Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels

To investigate the role of opioids in the acquired immune dysfunctional state that occurs after burns or trauma, plasma beta-endorphin levels were measured serially in nine severely burned patients, and the effect of four different opioids on normal neutrophil and lymphocyte function was quantitated. The rationale for these studies is that the neuroendocrine system appears capable of interacting with and modulating immune function. The plasma levels of beta-endorphin increased to higher than normal during the first 36 hours after burn (15 versus 3.4 pmol/L, p less than 0.05) but quickly returned toward normal. Morphine had the most profound effect on in vitro neutrophil function; it decreased neutrophil chemotaxis but increased neutrophil bactericidal activity for Staphylococcus aureus, as well as resting and zymosan-stimulated oxygen consumption. Other opioids (naloxone, met-enkephalin, and beta-endorphin) had no direct effect on neutrophil chemotaxis or bactericidal activity. Both naloxone and met-enkephalin increased neutrophil oxygen consumption in a dose-dependent fashion, whereas beta-endorphin impaired neutrophil oxygen consumption. None of the opioids altered resting lymphocyte blastogenesis. The only opioid that impaired the ability of normal lymphocytes to respond to mitogen stimulation at physiologically relevant doses was beta-endorphin. These results, documenting that beta-endorphin levels are altered after thermal injury and that opioids can modulate normal neutrophil and lymphocyte function in vitro, support the concept that changes in neuroendocrine activity may occur and potentially alter immune function.     

The influence of physical and mental training on plasma beta‐endorphin level and pain perception after intensive physical exercise

The intention of the study was to investigate a possible correlation between increase in circulating blood level of beta‐endorphin and decrease in pain perception after short‐term intensive physical exercise. In addition, we wanted to see if plasma beta‐endorphin level and pain perception were influenced by regular physical or mental training and if there was any difference in response between trained and untrained subjects. Twenty physically trained males were studied before and after a 6‐month intervention period while practising regular physical endurance training. Eleven of them were randomized to perform daily additional mental training (ACEM meditation). Nine untrained males served as control subjects and were investigated only at baseline. All participants were tested for maximum oxygen uptake (VO_2max) during treadmill exercise, and pain perception measured by an ischaemic pain test was performed just before and after VO_2max. Blood samples analysed for beta‐endorphin were drawn before and after the tests. There was a substantial decrease of 47 per cent (p < 0.005) in basal plasma beta‐endorphin level after the intervention. The plasma beta‐endorphin level increased two‐fold (p < 0.01) in response to the VO_2max test. The subjects experienced post‐exercise hypoalgesia (p < 0.001), but there was no correlation between the exercise‐associated opioid hyperendemia and the hypoalgesia. No difference was found between trained and untrained subjects regarding the circulating blood level of beta‐endorphin or the exercise‐induced hypoalgesia. Practising regular meditation had no influence on beta‐endorphin level or pain tolerance level. Peripheral beta‐endorphin level and pain perception are modulated by intensive physical exercise and by regular physical, but not by mental training. It could be speculated that the observed initial high basal level of beta‐endorphin is due to pre‐experimental stress and tension. Copyright © 2001 John Wiley & Sons, Ltd.     

Effects of naloxone on upper airway collapsibility in normal sleeping subjects.

BACKGROUND: To evaluate the possible influence of endorphin release on upper airway collapsibility the effects of naloxone, an opiate receptor antagonist, were measured. METHODS: The effects of naloxone on upper airway collapsibility were studied in five normal sleeping men in a pilot study. During a sleep fragmentation night the subjects received either naloxone or a volume matched saline placebo in a double blind crossover design. Critical pressure (Pcrit) was measured during a morning nap following sleep fragmentation. RESULTS: The plasma levels of endorphins increased during sleep fragmentation nights. Pcrit was significantly greater after placebo than after naloxone infusion. CONCLUSIONS: Naloxone may reduce upper airway collapsibility in normal sleeping subjects following sleep fragmentation.     

Plasma cyclic nucleotide levels in 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.     

Response of the nose to exercise in healthy subjects and in patients with rhinitis and asthma.

