Biomedical subjects
Publications and source records attributed to R D Stark.
The effect of xamoterol as sole therapy was investigated in randomized, double-blind, placebo-controlled studies involving 425 patients with mild to moderate heart failure. When compared with placebo, xamoterol produced improvements in exercise capacity, clinical signs, symptoms and quality of life with a low incidence of adverse experiences. Xamoterol is effective as monotherapy in heart failure.
1. In eight normal volunteers, the adductor pollicis (AP) was fatigued using intermittent trains of programmed, supramaximal stimulation at 1, 10, 20, 50, 100 and 1 Hz. Activity protocols were performed both with and without circulatory occlusion, both without and during propranolol 80 mg thrice daily in order to investigate the effects of beta-adrenoceptor blockade on 'peripheral' fatigue mechanisms. 2. The degree of beta-adrenoceptor blockade was assessed by the reduction of exercise tachycardia during cycle ergometry, e.g. pulse rates at 210 watts were reduced from 190 +/- 15 to 127 +/- 5 beats min-1 (mean +/- 1 s.d.) indicating that beta-adrenoceptor blockade was substantial and highly significant (P less than 0.001). 3. Before, during and following fatiguing activity with circulatory occlusion force declines were identical during and without beta-adrenoceptor blockade. During and following activity without occlusion, there were slight declines in force which were questionably significantly different at 20 Hz (P less than 0.05). 4. The compound muscle action potential (CMAP) amplitude, measured from the skin surface over the muscle, was unaltered by beta-adrenoceptor blockade before, during or after activity whether with or without circulatory occlusion. 5. The maximal relaxation rate (MRR) was not significantly reduced in previously unfatigued muscle during beta-adrenoceptor blockade. During activity, both with and without circulatory occlusion, there was no evidence that MRR was reduced significantly more during beta-adrenoceptor blockade. 6. The absence of a convincing effect of beta-adrenoceptor blockade on peripheral fatigue mechanisms may indicate that central mechanisms are involved or that impairments of peripheral force production, of a specific nature or as a result of exacerbation of limitations of circulatory oxygen transport, though small are detected during voluntary exercise and give rise to increases in motor unit recruitment and/or firing rates, and hence increased perception of fatigue.
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We have shown in a previous study that indomethacin reduced breathlessness in normal subjects during exercise. In a double-blind randomized study we have determined the effects of both acute (50 mg) and chronic (25 mg twice daily for 7 days) oral treatment with indomethacin on breathlessness induced by exercise in patients with diffuse parenchymal disease of the lung. The relationship of breathlessness, as measured on a visual analogue scale, to ventilation was not significantly altered by either acute or chronic treatment with indomethacin compared to placebo. There was no significant change in the distance walked in 6 minutes after any of the treatments. Possible explanations for the differing effects on breathlessness observed in normal subjects and in patients are discussed.
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This study was devised to test the hypothesis that dyspnoea could be mediated by unmyelinated vagal sensory nerve endings (type J receptors) situated at alveolar level in the lung. A modified jet nebulizer was used to generate an aerosol of local anaesthetic in particles small enough to allow alveolar deposition. Lignocaine (2% and 5%) produced aerosols with an arithmetic mean diameter (+/- SD) of 1.5 +/- 0.3 and 1.2 +/- 0.6 micron respectively, the mass median diameters being 1.7 (geometric standard deviation = 1.2) and 2.5 (geometric standard deviation = 1.7) micron respectively. In experimental animal models a vagally mediated tachypnoea may be induced acutely by pulmonary microembolism. This response is known to be mediated by unmyelinated pulmonary afferent nerves in the vagus. Local anaesthetic agents administered as small particles, but not as large particles, obtunded this response, which suggests that the aerosol was capable of penetration to alveolar level. Upon this background, a clinical study was designed to compare the effects of lignocaine with placebo both given as small-particle aerosols. Six patients, including two with diffuse alveolar pathology and four with chronic airflow obstruction, were studied. Respiratory frequency was determined before and after the aerosol, and exercise tolerance and breathlessness were measured with a 6 min walking test and visual analogue scales. After lignocaine there was no clinical evidence of anaesthesia of the upper airways but bronchoconstriction occurred. While no overall effect of lignocaine on dyspnoea was apparent, individual patients showed some evidence of benefit.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and to determine the contributions from promethazine's major pharmacological actions. Twelve healthy subjects participated in a double-blind, within-subject comparison of promethazine and placebo each given acutely by mouth. Breathlessness was assessed with visual analogue scales during a progressive exercise test and was related to minute ventilation. Promethazine had no significant effect on breathlessness nor on the relationship between breathlessness and ventilation. The role of histamine-antagonism was investigated in a subgroup of the subjects by administration of mebhydrolin. No effect on breathlessness was detected. In contrast, the standard phenothiazine, chlorpromazine, caused a marked and statistically significant reduction in breathlessness without affecting ventilation and without causing detectable sedation. This unexpected finding merits further study in patients and is discussed with reference to the role of chlorpromazine as a constituent of Brompton's Mixture.
The effects of indomethacin on the relationship between breathlessness and minute ventilation during exercise have been determined in a double-blind, randomized study on 6 normal subjects. Indomethacin did not significantly after ventilation or oxygen uptake either at rest or during submaximal exercise. Breathlessness was assessed with visual analogue scales, and, when compared with placebo, the sensation was significantly reduced in relation to ventilation (p less than 0.02). These findings provide evidence of a possible role for prostanoids in the mechanisms that give rise to breathlessness.
