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Biomedical subjects

D H Yates

Publications and source records attributed to D H Yates.

17 recordsLinked to original sources
PubMed1996

Sidestream smoke inhalation decreases respiratory clearance of 99mTc-DTPA acutely.

BACKGROUND: The permeability of the alveolar-capillary barrier to an inhaled aerosol of technetium 99m labelled diethylenetriamine penta-acetate (99mTc-DTPA) is used as an index of alveolar epithelial injury. Permeability is greatly increased in active smokers. AIMS: To determine the effect of sidestream smoke inhalation on permeability as this has not been described previously. METHODS: We measured lung clearance of inhaled 99mTc-DTPA aerosol in 20 normal non-smoking subjects before and after exposure to one hour's sidestream smoke inhalation. RESULTS: Measured carbon monoxide (CO) levels rose to maximum of 23.5 +/- 6.2 ppm (mean +/- SD) from baseline values of 0.6 +/- 1.3 (p < 0.001) and plasma cotinine levels to a maximum of 9.5 +/- 4.5 nmol/L (mean +/- SD). The half time (T1/2 in minutes) for 99mTc-DTPA clearance rose from baseline 69.1 +/- 15.6 (mean +/- SD) to 77.4 +/- 17.8 (p < 0.05) after smoke exposure. No effect of 99mTc-DTPA scanning or of sidestream smoke was demonstrated on lung function. CONCLUSIONS: We conclude that low level sidestream smoke inhalation decreases 99mTc-DTPA clearance acutely in humans. The mechanism of this unexpected result is not established but may include differences in constituents between sidestream and mainstream smoke, alterations in pulmonary microvascular blood flow, or changes in surfactant due to an acute phase irritant response.

Adult↗
PubMed1996

Respiratory sensation during bronchial challenge testing with methacholine, sodium metabisulphite, and adenosine monophosphate.

BACKGROUND: There is some evidence that the perception of bronchoconstriction may very according to the nature of the provoking stimulus. The aims of this study were, firstly, to develop a method for measuring dyspnoea during induced bronchoconstriction in patients with asthma and, secondly, to apply this method to testing differences between directly and indirectly acting bronchoconstricting stimuli. METHODS: Descriptive terms suitable for quantifying respiratory discomfort due to bronchoconstriction in patients with asthma were identified in a preliminary investigation. The relation between reduction in forced expiratory volume in one second (FEV1) and respiratory discomfort, measured using a visual analogue scale (VAS), was then studied during challenges with three different inhaled stimuli: methacholine (MCH), sodium metabisulphite (MBS), and adenosine monophosphate (AMP). Three indices were calculated to describe the relation: the VAS value associated with a 20% fall in FEV1 (FEV20 VAS); the ratio of the final VAS value to the final percentage fall in FEV1 (VAS-FEV1 ratio); and the regression coefficient for predicting VAS from the percentage fall in FEV1 within each challenge (beta VAS FEV1). RESULTS: "Difficulty in breathing" and "chest tightness" were selected as suitable terms for quantifying respiratory discomfort. There were no differences between the three agonists in the qualitative aspects of the respiratory sensation. In paired challenges with the same agonist the three indices were all found to be reproducible for both sensations measured. MCH induced less intense difficulty in breathing and chest tightness for a given fall in FEV1 than did AMP. There was a trend in the same direction for the comparison between MCH and MBS. There were no differences between AMP and MBS. FEV20 VAS was less powerful in discriminating between agonists than the two slope indices. CONCLUSIONS: The relation between induced reduction in FEV1 and the intensity of respiratory discomfort can be measured reliably. The indirectly acting bronchoconstricting agonists AMP and MBS induced more intense respiratory discomfort for a given fall in FEV1 than the direct agonist MCH. This may be due to differences in unmeasured mechanical changes in the lungs or to an additional action on airway sensory nerves.