BACKGROUND--Although the nose and the bronchi are both involved in the process of regulating respiratory heat exchange, thermal changes may precipitate airway obstruction during exercise but rarely cause nasal obstruction in patients with rhinitis. The cause of the different response of the nose and bronchial tree has hardly been investigated. This study was performed to assess the response of the nose during exercise in the presence of rhinitis, asthma, and in normal controls. METHODS--Ten healthy subjects (group 1), 15 patients with asthma and rhinitis (group 2), 10 with rhinitis only (group 3), and 11 with asthma only (group 4) were included in the study. Exercise was performed on a bicycle ergometer for six minutes, reaching a heart rate of 80% of predicted. Bronchial and nasal responses were measured by forced expiratory volume in one second (FEV1) and posterior rhinomanometry, respectively. A drop in the FEV1 of 20% or more was considered a positive exercise induced asthma challenge test. RESULTS--Heart rate and ventilation increased by a similar proportion in the four groups. The FEV1 significantly decreased in asthmatic patients (groups 2 and 4) but it did not change in healthy subjects (group 1) or in those with rhinitis (group 3). Thirteen asthmatic patients developed exercise induced asthma. Nasal patency increased with exercise by a similar proportion in all groups, and no differences were detected between those with rhinitis (groups 2 and 3) and those without (groups 1 and 4). Nasal patency had returned to basal values at 25 minutes after completion of exercise in the four groups. The nose of patients with exercise induced asthma, however, remained significantly more patent than in patients without exercise induced asthma between 10 and 30 minutes after exercise. CONCLUSIONS--These results suggest that the nose responds differently from the bronchi during exercise induced airway obstruction: whereas the bronchial tree responds by becoming narrowed, the nose becomes more patent. These findings suggest that the mechanisms regulating the response of the nose to exercise are different from those involved in the response of the bronchial tree.     

Circulating adrenaline and noradrenaline concentrations during exercise in patients with exercise induced asthma and normal subjects.

A failure of the usual increase in plasma adrenaline and noradrenaline concentrations during submaximal exercise has been suggested as a contributory cause of exercise induced asthma. Six normal subjects and six asthmatic patients underwent a standard graded maximal exercise test. Measurements of oxygen consumption, minute ventilation, exercise time, blood lactate concentration, and heart rate indicated that the two groups achieved similarly high work loads during exercise. Mean FEV1 fell by 20% in asthmatic patients after exercise. Basal plasma adrenaline concentrations (nmol/l) increased in normal subjects from 0.05 to 2.7 and in asthmatic patients from 0.12 to 1.6 at peak exercise. Noradrenaline concentrations (nmol/l) increased in normal subjects from 2.0 to 14.3 and in asthmatic patients from 1.9 to 13.7 at peak exercise. The increases in adrenaline and noradrenaline in the asthmatic patients did not differ significantly from the increases in normal subjects. Thus a reduced sympathoadrenal response to exercise seems unlikely to be an important mechanism in the pathogenesis of exercise induced asthma.     

Circulating plasma concentrations of atrial natriuretic peptide and catecholamines in response to maximal exercise in normal and asthmatic subjects.

BACKGROUND: Intravenous infusion of atrial natriuretic peptide has been shown to cause bronchodilatation in patients with asthma and endogenous atrial natriuretic peptide is known to rise with exercise. Whether an aberration in release of atrial natriuretic peptide is concerned in the pathogenesis of exercise induced bronchoconstriction has not been studied. METHODS: The atrial natriuretic peptide response to exercise was studied in eight men with exercise induced asthma and eight age matched non-asthmatic men. Subjects exercised to exhaustion on a treadmill, using the Bruce protocol. Atrial natriuretic peptide and catecholamines were measured at the end of each stage of exercise and oxygen consumption and heart rate were monitored throughout. RESULTS: Both groups showed a 3.5 fold increase in plasma atrial natriuretic peptide during exercise (mean (SE): normal subjects 25 (4) pmol/l; asthmatic subjects 24 (5) pmol/l), with no difference between the two groups. There was a close correlation between plasma atrial natriuretic peptide concentrations and oxygen uptake, catecholamine release, and heart rate in both groups. The catecholamine response was similar in the asthmatic and normal subjects, both groups showing a four fold rise in plasma adrenaline and a 4-5 fold rise in plasma noradrenaline. CONCLUSION: A defect in the release of circulating atrial natriuretic peptide does not account for exercise induced asthma; the concentrations of the circulating peptide that were achieved may effect a small reduction in airway reactivity. Our data do not support the idea that asthmatic patients have abnormal sympathoadrenal activity.     