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The effects of ICI 118,587 and atenolol on the responses to submaximal exercise and on breathlessness were studied in six healthy subjects. Atenolol reduced heart rate at rest and during exercise whereas ICI 118,587 increased resting heart rate but caused a small reduction in the highest heart rate achieved during exercise. Neither ICI 118,587 nor atenolol significantly changed minute ventilation or oxygen uptake either at rest or during exercise. There were no effects on bronchomotor tone. The assessment of breathlessness was validated for the subjects participating in the study. Atenolol increased the intensity of breathlessness in relation either to ventilation or to oxygen uptake. This effect was not secondary to a change in bronchomotor tone but was possibly related to changes in pulmonary haemodynamics. On the other hand, the relationships of breathlessness to ventilation or to oxygen uptake were unchanged by ICI 118,587. The effects of ICI 118,587 on exercise tolerance and dyspnoea in patients with impaired cardiac function should now be determined.
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In six healthy subjects, respiration and the sensation of breathlessness were assessed during submaximal exercise and the subsequent recovery. The overall responses were expressed by the relationship of breathlessness to minute volume. Because of the high subjective component in the assessments, validation of the method in these particular subjects was an integral part of the study. The relationship of breathlessness to ventilation during identical periods of exercise was highly reproducible and sensitivity was demonstrated by an alteration in this relationship in the presence of an inspiratory resistance. Codeine at a dose of 60 mg by mouth was compared with placebo, each treatment being given on two occasions. The study was conducted in a double-blind fashion with randomization of the order of treatments. Codeine at this dose allowed higher levels of carbon dioxide to be tolerated during breath-holding; oxygen uptakes at rest and during exercise were unaffected. Ventilation and breathlessness at the end of exercise were each slightly but significantly reduced by codeine but the relationship between breathlessness and ventilation was not changed. Codeine did not prevent detection of an inspiratory resistance.
A new test for assessing clinical dyspnoea with greater precision has been devised. This involves walking on a treadmill while ventilation is measured and dyspnoea is assessed serially with visual analogue scales. The test has been applied successfully in patients with chronic bronchitis and emphysema and in asthmatic patients. The reproducibility of the test was determined by comparing identical periods of exercise separated by an interval of five days in patients with chronic bronchitis and emphysema. The relationship between dyspnoea and ventilation showed acceptable within-patient reproducibility. The sensitivity of the test was investigated in asthmatic patients by comparing exercise after placebo and after salbutamol which had increased PEFR by a mean of 33%. After salbutamol, lower breathlessness scores usually occurred for a given level of ventilation and this indicates that the test was sensitive enough to detect an effective treatment. Thus more precise assessment of dyspnoea in patients is feasible and generally reliable. However, a proportion of patients respond unpredictably and it is necessary to apply this test critically and with an appreciation of its limitations.
1. Methods were devised and evaluated for inducing breathlessness by submaximal graded exercise in healthy subjects while objective measurements of cardiorespiratory function were made. Breathlessness was assessed with serial visual analogue scales (VAS), but with various measures to enhance repeatability. 2. A high level of reproducibility was obtained in spite of the subjective nature of the assessment. Individual responses were described by the relationship between breathlessness and ventilation. The sensitivity of the method was demonstrated by the use of inspiratory resistances which disturbed this relationship and caused greater breathlessness for a given level of ventilation. 3. These methods were applied to six healthy subjects to analyse the effects of acute doses of diazepam and promethazine on breathlessness induced by graded exercise or by rebreathing carbon dioxide in a double-blind study. 4. During exercise, diazepam and promethazine did not reduce breathlessness, although there was a minor trend with promethazine. During exposure to elevated levels of carbon dioxide, diazepam and promethazine had no effect on breathlessness. Diazepam and promethazine produced similar levels of sedation, but neither drug had significant effects on the ventilatory response to carbon dioxide. These preliminary findings contrast with those reported for chronic diazepam in 'pink puffers'. 5. Raised levels of carbon dioxide caused greater breathlessness in relation to ventilation than did exercise.
1 Healthy volunteers undertook submaximal graded exercise while objective measurements of cardio-respiratory function were made and breathlessness was assessed with serial visual analogue scales. 2 A useful and consistent relationship existed between breathlessness and ventilation for individual subjects. 3 Drugs were examined in this system to test whether they modified the relationship between ventilation and breathlessness such that less breathlessness occurred for a given level of ventilation. 4 Salbutamol, ipratropium bromide and disodium cromoglycate given by inhalation did not reduce breathlessness in healthy subjects during exercise.
Experimental evidence from animals suggests that the response of the pulmonary circulation to hypoxia is mediated by histamine. In 3 patients with chronic bronchitis the pulmonary vascular response to hypoxia was measured before and after administration of chlorpheniramine, a competitive antagonist of histamine. No convincing evidence was obtained of a reduction in the size of the response to hypoxia.
Five patients with chronic bronchitis and pulmonary hypertension were treated with oxygen in their homes for periods of between 6 and 24 months. Oxygen was supplied for 15 hours daily from cylinders or from an oxygen concentrator and few practical difficulties arose. After 23 to 59 weeks of treatment there were significant decreases in pulmonary arterial pressure and vascular resistance, and four of the five patients no longer had pulmonary hypertension at rest. Two of these patients had shown little response after three weeks of treatment. There was a reduction in the number of episodes of congestive cardiac failure compared with the corresponding period before treatment. Two of the patients improved enough to return to work. These results are encouraging enough to justify a controlled trial of the treatment in a large number of patients.
Patients with pulmonary hypertension due to chronic bronchitis may improve during long-term treatment with oxygen. The methods of administration which are currently available are expensive and present practical difficulties. The Rimer-Birlec domiciliary oxygen concentrator produces an oxygen concentration of 92% at a flow of 21./min. It has been used successfully in a patient's home but further use will require an increase in mechanical reliability and a decrease in noise. In view of its convenience and the economic advantages the oxygen concentrator is an important advance in treatment with oxygen and could prove to be the method of choice in the home.