Mucociliary clearance in COPD can be increased by both a D2/beta2 and a standard beta2 agonists.

In addition to breathlessness and cough, excessive mucus production is one of the main symptoms of chronic obstructive pulmonary disease (COPD). Excess mucus coupled with deteriorating mucociliary clearance is associated with a decline in lung function and an increased risk of death from pulmonary infection. The effect of Viozan (Sibenadet HCl, AR-C68397AA), a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, on mucociliary clearance was investigated together with that of a beta2-adrenoceptor agonist, salbutamol. Using a double blind, parallel group study design, 15 patients with COPD, all habitual smokers, were randomised to receive nebulised sidenadet (3mg tid; n = 7) or salbutamol (5mg tid; n = 8) for 10 days. Lung mucociliary clearance rates were measured, by a standard radioaerosol technique, before and after the treatment period, as were 24-h sputum volumes. Both sibenadet and salbutamol therapies resulted in significant (P<0.02) enhancement of lung mucociliary clearance. The 24-h sputum volume was significantly reduced following sibenadet therapy (P<0.03) whereas salbutamol therapy had no effect. Our results, in addition to illustrating the effects of a standard beta2 agonist on mucociliary clearance, strongly suggest the potential dual benefit of dual-agonist compounds in lessening sputum production whilst simultaneously enhancing mucociliary clearance. For reasons unconnected with the present study, development work on this specific formulation is no Longer proceeding.

A model for assessing bronchial mucus transport.

We propose a scheme for the assessment of regional mucus transport using inhaled Tc-99m aerosol particles and quantitative analysis of serial gamma-camera images. The model treats input to inner and intermediate lung regions as the total of initial deposition there plus subsequent transport into these regions from more peripheral airways. It allows for interregional differences in the proportion of particles deposited on the mucus-bearing conducting airways, and does not require a gamma image 24 hr after particle inhalation. Instead, distribution of particles reaching the respiratory bronchioles or alveoli is determined from a Kr-81m ventilation image, while the total amount of such deposition is obtained from 24-hr Tc-99m retention measured with a sensitive counter system. The model is applicable to transport by mucociliary action or by cough, and has been tested in ten normal and ten asthmatic subjects.

Controlled delivery of krypton-81m boli in normal subjects: results and implications.

Interregional sequential filling potentially affects lung ventilation imaging, depending on the distribution of the tracer within the inspired volume. We investigated its importance quantitatively under near tidal breathing conditions in the upright lung using a short-lived radioactive tracer. Ten normal volunteers performed two runs of 900-ml breaths (from functional residual capacity) in which 100 ml of 81mKr boli were delivered "early" or "late" in inspiration, i.e., 50 ml or 450 ml volumetric depth. Apex-to-base gradients in the vertical profile were -106 +/- 22 (s.e.) counts/cm (early) and -187 +/- 24 (s.e.) counts/cm (late). Ratios of upper-to-lower regional ventilation (U/L) were 0.88 +/- 0.01 (s.e.) (early) and 0.81 +/- 0.01 (s.e.) (late). Simulations with a compartment model show that a simple pattern of sequential filling can by itself account for the experimental results observed. Control over 81mKr delivery can be important to physiologically accurate assessment of ventilation-perfusion matching. Controlled delivery techniques could also modify effectiveness and targeting of other inhaled agents including therapeutic aerosols.

Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction.

It has previously been shown that unproductive coughing in both healthy subjects and patients with airways obstruction is not effective in clearing lung secretions. This study investigates the regional mucus transport in a group of subjects with airways obstruction who failed to expectorate following instructed cough and forced expiration technique. Fourteen patients (mean +/- SEM age: 68 +/- 2 years) with airways obstruction (mean +/- SEM percent predicted. FEV1: 54 +/- 5; daily wet weight sputum: 9.1 +/- 2.0 g) took part in the study which was a randomized, three-way crossover within-patient design. Each patient underwent three treatment maneuvers: control, cough (30 coughs over a 10-min period), and forced expiration (30 forced expirations over a 10-min period). An objective radioaerosol technique was used to monitor regional mucus movement within the lungs of the patients. The lungs were divided arbitrarily into four regions of interest: tracheal, inner, intermediate, and outer. Peak expiratory flow rate during cough and forced expiration was measured at the mouth. There was no correlation between the radioaerosol clearance from all regions and (1) mean peak flow during cough and forced expiration, and (2) mean 24-h sputum production prior to the study day. There were no differences in regional radioaerosol clearance between cough and forced expiration. However, both cough and forced expiration resulted in significant clearance compared with control for all regions with the exception of the forced expiration in the outer region. To our knowledge, this study is the first to demonstrate that unproductive cough and forced expiration result in movement of secretions proximally from all regions of the lung in patients with airways obstruction.

