Biomedical subjects
Publications and source records attributed to J P Hartley.
Various formulations have been developed in an effort to reduce the toxicity of amphotericin B. We report a case of cryptococcal meningitis in a 31-year-old HIV-positive man which was successfully treated with amphotericin B lipid emulsion.
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We review some of the evidence that supports the existence of psychosomatic triggers to bronchospasm in asthmatics, and hypothesize that it may also be possible to consciously reverse bronchospasm using trachea-noise biofeedback. We precipitated significant levels of bronchospasm in 16 asthmatics using exercise or eucapnic-hyperventilation challenges on five occasions, and administered four different treatments and a no-treatment control. The treatments were trachea-noise biofeedback (TNBF), wrong-information TNBF, an inhaled adrenergic bronchodilator, and a placebo inhaler, all given double blind. Half of the subjects had 3 training days in the use of the TNBF device before study. Our results show that TNBF, in the trained subjects only, is associated with a detectable, but not statistically significant, increase in the rate of recovery from bronchospasm over that found with no treatment. We conclude that, although asthmatics seem to have a strong ability to consciously induce bronchospasm, conscious reversal of a full asthma attack using TNBF is limited. Despite contrary conclusions by other investigators, we believe that this study demonstrated little TNBF-assisted recovery from bronchospasm. We suggest that this is because its effect may be inhibited by humoral mechanisms that sustain the attack, but we believe further work is required to support this.
Forty adult patients with chronic asthma completed a 3-month double-blind crossover study to compare the effect of sustained-release theophylline given both as a fixed 300 mg twice daily dose (standard) and an individually titrated dose (titrated) with placebo. Theophylline was given in addition to other usual therapy, inhaled bronchodilators, inhaled steroids and, in 12 patients, oral steroids. The 3-month period was preceded by a run-in phase to determine the dose of theophylline which each subject required to achieve peak serum levels of 12-20 mg/litre and trough levels of 8-12 mg/litre. Doses ranged from 300 mg to 700 mg twice daily. Twenty-one patients needed more than the standard dose to achieve satisfactory serum levels. Patients recorded daily peak flow rates and symptom scores and were seen at monthly intervals to measure lung function, check serum theophylline levels and change treatments, which were given in random order. FEV1 was significantly higher for the whole group after standard (2.11 litres) and titrated (2.15 litres) theophylline therapy than after placebo (1.89 litres), as was FVC, but in the large subgroup whose titrated dose was greater than the standard dose, the FEV1 only improved with the titrated dose. Peak flow measurements at home showed the same pattern. Patients taking oral steroids appeared to derive less benefit from theophylline than others. It is concluded that theophylline can usefully be added as a third-line drug in chronic asthma, but that since half the patients are likely only to benefit from a dose greater than 300 mg twice daily, while the other half may have high serum levels above this dose, it is essential to measure serum levels in order to use the drug effectively and safely.
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Airway reactivity is taken to mean the bronchoconstrictor response of airways to non-specific (i.e. non-allergic) stimuli, most commonly to aerosols of histamine, methacholine or prostaglandin F2 alpha, to exercise, cold air or hyperventilation. Reactivity is greatly increased in subjects with asthma when compared with normal. Normal subjects may transiently acquire hyperreactivity following viral infections or exposure to ozone, although usually not in the asthmatic range. In asthma, an initiating stimulus may also be required for the development of hyperreactivity, but genetic susceptibility may be important. Once acquired, the hyperreactivity which is characteristic of asthma varies with time, and with environmental factors. The mechanisms underlying hyperreactivity are incompletely understood. One important feature appears to be the role of continuing mediator release and inflammation in the airways. Reactivity may be increased by levels of mediators which are themselves insufficient to affect lung function, as we have shown in a recent study using histamine challenge following pre-treatment with small doses of prostaglandin F2 alpha. It is possible to imagine how a succession of sub-threshold allergic, or even physical stimuli might maintain bronchial hyperreactivity in this way. Recent studies have described the importance of bronchial hyperreactivity in the pathogenesis of asthma in allergic individuals. The level of bronchial hyperreactivity can determine the asthmatic response to an inhaled allergen, since a high degree of allergy coupled with a low reactivity to released mediators such as histamine would only produce a small response, whereas even a small amount of mediator might produce a large response in a very reactive individual.
1. Arterial plasma histamine concentrations, forced expiratory volume in 1.0 s (FEV1.0) and peak expiratory flow rate were determined in nine patients with exercise-induced asthma and in five control subjects before and after 8 min of cycle-ergometer exercise. 2. In the controls neither FEV1.0 nor peak expiratory flow rate fell by more than 5% in any individual during the 30 min postexercise period. The asthmatic patients all experienced a fall in FEV1.0 or peak expiratory flow rate, or both, of 15% or more in the period 5-20 min after completion of the exercise. 3. There was no difference between the control subjects and the asthmatic patients in the plasma histamine response to exercise. In both groups there was an insignificant rise of about 40% during exercise, although the initial levels were higher in the asthmatic patients. 4. The mean plasma histamine peak of the asthmatic patients preceded the mean maximal fall of FEV1.0 and peak expiratory flow rate by approximately 15 min. However, no positive correlation was found between rise in, or peak, plasma histamine levels and decrease in lung function. 5. Three non-atopic asthmatic patients had a significantly higher mean plasma histamine concentration during exercise than had the atopic subjects. 6. A strong positive correlation in asthmatic patients, and asthmatic and control subjects together was found between age and mean postexercise plasma histamine concentrations. 7. The results do not support a direct role for histamine in the production of exercise-induced asthma.
