epithelium by correcting the measurements of total 99mTc-DTPA clearance for mucus transport. On two separate study days, each normal, nonsmoking subject (n = 8) breathed an aqueous aerosol (2.0 microns MMAD, sigma g = 2.0) containing 99mTc bound to DTPA or human serum ablumin (HSA) (a relatively nonpermeable solute that is cleared only by mucus transport over the period of measured clearance) while seated in front of a gamma camera. Breathing pattern was standardized to produce a similar central deposition of particles on both study days. From measurements of retention versus time over a 1-h period, exponential rate constants (Ktot and Km) were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modeling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. Results showed that mucus clearance (Km) accounted for two thirds of the total rate of 99mTc-DTPA clearance (Ktot) (mean Ktot = 0.00985, Km = 0.00698, and Kp = 0.00287/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1989

Permeability of the bronchial mucosa to 99mTc-DTPA in asthma.

Previous investigators, using 99mTc-DTPA aerosol as a marker to assess epithelial permeability in asthma, did not find an increased permeability in this group. However, they either failed to deliver the aerosol to the optimal site (bronchial mucosa, not alveoli) or failed to account for mucociliary clearance in analyzing their results. We studied 10 asthmatics and eight age-matched control subjects using a dosimeter (Spira-Elektra 2) and a carefully controlled breathing pattern to deliver aerosol to the subjects' airways. Two aerosols were delivered on separate days in each patient; 99mTc-DTPA aerosol, and 99mTc-HSA (human serum albumin), using similar breathing patterns to ensure reproducibility of the deposition pattern with the two aerosols. From measurements of retention versus time over a 1-h period, rate constants Ktot and Km were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modelling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. There was no significant difference between Ktot in normal subjects and asthmatics; however, because of the slower mucociliary clearance in the asthmatic group, and the relative importance of mucociliary clearance in determining the washout of 99mTc-DTPA aerosol, there was a significant difference in airway permeability between the normal subjects and the asthmatics (t1/2 = 296 min +/- 141 SD and 126 min +/- 58, p less than 0.01, in normal subjects and asthmatics, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1989

How we marketed drug abuse testing.

Careful laboratory planning, a commitment to quality, and extensive documentation are ingredients of a successful drug testing program.

Community Health Services↗
PubMed1988

Use of aerosols to estimate mean air-space size in chronic obstructive pulmonary disease.

Using in vivo measures of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981), we estimated the mean diameter (D) of the pulmonary air spaces in subjects diagnosed with chronic obstructive pulmonary disease (COPD) (n = 8) and in subjects with normal pulmonary function (n = 10). For each subject, RC (aerosol expired/aerosol inspired) decreased exponentially with t. Based on a model of the lung as a system of randomly oriented cylindrical tubes, the half time (t1/2) (i.e., the breath-hold time to reach 50% of RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. Subjects with normal pulmonary function had a mean t1/2 = 6.5 +/- 0.8 s, corresponding to a mean D = 0.36 +/- 0.05 mm. On the other hand, subjects with COPD had a mean t1/2 = 12.7 +/- 3.2 s, corresponding to a mean D = 0.70 +/- 0.18 mm [i.e., twice as large (P less than 0.01) as normal subjects]. Furthermore, D correlated significantly with diffusing capacity in the patients with COPD (r = -0.95, P less than 0.001 for D vs. percent predicted diffusing capacity of CO) but not with any other measure of pulmonary function. In contrast, D varied only slightly in normals and did not correlate with any measure of pulmonary function. We conclude that in vivo measures of RC vs. t, in conjunction with other pulmonary function tests, may be a useful tool for identifying actual changes in pulmonary air-space sizes associated with pulmonary disease.

Aerosols↗
PubMed1987

In vivo hysteresis of airspace dimensions measured by aerosol recovery.

In anesthetized mongrel dogs, we made measurements of single breath aerosol recovery (RC) at equal volume points on the inflation and deflation limb of the quasi-static pressure-volume (P-V) curve of the lungs. Using a 1.2 micron monodisperse aerosol, a large aerosol tidal volume (Vt), and a breathing period of 5 sec, we found that losses of particles were primarily due to sedimentation in pulmonary airspaces distal to anatomic dead space. Thus, the RC measurements could be related to a mean radius (R) of airspaces filled with aerosol over the course of the breath. Furthermore, at a given volume, differences between inflation and deflation limb RC could be attributed to differences in R for the two measurements (i.e., RI vs RD). We found that at isovolume, RC as measured from the inflation limb was larger than that measured from the deflation limb for low lung volumes (less than 0.75 TLC). However, the recoveries were similar as lung volume approached TLC (greater than 0.75 TLC). These results implied that at the same volume, RI greater than RD expect at volumes approaching TLC, i.e. a larger mean airspace dimension on the inflation limb than on the deflation limb at equal volume. The findings of this study support a model of nonuniform changes in airspace dimensions associated with in vivo inflation and deflation of the lungs.

Aerosols↗
PubMed1987

Human variation in the peripheral air-space deposition of inhaled particles.