Tracheobronchial clearance in patients with pulmonary sarcoidosis.

Lung mucociliary clearance was measured using an objective, noninvasive radioaerosol technique in 13 patients with pulmonary sarcoidosis and 13 matched, healthy control subjects. Four of the sarcoid patients had never received any steroid therapy, five were currently receiving oral corticosteroids, and the remaining four were using inhaled corticosteroids only. A statistically significant retardation in tracheobronchial clearance (p less than 0.02) was observed in the sarcoid patients compared to the control subjects. The sarcoid patients using inhaled corticosteroids appeared to demonstrate the greatest degree of mucociliary transport impairment. The sarcoid patients in apparent remission and those receiving oral corticosteroid therapy had clearances better than those using inhaled corticosteroids, but they were still reduced compared to the control subjects. This study demonstrates that lung mucociliary clearance is adversely affected in patients with pulmonary sarcoidosis and raises the question of the possible consequences that could follow long-term inhaled immunosuppressive therapy on the prime clearance defense mechanism within the human lungs.

Lung mucociliary clearance in patients wit Young's syndrome.

Lung mucociliary clearance was measured in 14 patients with primary obstructive azoospermia and chest involvement (Young's syndrome) using the objective, in vivo radioaerosol technique. Lung mucociliary transport was significantly reduced in patients with Young's syndrome compared to 14 control subjects matched for physical characteristics, tobacco consumption and initial topographic distribution of tracer particles within the lungs. This finding indirectly supports the hypothesis that congenital abnormality in the propulsion of sperm in the ciliated epididymis results in the absence of sperm in the ejaculate.

The effect of unproductive coughing/FET on regional mucus movement in the human lungs.

The study was designed to ascertain the movement of mucus from proximal and peripheral regions within the human lungs during cough and the forced expiration technique (FET). Mucus movement was measured using a radioaerosol technique. Seven patients (mean +/- SEM age: 63 +/- 3 years) with airways obstruction (% predicted FEV1: 44 +/- 4) participated in the study. Each patient underwent three assessments in a randomized manner: control/cough/FET. Peak expiratory flow rate (PEFR) was measured at the mouth during cough and FET. None of the patients produced sputum during the assessment periods. Both cough and FET compared with control increased, on average, mucus clearance from all regions; statistical significance was achieved only for central lung regions with cough (P less than 0.05). There was no significant correlation between PEFR during cough/FET and regional lung clearance.

No effect of gender on lung mucociliary clearance in young healthy adults.

Lung mucociliary clearance (LMC) depends on age and it is adversely affected by cigarette smoking. When using the radioaerosol technique for measuring LMC the initial site of deposition of the radioaerosol within the lungs affects its rate of removal. Whether there is a difference in gender for LMC is still an open question. Forty-one (20 female, 21 male) healthy, non-smoking subjects had their lung mucociliary clearance measured using an objective, non-invasive radioaerosol technique. The male and female groups were closely matched for initial distribution of the radioaerosol. There was no statistical significant difference between males and females in the rate of clearance of inhaled radioaerosol over a 6 h observation period. When comparing the LMC of two groups although it is important to match them for age, smoking habits and initial topographical distribution of the tracer radioaerosol it does not seem essential to also match the two groups for gender.

Effect of oral antibiotics on lung mucociliary clearance during exacerbation of chronic obstructive pulmonary disease.

It has been well established that lung mucociliary clearance is depressed in patients with chronic obstructive pulmonary disease. This study examines whether oral antibiotics have a detectable effect on this clearance mechanism during exacerbation in patients with such disease. Twelve patients with a mean +/- SE age of 63 +/- 2 years participated in a randomized, double-blind, parallel group study to assess the effect of 1 week of treatment with amoxycillin (500 mg t.d.s.) or ciprofloxacin (500 mg b.d.) on lung mucociliary clearance during exacerbation. Lung mucociliary clearance rates were measured by a non-invasive radioaerosol technique. Both drugs on average resulted in small, non-significant, enhancement of mucociliary clearance. Following treatment, the numbers of coughs were reduced in both groups and significantly (P < 0.05) after treatment with ciprofloxacin. Sputum production was also significantly reduced (P < 0.01) in both groups. The magnitude of improvement in lung mucociliary clearance was relatively modest following 1 week of treatment with either antibiotic. Since the number of coughs was significantly less after ciprofloxacin treatment the measured enhancement of lung mucociliary transport is probably, however, an underestimate.

Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma.