Adenosine Monophosphate↗
PubMed1996

Asbestos-related bilateral diffuse pleural thickening: natural history of radiographic and lung function abnormalities.

Sixty-four subjects with asbestos-related diffuse pleural thickening attending the London Medical Boarding Centre for Respiratory Diseases (formerly, the Central Pneumoconiosis Panel) were studied to investigate symptomatology, lung function, and radiographic change over an average period of 8 to 9 yr. Chest pain was a common symptom, occurring in over half of the subjects. Approximately one-third of the subjects had a history of pleurisy or pleural effusion. Full long function, available in all cases, showed a highly significant decrement (p < 0.001) compared with predicted values in all variables except gas transfer coefficient (Kco) at initial presentation, consistent with a restrictive ventilatory defect. Longitudinal lung function, available over a mean period of 8.9 yr in 36 subjects, showed a significant decrement above that predicted in FEV1 and FVC only (p < 0.05). Decreases in other parameters were observed, although statistical significance was not achieved. Radiographic score increased with time but there was no correlation between change in lung function and increasing radiographic score, probably reflecting the initial severity of the disease in subjects studied. These observations confirm an initial decrement in lung function in diffuse pleural thickening which is followed by comparatively little change over time.

Aged↗
PubMed1996

Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.

Exhaled nitric oxide (NO) is elevated in untreated patients with asthma but not in patients treated with inhaled glucocorticoids. This may reflect an inhibitory effect of glucocorticoids on the induction of the enzyme NO synthase in the respiratory tract. We have now studied the effect of an inhaled glucocorticoid (budesonide 800 micrograms twice daily via a dry powder delivery system for 3 wk) on exhaled NO in 11 patients with mild asthma in a double-blind crossover randomized-order placebo-controlled study. Exhaled NO was reduced from a baseline value of 203 +/- 29 parts per billion (ppb) to 120 +/- 26 ppb after 3 wk of treatment (p < 0.01), whereas there was no change after a matched placebo (169 +/- 20 at baseline compared with 184 +/- 16 ppb after 3 wk). A significant and progressive fall in exhaled NO was found from 1 to 3 wk. There was no significant change in FEV1 after inhaled steroids (although mean FEV1 was 92% predicted normal at baseline), although there was a reduction in airway responsiveness to methacholine (approximately 2.5 doubling dilutions). These results add further support to the view that the elevated levels of exhaled NO in asthma may derive from induction of an inducible isoform of NO synthase and indicate that exhaled NO may be a useful way of monitoring the anti-inflammatory effects of glucocorticoids and other anti-inflammatory treatments in asthma.

Administration, Inhalation↗
PubMed1996

Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase.

Exhaled nitric oxide (NO) may be derived from constitutive NO synthase (NOS) in normal airways, but the increased concentration in asthma is likely to be derived from inducible NOS expressed in inflamed airways. To investigate this, we administered a nonselective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor of inducible NOS, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in both normal subjects and subjects with asthma. L-NAME resulted in a significant reduction in exhaled NO compared with saline control in eight normal subjects (maximum fall from baseline, 53 +/- 7.6% versus 8.9 +/- 6.5%; P < 0.05) and in seven patients with asthma (maximum fall, 67 +/- 7.4% versus 10 +/- 7.4% versus 10 +/- 9.3%; p < 0.05). Aminoguanidine at the same molar concentration decreased exhaled NO in subjects with asthma (maximum fall, 53 +/- 7.2% versus 7.1 +/- 10.4%; p < 0.05), but caused no significant change in normal volunteers (maximum fall, 28 +/- 9.3 versus 15 +/- 11). No rise in blood pressure, fall in FEV1, or adverse effects were observed in either subject group. We have demonstrated that NOS inhibitors can safely be given by inhalation in a single does in normal subjects and subjects with asthma. The raised exhaled NO concentration in patients with asthma may be attributable to induction of NOS, with that in normal subjects reflecting basal constitutive NOS activity.