Neuropeptides in human memory and learning processes

The neuropeptides vasopressin, adrenocorticotropin (ACTH), and beta-endorphin seem to have important effects on memory and learning. Animal studies attempting to demonstrate these effects are difficult to interpret because of the complexity of behavior that is described as "learning" and the impossibility of assessing verbal learning in animals. This article therefore reviews some of the animal literature on neuropeptides and learning, but focuses primarily upon studies in humans, both in normal volunteers and in patients with neurological disorders. Vasopressin enhances learning under some conditions. Intranasal administration has been associated with improvement on psychometric tests in patients with mild Alzheimer's disease and Korsakoff's psychosis, although these findings are not uniform. It improves performance on memory tests in normal volunteers, but does not seem to improve the memory deficit after head trauma. Cerebrospinal fluid levels are low in patients with Alzheimer's disease. ACTH and melanocyte-stimulating hormone (MSH) are two peptides the primary behavioral effect of which seems to be on attention or goal-motivated behavior rather than on memory processes themselves. Visual discrimination and the ability to continue repetitive tasks are enhanced; in mentally retarded subjects, the administration of ACTH or MSH improves performance on a variety of neuropsychological tests. It does not, however, improve cognitive function in the elderly. Endogenous opioids including beta-endorphin and met-enkephalin seem to have primarily an amnesic effect in animal studies. Their role in human learning is still uncertain, although naloxone, which antagonizes their effects, has been associated with improved cognitive performance in patients with Alzheimer's disease. These data underscore the complexity of the processes associated with human memory and the rudimentary state of our present knowledge. Whatever the mechanisms, however, vasopressin, ACTH, and endogenous opioids seem to have important effects upon memory.     

Naloxone Does Not Reverse the Pain-Reducing Effect of Vibratory Stimulation

Fifteen patients suffering from chronic epicondylitis pain who obtained alleviation of pain with vibratory stimulation were studied to investigate the possible role of endogenous opioids in the mediation of pain alleviation of vibratory stimulation. The patients' subjective pain intensity was rated using a graphic rating scale. In five patients the changes in peripheral blood flow before, during and after vibratory stimulation were also studied. After 30 min of mechanical vibratory stimulation at 100 Hz, patients were given a double-blind intravenous injection of naloxone or saline (placebo). Twelve patients did not experience reversal of pain relief from naloxone (0.4 mg). Reversal of the pain alleviation induced by vibratory stimulation was seen in two patients after i.v. injections of naloxone and in one patient after i.v. injections of naloxone or saline. When an i.m. injection of naloxone 0.01 mg/kg was administered before and during vibratory stimulation, none of the patients experienced an antagonistic effect of the pain-reducing effect of vibratory stimulation. The results suggest that the pain relief obtained with vibratory stimulation at 100 Hz is not associated with release of endogenous opioids.     

纳络酮治疗急性重型颅脑损伤患者血浆内皮素含量变化及其临床意义

目的 探讨纳络酮治疗急性重型颅脑损伤患者血浆内皮素（ET）含量变化及其临床意义，评价纳络酮治疗急性重型颅脑损伤的意义。方法 观察了52例纳洛酮治疗急性重型颅脑损伤患者血浆ET含量在治疗前1d、治疗后3、8d及2周的变化，并且以46例颅脑损伤患者按常规治疗作对照组。结果 颅脑损伤24h内两组患者血浆内皮素较正常人均明显升高（P〈0．05），伤后第3天、第8天两治疗组血浆内皮素较治疗前均明显下降（P〈0．05），但纳络酮治疗组低于常规治疗组（P〈0．05），治疗2周后两组ET水平基本恢复到正常水平。结论 急性重型颅脑损伤患者血浆内皮素含量明显升高，与病情轻重相关，纳络酮治疗较常规治疗能更迅速地降低血浆ET水平。     

Platelet activation during exercise induced asthma: effect of prophylaxis with cromoglycate and salbutamol.

Peak expiratory flow (PEF) and plasma concentrations of platelet factor 4 and beta thromboglobulin were measured before and after exercise in nine asthmatic patients and 12 non-asthmatic volunteers. Exercise was preceded by administration in random order of either placebo, salbutamol 200 micrograms, or sodium cromoglycate 2 mg from a pressurised inhaler. In control subjects there were minimal changes in PEF and plasma concentrations of platelet factor 4 and beta thromboglobulin. In the asthmatic patients the typical changes in PEF were seen on exercise; plasma concentrations of platelet factor 4 and beta thromboglobulin rose significantly in parallel, the rise preceding the fall in PEF. The changes in peak flow and platelet activation induced by exercise were attenuated by prior administration of salbutamol or cromoglycate. These results indicate that exercise induced asthma is associated with a rise in platelet release products similar to that observed in antigen induced asthma.     

Absence of refractoriness in asthmatic subjects after exercise with warm, humid inspirate.