Lung mucociliary clearance is impaired in stable asthma. The long-acting beta2-agonist salmeterol has been shown in vitro to cause a significant increase in ciliary beat frequency. It seemed possible therefore that salmeterol may also have a favourable effect on lung mucociliary transport in asthmatic patients. Fourteen patients with asthma participated in a double-blind, placebo-controlled, crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI (50 microg b.d.) on lung mucociliary clearance. The 11 patients who completed the study (seven males, four females) had a mean +/- SE age of 50 +/- 4 years, % predicted FEV1 of 74 +/- 8% and a tobacco consumption history of 13 +/- 7 pack-years (seven non-smokers, four exsmokers). Lung mucociliary transport was measured by a radioaerosol technique. Pulmonary function indices (FEV1, FVC, and PEF) were significantly improved on salmeterol relative to placebo. The main radioaerosol finding was a significant increase in the penetration of radioaerosol into the lung with 24-h radioaerosol rising from 40 +/- 5% on placebo to 49 +/- 4% (P < 0.01) on salmeterol. Despite this increased penetration, a slight favourable change occurred in tracheobronchial aerosol clearance. This study demonstrates that 2 weeks salmeterol treatment influences deposition of particles within the lung by increasing airway patency and indicates a beneficial effect of MDI salmeterol on lung mucociliary clearance.

Aerosol particle impaction in the conducting airways.

Modelling of inhaled particle deposition in the lungs potentially offers data relevant to assessing hazards from toxic inhaled particles, to studying mucus clearance or lung permeability by aerosol techniques, and to achieving better utilisation of drugs administered as aerosols. Analysis of published modelling studies is complicated by differing approaches to the quantitative estimation of physical factors determining deposition and by differing choices of anatomical data. Published formulae for predicting aerosol particle impaction are compared by applying them to the deposition of 5 micron particles in the human conducting airways using the morphological data of Weibel together with information from other sources about airways branching angles. The results indicate the range of deposition estimates that may be obtained from currently available impaction formulae. All but one of the formulae considered agree in indicating maximum deposition by impaction in, or close to, the segmental or subsegmental bronchi. Data are presented to indicate how the principal physical determinants of deposition depend on particle size, inhalation flow rate and lung volume during inhalation.

Bone density and cortical thickness in nutritional vitamin D deficiency: effect of secondary hyperparathyroidism.

Measurements of bone mineral index, mean metacarpal cortical thickness, plasma calcium, alkaline phosphatase and serum 25-hydroxyvitamin D and parathyroid hormone concentrations were carried out in 39 Asian vegetarian patients with hypovitaminosis D. It was concluded that PTH is probably the major determinant of osteopenia in patients with osteomalacia and secondary hyperparathyroidism; and that the presence of secondary hyperparathyroidism in association with hypovitaminosis D should be an absolute indication for vitamin D supplementation even in asymptomatic patients.

Clinical trial of four pancreatic scanning agents.

Four 75Se-labelled amino acids have been tested in 22 patients. In 11 of the patients pancreatic function was estimated by the Lundh test. Scans at varying time intervals up to 30 hours from isotope administration were assessed by blind marking. Pancreatic visualization with all four agents was markedly poorer than would have been expected with 75Se-selenomethionine. Whole-body retention was estimated for all four agents; two showed faster 75Se clearance than selenomethionine. Radioactivity in duodenal aspirate was measured for two of the agents.

Pancreatic scanning.

The 75Se-selenomethionine pancreas scan cannot differentiate between chronic pancreatitis and carcinoma of the pancreas and may--although chiefly in certain defined clinical conditions--give a false-positive result. It is also rather more time-consuming than other radioisotopic scanning procedures. Its value in clinical practice stems from the fact that all the other methods currently available for studying the pancreas have their own disadvantages. Because a normal scan is only rarely seen in patients with carcinoma of the pancreas, pancreatic scanning can be particularly useful in helping to decide which patients should, and which should not, be subjected to other procedures involving greater discomfort or risk.

Liver and pancreas scanning in extrahepatic obstructive jaundice (with special reference to tumours of the bile and hepatic ducts).

198-Au-gold colloid liver scans and 75-Se-selenomethionine pancreas scans in 72 patients with extrahepatic obstructive jaundice were assessed by blind marking. They were compared with liver and pancreas scans from 20 control patients and liver scans from 33 patients with diffuse liver disease. 56 per cent of the liver scans in extrahepatic obstructive jaundice showed a filling defect in the hilar region of the liver. This was most frequently seen in the most deeply jaundiced patients, and was reported in 80 per cent of patients with a serum bilirubin greater than 15 mg/100 ml. The liver scan alone cannot distinguish between different forms of extrahepatic obstructive jaundice although severe loss of left lobe uptake appeared to favour a diagnosis of carcinoma of the bile or hepatic ducts. A normal pancreas scan virtually excludes a pancreatic carcinoma as the cause of obstructive jaundice. A pancreas scan showing severely reduced uptake suggests a carcinoma of the pancreas or of the lower end of the common bile duct.