Administration, Inhalation↗
PubMed1996

An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist.

There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo-controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 12 h [corrected] after the last salmeterol dose. Mean FEV1 increased significantly after 2 wk of budesonide (p < 0.05) and increased further after salmeterol (p < 0.05) compared with placebo. After 2 wk, the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo (3.4 versus 2.4 doubling dilutions; p < 0.05), consistent with an improvement in airway hyperresponsiveness with budesonide therapy. However, regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge, both with budesonide and with placebo (-1.1 +/- 0.42 and -1.41 +/- 0.30 doubling dilutions, respectively). There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods. Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy.

Administration, Inhalation↗
PubMed1996

Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients.

An increased concentration of nitric oxide (NO) in the exhaled air of asthmatic patients may reflect inflammation of the airways, and exhaled NO may, therefore, be useful in monitoring asthma control and the optimal use of anti-inflammatory treatment. We have studied the effect of reducing and then increasing the dose of inhaled steroid on exhaled NO, lung function and symptoms in 14 asthmatic patients treated with twice daily budesonide. Baseline measurements were made at the end of a 2 week run-in period, 2 weeks after the daily dose of budesonide was reduced by 200 micrograms daily, and 2 weeks after the dose was then increased by 200 micrograms daily. Exhaled NO increased significantly compared with baseline after the dose was reduced by 200 micrograms daily (from 122 +/- 13 to 246 +/- 52 ppb); whereas, there was no significant decrease in spirometry or change in peak flow variability. There was also a significant increase in symptoms at night, but no change during the day or in the number of rescue doses of inhaled beta 2-agonist. The level of exhaled NO decreased when the dose of inhaled steroids was increased, and this was associated with a reduction in diurnal variability of peak expiratory flow, and in nocturnal symptoms. Our study suggests that exhaled nitric oxide may be a useful means of monitoring control of asthma. Further longitudinal studies in patients of differing asthma severity are now indicated.

Administration, Inhalation↗
PubMed1996

The effect of alcohol ingestion on exhaled nitric oxide.

The concentration of nitric oxide (NO) is increased in the exhaled air of patients with inflammatory lung diseases, including asthma, possibly reflecting cytokine-mediated chronic airway inflammation. Endogenous NO is generated from L-arginine by the action of several types of NO synthase (NOS). NOS have structural similarities with cytochrome P450 reductases. Alcohol decreases exhaled NO in animals, but this has not previously been investigated in man. We studied the effect of alcohol ingestion in nine asthmatic and 12 normal subjects, measuring the peak concentration of exhaled NO using a modified chemiluminescence analyser. A significant decrement in NO occurred in asthmatic patients (mean +/- SEM before ethanol 204 +/- 58 to 158 +/- 59 parts per billion (ppb) after ethanol; p < 0.02), without significant change in the normal subjects (122 +/- 14 to 114 +/- 15 ppb). Thus, in our study, alcohol decreased exhaled nitric oxide in asthmatic subjects but not in normal individuals. This may reflect preferential action on inducible nitric oxide synthase which is expressed in asthmatic airways. An inhibitory effect of ethanol on inducible nitric oxide synthase may contribute towards the effect of alcohol in asthma.

Adult↗
PubMed1995

Cytokine expression in normal, atopic, and asthmatic subjects using the combination of sputum induction and the polymerase chain reaction.

