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A randomised, double blind, placebo controlled crossover trial of high dose nebulised ipratropium was carried out in 10 asthmatic patients with documented nocturnal bronchoconstriction. Patients received nebulised saline or ipratropium 1 mg at 10 pm and 2 am on two nights. Absolute peak flow (PEF) rates were higher throughout the night after the patients had received ipratropium (at 2 am, for example, mean (SEM) PEF was 353 after ipratropium and 285 l/min after placebo). The fall in PEF overnight, however, was similar with ipratropium and placebo. Patients were given a further 1 mg nebulised ipratropium at 6 am on both nights. There was a significant overnight fall in PEF on the ipratropium night even when comparisons were made between the times that maximal cholinergic blockade would be expected, PEF falling between 11.30 pm and 7.30 am from 429 to 369 l/min. The percentage increase in PEF, though not the absolute values, was greater after ipratropium at 6 am than at 10 pm. These results confirm that ipratropium raises PEF throughout the night in asthmatic patients, but suggest that nocturnal bronchoconstriction is not due solely to an increase in airway cholinergic activity at night.
Thorax 1988 Sep
PMID:Is nocturnal asthma caused by changes in airway cholinergic activity? 297 65

Inhalation treatment may be less effective in the presence of bronchoconstriction because of the reduced penetration of drugs into the airways. The effect of bronchoconstriction on the lung deposition and plasma pharmacokinetics of inhaled sodium cromoglycate was examined. Ten subjects attended the laboratory on three occasions. On the first occasion a bronchial provocation test was performed to determine the concentration of methacholine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20). On the two subsequent occasions subjects inhaled either saline or their PC20 methacholine, followed five minutes later by an aerosol containing sodium cromoglycate and stannous phytate labelled with technetium-99m. Twenty minutes later a gamma emission lung scan was performed to determine the intrathoracic deposition of the nebulised aerosol. The central:peripheral (C:P) ratio of lung deposition was then calculated. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for four hours. Methacholine led to a 23.4% (SEM 0.6%) lower FEV1 and a 2.8 times higher C:P ratio than those observed after saline. There was a direct correlation between log PC20 methacholine and the increase in the C:P ratio (r = 0.81). Despite these changes with methacholine, the plasma pharmacokinetics of inhaled sodium cromoglycate were not significantly different after methacholine and after saline, except that the maximum concentration achieved (Cmax) was increased. These observations suggest that the area of cromoglycate deposition and the anatomical site are less important in determining the plasma pharmacokinetics of cromoglycate than is the total dose delivered to the lung.
Thorax 1988 Aug
PMID:Effect of methacholine induced bronchoconstriction on the pulmonary distribution and plasma pharmacokinetics of inhaled sodium cromoglycate in subjects with normal and hyperreactive airways. 314 Apr 7

Increased production of the serum protease plasminogen activator is associated with tissue damage. The in vitro production of plasminogen activator by alveolar macrophages obtained by bronchoalveolar lavage was studied in 22 normal subjects and 28 patients with interstitial lung disease to determine whether plasminogen activator is produced by normal alveolar macrophages and whether this is increased in patients with interstitial lung disease. Plasminogen activator activity, measured with an iodine-125 labelled fibrin release assay, was found to be dependent on time, effector cell numbers, and plasminogen concentration. Plasminogen activator production by alveolar macrophages from 14 normal non-smokers and eight normal smokers was similar and the mean value was 0.78 (SEM 0.16) urokinase (UK) units x 10(-8)/cell/hour. Alveolar macrophages from the seven patients with cryptogenic fibrosing alveolitis and six patients with histiocytosis-X produced more plasminogen activator (1.89 (0.25) and 4.54 (1.3) x 10(-8) UK units/cell/hour respectively) than macrophages from normal subjects (p less than 0.05), whereas those from 15 patients with sarcoidosis did not (1.09 (0.2) x 10(-8) UK units/cell/hour). Exposure of normal alveolar macrophages to immune complexes enhanced plasminogen activator production to 2.07 (0.27) x 10(-8) UK units/cell/hour, whereas exposure to products of activated T cells and to purified gamma interferon reduced plasminogen activator production (to 0.38 (0.11) and 0.62 (0.11) x 10(-8) UK units/cell/hour respectively). These studies show that plasminogen activator is produced by normal human alveolar macrophages and that its production is increased in patients with cryptogenic fibrosing alveolitis and histiocytosis-X.
Thorax 1988 Jul
PMID:Production of plasminogen activator by alveolar macrophages in normal subjects and patients with interstitial lung disease. 321 49