Radioaerosol assessment of mucociliary clearance: towards definition of a normal range.

Radioaerosol measurements of mucociliary clearance have been assessed in relationship to depth of particle penetration into the lung. The tests analysed were performed with 5 microns diameter 99Tcm particles inhaled under standardised conditions but at varying inhalation flow rates. Aerosol lung penetration was assessed by (i) penetration index (PI), a ratio of outer to inner zone radioactivity determined from a gamma camera image; and (ii) alveolar deposition (AD), a measure of activity retained at 24 hours and taken to represent deposition distal to the ciliated airways. Clearance rates in 30 tests on 19 normal non-smokers under the age of 50 varied significantly with aerosol inhalation flow rate, PI and AD. A normal range varying with PI is proposed although normal inter-subject variability remains high even after allowance for PI. Nevertheless 8 out of 12 patients with stable asthma and 21 out of 24 patients with chronic bronchitis demonstrated slow clearance lying outside the PI-based normal range.

Sacroiliac joint uptake ratios in inflammatory bowel disease: relationship to back pain and to activity of bowel disease.

Sacroiliac uptake ratios based on 99Tcm methylene diphosphonate images were calculated in 14 patients with ankylosing spondylitis, 23 patients with non-specific backache, 33 patients with inflammatory bowel disease (ulcerative colitis 19, Crohn's disease 14) and 33 control subjects. Twenty-eight of the control subjects were patients referred from a breast cancer clinic. In the control subjects, and in 20 patients with inflammatory bowel disease who did not have back pain, sacroiliac ratios decreased significantly with increasing age (p less than 0.001 and p less than 0.01 respectively). Sacroiliac uptake ratios were significantly higher in ankylosing spondylitis than in patients with non-specific backache. Seven of the 14 patients with ankylosing spondylitis had higher sacroiliac ratios than any recorded in the control subjects. Eleven patients with inflammatory bowel disease had abnormally high sacroiliac uptake ratios; ten of these patients had back pain. Increased sacroiliac joint uptake in such patients may reflect early sacroiliitis. No relationship was detected between sacroiliac uptake and the activity of the bowel disease. Sacroiliac uptake ratios were significantly higher in the inflammatory bowel disease patients suffering from back pain than in age and sex matched patients with (a) inflammatory bowel disease but no back pain or (b) non-specific backache.

The particle size distribution of technegas and its influence on regional lung deposition.

The size distribution of the aerosol produced by a technegas generator has been measured with a screen diffusion battery. The median diameter of the active aerosol was found to be of the order 140 nm and not to vary with the delay between generation and use. The measurements indicate that about 20% of the aerosol should be deposited in deep lung with about 5% deposited in the upper airways.

Risk assessment for a radionuclide area: structure and scope.

As with all places of employment, nuclear medicine, medical physics and research departments in the United Kingdom which use radiation are required by legislation to make risk assessments associated with their work. Many have been slow to complete these, finding little guidance as to the best approach to take for departments which handle ionizing radiation. The Royal Free Hospital has set up a project to examine the whole procedure and approach to risk assessments in departments which use ionizing radiations, and has produced a standardized approach using matched risk assessment forms for both general risks and ionizing radiation risks. A worked example is included to illustrate the methodology and the standardized risk assessment forms.

Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major.

We have previously shown a high incidence of osteopenia and osteoporosis in patients with thalassaemia major. These bone changes, were more severe in males than females, in those with diabetes mellitus and with hypogonadal-hypogonadism. Our recent studies concern the relationship of erythroid activity, assessed by serum transferrin receptors as an overall measure of anaemia, to osteoporosis. Serum transferrin receptor levels correlated with the mean pre-transfusion haemoglobin level, but there was no correlation with the incidence of osteopenia and osteoporosis. As osteoporosis has a strong genetic component we have also studied the COLIA1 and COLIA2 genes which code for the major protein of bone (type 1 collagen). Studies by others have shown in non-thalassaemic patients that a polymorphism G-->T or TT in a regulatory region of COLIA1 at the recognition site for transcription factor Sp1 is associated with the presence of osteoporosis. Our studies suggest that Sp1 polymorphism is not specific to any one ethnic group; the polymorphism occurs more commonly in females (female to male ratio 2:1). In male thalassaemia major patients the presence of the Sp1 mutation was associated with more severe osteoporosis of the spine and the hip compared with female patients. There is failure of improvement in spinal osteoporosis with bisphosphonate therapy (intravenous Pamidronate) in male patients with the Sp1 mutation.