BACKGROUND: The importance of cytokines in the asthmatic inflammatory response is becoming apparent. The aim of this study was to determine whether the non-invasive method of induced sputum combined with the polymerase chain reaction would allow the detection of messenger RNA (mRNA) encoding a range of cytokines on a qualitative basis. METHODS: Four groups were studied comprising 10 normal subjects, six atopic, 10 mild and five moderately severe asthmatic subjects. Sputum was induced by the inhalation of nebulised 3.5% saline and total RNA extracted from the expectorated cells. Expression of cytokine message within induced sputum was examined by reverse transcription and the polymerase chain reaction (PCR) using primers specific for a range of cytokines (IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, TNF alpha, IFN alpha, IFN gamma). Presence or absence of the signal was determined at 35 and 70 cycles of PCR by electrophoretic size fractionation on ethidium bromide stained agarose gels. RESULTS: Cytokine message was detectable in sputum by this method. All samples showed a positive result for actin control. Analysis of signal for the cytokines in all subjects showed that, at 70 cycles, IL-1, IL-5, IL-8, and TNF alpha were detected in more subjects than would be expected by chance. IL-5 mRNA was detected in more of the asthmatic patients (moderate 80%, mild 40%) than in the atopic subjects (33%), who in turn showed expression of this cytokine in more individuals than nonatopic subjects (10%). CONCLUSIONS: The combination of sputum induction and PCR appears to be a useful, non-invasive tool to explore the chronic inflammation of asthma and possibly other lung disorders. It should enable differences between normal and asthmatic subjects to be identified for future confirmation by quantitative techniques.

Adult↗
PubMed1995

Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects.

The effect of inhaled recombinant human tumor necrosis factor-alpha (rhTNF alpha) on airway responsiveness and the cellular composition of sputum was studied in eight normal subjects using a placebo-controlled study design. Spirometric data and bronchial responsiveness (BR) to methacholine were studied, and an estimate of pulmonary-cell infiltration was made using the technique of induced sputum. A single dose of rhTNF alpha (60 ng) caused an increase in BR, with a leftward shift in the concentration-based response to methacholine at all time points after inhalation, as compared with a saline control challenge. Likewise, there was a decrease in the log provocative concentration of methacholine causing a 15% decrease in FEV1, which reached a maximum at 24 h (1.37 +/- 0.22 versus 1.87 +/- 0.24, rhTNF alpha and control, respectively; p < 0.05). No change was observed in baseline spirometric measures at any of the time points. A significant increase in the percentage of neutrophils occurred in the induced sputum, reaching a maximum at 24 h (44.2 +/- 9.9% versus 16.6 +/- 7.1%, rhTNF alpha and control, respectively; p < 0.05). We conclude that TNF alpha can induce an increase in airway responsiveness in normal subjects, and is associated with a neutrophil infiltration, thus making it a candidate cytokine for the induction of airway inflammation and hyperresponsiveness.

Adult↗
PubMed1995

Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide.

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, including inflammatory epithelial cells. NO has been detected in the exhaled air of normal human subjects, and its concentration is raised in asthmatic patients. To study whether exhaled NO arises from the respiratory tract, we administered a NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), by inhalation (490 mg) in a double-blind randomized manner in nine normal and six asthmatic subjects. Because exhaled NO may arise from an inducible isoform of NO synthase that may be inhibited by glucocorticosteroids, we also studied the effects of oral prednisolone (30 mg orally for 3 d) in seven normal and six asthmatic subjects in a separate double-blind crossover study with matched placebo. After nebulized L-NMMA, there was a significant fall in peak exhaled NO compared with saline control values, with a mean fall of 43.6 +/- 5.6% in normal subjects (p < 0.01) and of 39.7 +/- 6.5% (p < 0.01) in asthmatic subjects, which persisted for 4 h. There were no effects of L-NMMA inhalation on heart rate, blood pressure, or FEV1 in either normal or asthmatic patients. Administration of oral prednisolone (30 mg) resulted in a fall in exhaled NO concentrations in asthmatic subjects by 21.6 +/- 5.0% at 48 h (p < 0.01) but no significant change in normal subjects. These data suggest that NOS inhibitors may be safely given in normal and asthmatic patients and that the increased exhaled NO seen in asthmatic patients is likely to be caused by induction of inducible NOS.

Adult↗
PubMed1995

Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment.