A one year study of the efficacy of the antifungal agent ketoconazole in non-invasive pulmonary aspergillosis was carried out. Ten patients, seven with allergic bronchopulmonary aspergillosis and three with mycetoma, were studied. They were randomly allocated to receive 400 mg daily or placebo orally in a double blind fashion. In the treated group (n = 6), concentrations of serum IgG specific for Aspergillus fumigatus fell significantly during treatment (mean reduction 42% (SEM 2.2%) compared with determinations preceding the study). This effect was evident by three months and continued for the 12 months of treatment. Patients receiving placebo (n = 4) showed no significant change in serum IgG concentration (mean change + 10% (SEM 5.3%]. Asthmatic patients treated with ketoconazole (n = 4) had significantly lower symptom scores than those receiving placebo (n = 3) (+0.45%/month (SEM 6.9%) versus +27%/month (SEM 6.5%); p less than 0.001). None of the patients treated with ketoconazole reported any adverse effects. Ketoconazole may cause serious liver damage but its use may be justified in bronchopulmonary aspergillosis if further experience confirms its ability to alter the course of a potentially serious disease.
Thorax 1987 Jan
PMID:Trial of ketoconazole in non-invasive pulmonary aspergillosis. 330 24

The metabolic effects of four weeks' high dose inhaled beclomethasone dipropionate (500 micrograms twice daily) were studied in nine normal subjects with an open study design. No effect was found on fasting blood glucose concentration or glycosylated haemoglobin concentration. Peak blood glucose concentration 30 minutes after a 75 g oral glucose load was, however, significantly higher (7.1 (SEM 0.2) versus 6.7 (0.1) mmol/l, or 128 (3.6) v 121 (1.8) mg/100 ml). After treatment there was a 36% increase in fasting serum insulin concentration (7.6 (0.7) versus 5.6 (0.5) mU/l) and a 32% increase in the area under the serum insulin concentration curve after glucose challenge. High dose inhaled beclomethasone dipropionate treatment raised the fasting plasma cholesterol concentration (4.62 (0.25) v 4.16 (0.26) mmol/l, or 178 (9.7) v 161 (10.0) mg/100 ml) and high density lipoprotein cholesterol (1.19 (0.065) versus 0.97 (0.065) mmol/l, or 45 (2.5) v 37 (2.5) mg/100 ml). Fasting blood lactate and pyruvate concentrations were also significantly higher and blood glycerol lower. The findings indicate that high dose inhaled beclomethasone dipropionate may disturb both carbohydrate and lipid metabolism.
Thorax 1987 Nov
PMID:Effect of high dose inhaled beclomethasone dipropionate on carbohydrate and lipid metabolism in normal subjects. 332 44

The rate of clearance of technetium-99m labelled diethylene triamine pentacetic acid (99mTc DTPA) was measured in 32 patients with adult respiratory distress syndrome to determine if a more rapid clearance rate, possibly reflecting a more severe abnormality of pulmonary function, was associated with a reduced likelihood of recovery from pulmonary failure. Although the mean rate of clearance from lung to blood (T1/2LB) of 99mTc DTPA was more rapid in the patients (T1/2LB = 29 (SEM 3.2) min than in 42 normal subjects (T1/2LB = 59 (1.8)min), there was no difference between the clearance rate in the 18 patients who recovered from respiratory failure (T1/2LB = 31 (5) min) and the 14 who died (T1/2LB = 27 (4) min). Additionally, not all patients studied had abnormally rapid clearance rates. In 12 of the 32 patients the T1/2 fell within the range for normal individuals; this was found more commonly in patients who were predisposed to develop adult respiratory distress syndrome by pancreatitis or massive blood transfusion. These data suggest that a single measurement of 99mTc DTPA clearance in patients with established respiratory failure and adult respiratory distress syndrome is of no value in assessing the likelihood of recovery from this condition.
Thorax 1987 Jul
PMID:Failure of aerosolised 99mTc DTPA clearance to predict outcome in patients with adult respiratory distress syndrome. 332 12

Cardiac catheterization data from eight patients with severe chronic obstructive lung disease and pulmonary hypertension at rest (greater than 25 mm Hg) were compared with those obtained from 14 patients with mild to moderate disease whose pulmonary artery pressure was within the normal range at rest (mean 15 (SEM 1) mm Hg), but increased with exercise (30 (2) mm Hg). We obtained lung sections from necropsy material from the group with severe disease, and from surgical specimens in the group with mild to moderate disease, and compared the structure of the vasculature in these groups with that obtained from surgical specimens in a non-smoking control group of seven patients. Oxygen administration either at rest or during exercise did not greatly affect the pulmonary arterial pressures. When cardiac index was plotted against pulmonary artery pressure at rest and during exercise and extrapolated to the axis there was no evidence for a critical closing pressure in either group. The vessels in the groups with mild to moderate and severe chronic obstructive lung disease showed intimal thickening (each 19% (SD 0.5%)) by comparison with the non-smoking group (16% (0.5%]. The group with severe disease, in addition, had medial hypertrophy (27% (0.5%) versus 24% (SD 1%) in the non-smoking group). These data are consistent with the idea that the diseased vessels are distorted and rigid. The lack of effect of breathing oxygen on the vascular response at rest and during exercise suggests that hypoxic vasoconstriction has a minimal role in the pulmonary hypertension of chronic obstructive lung disease. The data suggest that the intimal changes could narrow the vessel calibre in those patients with mild to moderate disease, and that the thickened media present in the vessels from patients with severe disease may act in concert with the enlarged intima to produce more severe vascular obstruction.
Thorax 1988 Mar
PMID:Pulmonary vascular structure and function in chronic obstructive pulmonary disease. 340 2