Intersubject variability in both peripheral air-space dimensions and breathing pattern [tidal volume (VT) and respiratory frequency (f)] may play a role in determining intersubject variation in the fractional deposition of inhaled particles that primarily deposit in the lung periphery (i.e., distal to conducting airways). In healthy subjects breathing spontaneously at rest, we measured the deposition fraction (DF) of a 2.6-microns monodisperse aerosol by Tyndallometry while simultaneous measurement of VT and f were made. Under these conditions particle deposition occurs primarily in the peripheral air spaces of the lung. As an index of peripheral air-space size, we used measurements of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981). In each subject, we measured RC (aerosol expired/aerosol inspired) of a 1.0-micron monodisperse aerosol as a function of breath-hold time for inspiratory capacity breaths of aerosol. The half time (t1/2) (the breath-hold time to reach 50% RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. In the 10 subjects studied, we found a variable DF, range 0.04-0.44 [0.25 +/- 0.12 (SD)]. DF correlated most closely with 1/f, or the period of breathing (r = 0.96, P less than 0.01). There was no significant correlation between DF and t1/2 as an index of peripheral air-space size. In fact there was little deviation in t1/2 in these normal subjects [coefficient of variation (CV) = 0.12].(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1985

Use of aerosols to measure in vivo volume-dependent changes in lung air space dimensions.

Using measurements of aerosol recovery following a 5-s breath hold [NRC(5)] as indices of lung air space dimensions, we evaluated the in vivo changes in these dimensions associated with changes in lung volume (VL). In anesthetized dogs, single breaths of a 1.2-micron monodisperse aerosol were introduced into the respirator's cycle at a number of isovolume points on the inflation and deflation limb of the pressure-volume curve for the dog's lungs. At isovolume, NRC(5) measured off the inflation limb was slightly larger than NRC(5) measured off the deflation limb, implying a larger mean air space dimension for the air space configuration on the inflation vs. the deflation limb. Since a constant aerosol tidal volume (VT) was used for all VL in all dogs, the proportion of the lung filled with aerosol, VT/VL = Pn (where Pn is defined as an index of aerosol penetration into the lung periphery), varied along with VL. In all dogs, we found that, for NRC(5) measurements with Pn less than 0.33, NRC(5) steadily increased with increasing VL, which implies an increasing mean air space dimension as VL increases. However, when we account for the effect that changes in Pn with increasing VL have on NRC(5), we conclude that the observed increase in NRC(5) with VL is primarily due to decreases in Pn and not increases in the mean air space dimension as VL increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1985

Effect of exercise on deposition and subsequent retention of inhaled particles.

To investigate the effect of exercise and its associated increase in ventilation on the deposition and subsequent retention of inhaled particles, we measured the fractional and regional lung deposition of a radioactively tagged (99mTc) monodisperse aerosol (2.6 microns mass median aerodynamic diam) in normal human subjects at rest and while exercising on a bicycle ergometer. Breath-by-breath deposition fraction (DF) was measured throughout the aerosol exposures by Tyndallometry. Following each exposure gamma camera analysis was used to 1) determine the regional distribution of deposited particles and 2) monitor lung retention for 2.5 h and again at 24 h. We found that DF was unchanged between ventilation at rest (6-10 l/min) and exercise (32-46 l/min). Even though mouth deposition was enhanced with exercise, it was not large enough to produce a significant difference in the deposition fraction of the lung (DFL) between resting and exercise exposures. The central-to-peripheral distribution of deposited aerosol was larger for the exercise vs. resting exposure, reflecting a shift of particle deposition to more central bronchial airways. Apical-to-basal distribution was not different for the two exposures. Retention at 2.5 h and 24 h (R24) was reduced following the exercise vs. the resting exposure, consistent with greater bronchial deposition during exercise. The product of DFL and R24 gave a measure of fractional burden at 24 h (B24), i.e., the fraction of inhaled aerosol residing in the lungs 24 h after exposure. B24 was not significantly different between rest and exercise exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effect of alkyl-lysophospholipids on phosphatidylcholine biosynthesis in leukemic cell lines.

Alkyl-lysophospholipids are ether analogues of lysophospholipids that have tumoricidal activity mediated through activation of macrophages or by direct effect on tumor cells by disturbance of phospholipid metabolism. The effect of racemic 1-octadecyl-2-methyl-sn-glycero-3 phosphocholine on phosphatidylcholine synthesis was investigated in sensitive (HL-60) and resistant (K-562) human leukemic cell lines. Radiolabeled lysophosphatidyl-choline, choline, and methionine incorporation into phosphatidylcholine was measured in intact cells exposed for 24 h to varying concentrations of the compound. In HL-60 cells, marked inhibition of phosphatidylcholine synthesis was demonstrated using lysophosphatidylcholine or choline as precursors, but no effect was observed on methionine incorporation. No effects were observed in K-562 cells. These investigations suggest that alkyl-lysophospholipids inhibit phosphatidylcholine synthesis via the acyltransferase reaction and from choline, but not from methionine.

Carbon Radioisotopes↗