Regular beta 2-adrenoceptor agonist therapy may lead to a rebound increase in bronchial responsiveness on discontinuation of therapy and a reduction in bronchoprotective effects. Formoterol, a long-acting beta 2-agonist, is effective in single doses in the prevention of methacholine-induced bronchoconstriction. In a double-blind, placebo-controlled cross-over study, we examined the effect of an inhaled long-acting beta 2-adrenoceptor agonist, formoterol (24 micrograms twice a day) for 2 wk on airway function and responsiveness in 17 subjects with mild asthma (mean age, 26.3 +/- 1.4 yr) who were not taking inhaled glucocorticosteroids. FEV1 and the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) were measured at 36, 60, and 108 h and at 2 wk after the last dose of regular treatment. In addition, PC20 was measured 12 h after the first and the last dose of formoterol and placebo. PC20 values at 36, 60, and 108 h and at 2 wk after formoterol treatment cessation were not significantly different from those after placebo. Mean FEV1 was 3.44 +/- 0.18 L after placebo compared with 3.79 +/- 0.20 L after formoterol (p < 0.001) 12 h after the first dose, and mean PC20 was 0.53 (GSEM 1.4) mg/ml after placebo compared with 2.0 (GSEM 1.4) mg/ml after formoterol (p < 0.001). After 2 wk of regular treatment, mean FEV1 at 12 h after the final dose of formoterol fell to 3.51 +/- 0.23 L compared with 3.41 +/- 0.18 L after the final dose of placebo (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1995

Effect of acute and chronic inhaled furosemide on bronchial hyperresponsiveness in mild asthma.

We determined whether chronic administration of furosemide aerosol would be beneficial for the treatment of asthma. First, we showed that furosemide aerosol delivered from a metered-dose inhaler (10 and 20 mg) significantly protected against sodium metabisulfite (MBS) challenge by 0.6 and 1.3 doubling dilutions respectively in 12 volunteers with mild asthma. In a double-blind cross-over study, we examined the effect of furosemide aerosol from a twice more efficient metered-dose inhaler (10 mg four times per day) inhaled over 4 wk versus placebo in 12 other asthmatic subjects. There was no significant effect of furosemide on bronchial responsiveness to methacholine or MBS. Treatment with furosemide over 1 mo did not improve bronchial hyperresponsiveness in subjects with mild asthma.

Administration, Inhalation↗
PubMed1995

Reduced dose salbutamol in comparison with standard dosage for symptom relief in asthma.

Regular treatment with beta 2-agonists has been reported to be associated with an increase in risk of asthma death or near death, and with a deterioration in asthma symptom control. Low-dose beta 2-agonists provide effective bronchodilatation and bronchoprotection, even though maximal bronchodilatation is not achieved, and they may offer a better safety profile. In a double-blind, randomized,, cross-over study, we evaluated the efficacy of low-dose salbutamol metered-dose inhaler (50 micrograms.puff-1), used over a period of 2 weeks, compared with a standard dose (100 micrograms.puff-1) in control of asthma symptoms in 20 moderately severe asthmatic subjects using inhaled glucocorticosteroid therapy. Asthma control was assessed by symptom scores, peak flow rates, spirometry, inhaler usage and, where possible, by bronchial responsiveness to methacholine. Despite a 46% reduction in mean weekly salbutamol dosage, mean forced expiratory volume in one second (FEV1), morning and evening peak expiratory flow (PEF), PEF variability, dose of methacholine provoking a 20% decrease in FEV1 (PC20) (n=9), and symptom scores showed no difference between low-dose and standard inhaler treatment periods. Low-dose inhaler administration resulted in a small but significant increase in number of inhaler actuations. Low-dose salbutamol metered-dose inhaler may, thus, be useful for control of symptoms in moderately severe asthma. This strategy could be used to achieve a reduction in total beta 2-agonist usage, which may minimize any potential for adverse effects.

Administration, Inhalation↗