Antibiotic aerosol treatment is successful in treating Pseudomonas infection in some patients with cystic fibrosis, but the amount of drug reaching the lungs is unknown. The deposition patterns of carbenicillin aerosols delivered from two commercially available nebuliser systems (the Turret nebuliser plus Maxi compressor and the Inspiron nebuliser plus Traveller compressor) have been compared in six patients with cystic fibrosis during tidal breathing. The aerosol mass median diameters were 3.2 and 7.3 microns. In addition, the aerosol from the Turret-Maxi nebuliser system was inhaled by a combination of tidal and deep breathing. After two minutes' breathing via a mouthpiece the mean (SEM) deposition in the lungs was 15.60 (1.5) mg carbenicillin with the Turret nebuliser plus Maxi compressor, but only 6.54 (1.09) mg with the Inspiron nebuliser plus Traveller compressor; the distribution pattern within the lung was significantly more peripheral with the former nebuliser system. These differences may be ascribed partly to the smaller droplet size from the Turret system and partly to the higher nebulisation rate from the more powerful Maxi compressor. Tidal plus deep breathing produced a further small but non-significant increase in lung aerosol deposition. A seventh patient, who failed to complete the trial, had little aerosol deposited in his lungs because he inhaled through his nose. These results emphasise the importance of correct selection of nebuliser equipment for antibiotic aerosol treatment.
Thorax 1988 Apr
PMID:Deposition of carbenicillin aerosols in cystic fibrosis: effects of nebuliser system and breathing pattern. 340 19

The thermal dye double indicator dilution technique for estimating lung water was compared with gravimetric analyses in nine human subjects who were organ donors. As observed in animal studies, the thermal dye measurement of extravascular thermal volume (EVTV) consistently overestimated gravimetric extravascular lung water (EVLW), the mean (SEM) difference being 3.43 (0.59) ml/kg. In eight of the nine subjects the EVTV -3.43 ml/kg would yield an estimate of EVLW that would be from 3.23 ml/kg under to 3.37 ml/kg over the actual value EVLW at the 95% confidence limits. Reproducibility, assessed with the standard error of the mean percentage, suggested that a 15% change in EVTV can be reliably detected with repeated measurements. One subject was excluded from analysis because the EVTV measurement grossly underestimated its actual EVLW. This error was associated with regional injury observed on gross examination of the lung. Experimental and clinical evidence suggest that the thermal dye measurement provides a reliable estimate of lung water in diffuse pulmonary oedema states.
Thorax 1987 Jan
PMID:Thermal dye double indicator dilution measurement of lung water in man: comparison with gravimetric measurements. 361 74

The effects of 2, 10, and 20 mg of sodium cromoglycate delivered by aerosol were compared with those of placebo in a double blind study in 11 patients with extrinsic and exercise induced asthma. The effect of nebulised sodium cromoglycate delivered through a Wright nebuliser (estimated dose 12 mg) was also studied. Patients exercised on a treadmill for six to eight minutes at submaximal work loads on five days, 30 minutes after inhaling placebo or sodium cromoglycate. The FEV1 was recorded before treatment, before exercise, and up to 30 minutes after exercise. Mean baseline values of FEV1 before and after placebo or sodium cromoglycate did not differ significantly on the five days. After exercise the mean (SEM) maximal percentage fall in FEV1 after placebo; 12 mg sodium cromoglycate nebuliser solution; and 2, 10, and 20 mg sodium cromoglycate aerosol were 31.1 (3.8); 9.4 (2.1); and 19.4 (4.6), 13.7 (3.5), and 9.4 (1.9). Sodium cromoglycate inhibited exercise induced asthma at all doses used; the protective effect of the aerosol increased from 2 to 20 mg. The protective effect of 20 mg sodium cromoglycate aerosol was similar to that seen with 12 mg nebulised solution. Our results suggest that the effect of sodium cromoglycate aerosol in exercise induced asthma is dose related.
Thorax 1985 Jan
PMID:Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma. 391 56


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