It is known that sympatho-adrenal control of airways is increased in asthma since beta blockade can cause severe bronchoconstriction in asthmatic individuals. It has not been established whether an altered catecholamine response to exercise plays any part in the production of the common symptom of exercise-induced asthma (EIA). We have investigated this indirectly by measuring arterial plasma cyclic nucleotide levels in 10 subjects with EIA and five normal subjects. Cyclic AMP, which in this context reflects beta stimulation, rose significantly by 25.4% in the normal subjects during exercise, while there was no significant change during or after exercise (less than 5%) in the asthmatic subjects. Cyclic GMP rose significantly after exercise in the asthmatic subjects. Six normal subjects repeated the protocol before and after inhalation of salbutamol aerosol, 1600 microgram daily for 18 days. This did not reduce the cAMP response to exercise, and we conclude that the diminished cAMP response of the asthmatic subjects was not caused by their medication. The results may indicate either impaired catecholamine production or endogenous beta receptor hyporesponsiveness in some asthmatic subjects and this may contribute to the development of EIA.
The ability of the H1 receptor antagonist clemastine to prevent exercise-induced asthma (EIA) has been studied in 10 adult asthmatic subjects. Exercise was performed for eight minutes on a cycle ergometer on two occasions on each of two days. The first test each day was without premedication and the second was preceded by inhalation of 0.05% clemastine or saline placebo given single blind in random order. Ventilatory function was assessed by serial measurements of peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV1). All four tests for each patient were closely matched in terms of oxygen uptake and total ventilation which were monitored throughout exercise. The response to exercise after clemastine or placebo has been compared both directly and in terms of the degree of protection afforded against EIA compared with the initial test on the same day. Clemastine was significantly better than placebo for both PEFR and FEV1. All 10 subjects had less EIA after clemastine, which suggests an important role for histamine in its production. Other mechanisms may also be involved to a variable degree in different individuals.
The contribution of vagal mechanisms to exercise-induced asthma has been studied in 10 adult asthmatic patients using the anticholinergic drug ipratropium bromide. Exercise tests were performed for eight minutes on a cycle ergometer and each individual's tests were standardised by matching oxygen uptake. Two tests were done on each of three study days, the first being without previous medication, and the second preceded by inhalation of ipratropium bromide, 0.1, or 1 mg or saline placebo given 90 minutes beforehand. The mean falls in FEV1 and PEFR after the initial tests were very similar on the three study days. The mean falls in FEV1 after the second test were 22.3%, 19.5%, and 12.5% with placebo, 0.1 mg, and 1 mg ipratropium bromide respectively. Only the higher dose was significantly better than placebo. The results were also analysed using a protection index to compare the first and second tests each day and 1 mg ipratropium bromide was significantly better than both 0.1 mg and placebo. Similar results were obtained using PEFR. Equal bronchodilatation was produced by the two doses of drug. We conclude that conventional doses of anticholinergic drugs are not effective in preventing exercise-induced asthma, while large doses may do so in the same group of subjects.
1 There is evidence that H2 receptors are present in the lung, both on bronchial smooth muscle and mast cells. In animal studies, stimulation of H2 receptors causes a diminution, and conversely H2 receptor blockade can increase, smooth muscle contraction and mediator release. 2 The effects of H2 receptor blockade in ten patients with asthma has been studied using oral cimetidine in a dose of 1 g daily for 1 week. Treatment was compared with placebo and the H1 receptor antagonist chlorpheniramine. 3 There was no alteration in the severity of naturally-occurring or exercise-induced asthma with cimetidine or chlorpheniramine. 4 H2 receptor blockade with oral cimetidine in conventional doses is without ill effect in asthma. The use of larger parenteral doses is discussed.
Salbutamol dry powder was compared with salbutamol aerosol in 38 asthmatic patients. The study was double-blind and took place over six months. Salbutamol powder in a dose of 200 micrograms per capsule was able to control asthma as well as the aerosol, but some patients needed to increase the frequency of dosage when using the powder. The device used for powder administration, the Rotahaler, was well accepted and was preferred to the pressurized aerosol by one-third of patients. Dry powder administered by Rotahaler allows salbutamol to be given by inhalation to many patients previously using aerosols inefficiently.
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1 delta1-trans-tetrahydrocannabinol, (delta1-THC) produces bronchodilatation in asthmatic patients. 2 Administered in 62 microliter metered volumes containing 50--200 microgram by inhalation from an aerosol device to patients judged to be in a steady state, it increased peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1). 3 The rate of onset, magnitude, and duration of the bronchodilator effect was dose related.
H1 receptor blocking antihistamines administered by mouth have not found a clear place in the management of bronchial asthma. We investigated the possibility that higher concentrations of these drugs, administered directly to the bronchial tree, might produce bronchodilatation. Twelve asthmatic patients inhaled aerosols generated from solutions of clemastine (0.05%), salbutamol (0.5%), and placebo. Bronchodilatation was assessed by changes in the forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR) over four hours. Both clemastine and salbutamol caused significant bronchodilatation. The mean maximum percentage increases in FEV1 for clemastine and salbutamol were 21.1% and 29.2% respectively. The mean maximum percentage increases in PEFR were 31.2% and 35.2% respectively. There was no significant difference in the maximum bronchodilatation produced by the two drugs. Clemastine, when administered by aerosol inhalation, appears to be an effective bronchodilator.