Twelve asthmatic adults each completed two six minute treadmill runs separated by an interval of 20 minutes. Running speed was constant for each subject, and inspired air temperature averaged 5.5 degrees C (SD 1.5 degree) for both tests. Total minute ventilation and total respiratory heat loss showed no significant difference between the two runs. Forced expiratory volume in one second (FEV1) was measured before exercise and at five minute intervals throughout the recovery periods, during which subjects breathed room air at an average temperature of 17.8 degrees C (1.8 degree). Reduction in FEV1 from pre-exercise readings averaged 39.3% (13.3%) for the first run and 11.5% (7.3%) for the second. On another day the subjects underwent an identical procedure except that the first exercise period was performed with the saturated inspirate at 37.3 degrees C (1.7 degree). This run produced a mean FEV1 reduction of only 3.1% (7.3%). The ensuing run, during which the inspiratory temperature averaged 6.0 degrees C (2.0 degrees), led to a mean fall in FEV1 of 37.3% (17.3%). This was not significantly different from the value recorded for the first of the paired runs with cool air. We therefore have been unable to confirm that exercise with warm humid inspirate may induce refractoriness to exercise induced asthma. Our data are compatible with the theory that refractoriness may be due to depletion of mediators during an initial exercise induced asthma attack.     

Relation of the hypertonic saline responsiveness of the airways to exercise induced asthma symptom severity and to histamine or methacholine reactivity.

BACKGROUND: Conflicting views exist over whether responsiveness of the airways to hypertonic saline relates to non-specific bronchial hyperresponsiveness measured by histamine or methacholine challenge. The bronchoconstrictor responses to exercise and hypertonic saline are reported to be closely related, but the relationship between the symptoms of exercise induced asthma and airway responsiveness to hypertonic saline is not known. METHODS: In 29 asthmatic patients with a history of exercise induced asthma, the response to an ultrasonically nebulised hypertonic saline (3.6% sodium chloride) aerosol, measured as the volume of hypertonic saline laden air required to produce a fall in forced expiratory volume in one second (FEV1) of > or = 20% (PD20), was compared with the concentration of histamine (PC20; group 1) and methacholine (PC20; group 2) producing a 20% fall in baseline FEV1 and exercise induced asthma symptom severity score (groups 1 and 2). The hypertonic responsiveness was determined in a dose-response manner to a maximum dose of 310 1 and the exercise induced asthma symptom severity was scored on a scale of 0-5. RESULTS: Of the 29 patients, 23 (79%) were responsive to the hypertonic saline, with PD20 values ranging from 9 to 310 1. A significant correlation was found between the PD20 hypertonic saline and the exercise induced asthma symptom score. There was no significant correlation between the PD20 response to hypertonic saline and the histamine PC20 or methacholine PC20. The exclusion of those subjects who failed to respond to hypertonic saline improved the relationship between hypertonic saline and methacholine PC20. No significant correlation was found between the exercise induced asthma symptom score and histamine PC20 or methacholine PC20. CONCLUSION: These findings suggest that hypertonic saline responsiveness bears a closer relationship to the severity of exercise induced asthma symptoms than to the non-specific bronchial hyperresponsiveness measured by histamine or methacholine reactivity.     

Exercise‐Induced Changes in Atrial Peptides in Relation to Neuroendocrine Responses and Fluid Balance in the Horse

Previous data show that, in horses, plasma atrial natriuretic peptides (ANP and NT‐ANP) remain elevated for a long time after exercise. To study whether exercise‐induced changes in hormonal and fluid balance explain this, we measured plasma concentrations of COOH‐ and NH₂‐terminal atrial natriuretic peptides (ANP_99–129 and NT‐ANP_1–98) together with arginine vasopressin (AVP), adrenocorticotrophin (ACTH), β‐endorphin, cortisol, catecholamines, and indicators of fluid balance in six Finnhorses after a graded submaximal exercise test on a treadmill. After exercise, AVP and catecholamines diminished rapidly; atrial peptides, ACTH, β‐endorphin, and cortisol remained elevated longer. ANP reached its peak value at 5 min and NT‐ANP at 30 min post‐exercise. At 60 min, ANP was still significantly increased and NT‐ANP even above its level at the end of exercise. The different temporal patterns of ANP and NT‐ANP are most probably explained by differences in their plasma half‐lives. The post‐exercise increase in NT‐ANP indicates that the release of atrial peptides is stimulated during recovery after exercise. The rapid decrease in AVP and catecholamines suggests that these hormones do not explain the long‐lasting increase in atrial peptides. Cortisol remained elevated longer and it may have contributed to some extent. After exercise, the packed cell volume (PCV) decreased more slowly than plasma total protein and electrolytes, which refers to a slow post‐exercise return in blood volume. Taken together, the present results show that the long‐lasting post‐exercise increase in plasma atrial peptides in horses is most probably explained by elevated central blood volume and that the role of vasoactive hormones is small.     

Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma.

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.     

Effect of inhaled procaterol on cough receptor sensitivity to capsaicin in patients with asthma or chronic bronchitis and in normal subjects.

BACKGROUND--To evaluate the effect of inhaled beta 2 adrenergic agonists on the sensitivity of airway cough receptors, the effect of inhaled procaterol on cough induced by aerosolised capsaicin, a stimulant of C fibres, was studied in patients with asthma or chronic bronchitis and in normal subjects. METHOD--Eleven patients with asthma and 10 with chronic bronchitis and 14 normal subjects participated. Increasing concentrations of capsaicin solution were inhaled for 15 seconds by tidal breathing through the mouth at one minute intervals until five or more coughs were elicited, before and 30 minutes after inhalation of 20 micrograms procaterol or placebo (freon gas alone) through a metered dose inhaler. Cough threshold was defined as the lowest concentration of capsaicin that elicited five or more coughs. To evaluate the bronchodilator effect of procaterol and the bronchoconstrictor effect of inhaled capsaicin, forced expiratory volume in one second (FEV1) was measured before and one minute after a capsaicin provocation test. This test was carried out both before and 30 minutes after treatment with procaterol or placebo. RESULTS--The geometric mean value of cough threshold to capsaicin was significantly increased by procaterol and placebo in both groups of patients but not in the control subjects. The increment in the cough threshold was not significantly different between the treatments with procaterol and placebo in each group. FEV1 was significantly increased by procaterol but not by placebo in all three groups. CONCLUSIONS--Inhaled procaterol has no effect on airway cough receptor sensitivity to capsaicin. The attenuation of the cough sensitivity seen after inhalation of procaterol in patients with asthma and bronchitis may result from tachyphylaxis to capsaicin.     

Effect of nebulised salbutamol on maximal exercise performance in men with mild asthma.

The effect of 5 mg nebulised salbutamol on the cardiorespiratory responses to a progressive maximal exercise test was investigated in eight asthmatic (mean forced expiratory volume in one second (FEV1) 3.48 (1.0) litres) and eight non-asthmatic men. Exercise tests were performed on a bicycle ergometer after administration of nebulised salbutamol or matched saline placebo. In the asthmatic subjects salbutamol increased the resting FEV1 by 11%. The mean (SD) percentage fall in FEV1 after exercise did not change significantly (salbutamol 9.4 (12.8); placebo 15.0 (8.0], but because the FEV1 before exercise was increased the lowest FEV1 after exercise was also significantly higher after salbutamol than placebo (3.60 (1.13) v 2.85 (0.80) litres). Despite the improvement in FEV1 before exercise there was no significant difference in maximal workload, oxygen uptake, heart rate, or ventilation during exercise after salbutamol compared with placebo in the asthmatic patients. Tidal volume was higher at maximal exercise after salbutamol but there was no change in perception of breathlessness or exertion in the asthmatic subjects. During submaximal progressive exercise the perceived rate of exertion was reduced in the asthmatic patients and oxygen pulse was reduced in both groups owing to a small and non-significant increase in heart rate. The FEV1 and cardiorespiratory response to the progressive maximal exercise test in the non-asthmatic subjects were otherwise unchanged after salbutamol. The results suggest that 5 mg nebulised salbutamol has little effect on the cardiorespiratory responses to progressive maximal exercise in patients with mild asthma and in non-asthmatic subjects. Salbutamol in this dose may reduce the severity of exercise induced asthma, but no ergogenic effect on maximal exercise performance was shown.     

Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol.

Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.     

Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma.

Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist, GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise, breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%, GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins, including PGD2, that act via the thromboxane receptor do not have an important role in exercise induced asthma.     

Effect of cetirizine on exercise induced asthma.

The effect of oral and inhaled cetirizine, a potent and specific H1 receptor antagonist, was studied in patients with exercise induced asthma. Twelve patients (five male; mean age 35.2 years) were given oral placebo or cetirizine 10 mg twice daily for one week, double blind and in randomised order, and exercised on a treadmill for six to eight minutes at a submaximal work load two hours after the final dose. There was no significant change in baseline FEV1 after treatment and cetirizine failed to inhibit exercise induced bronchoconstriction (maximum falls in FEV1 28% and 27% of baseline). In a further eight patients (four male; mean age 40.8 years) the effect of 1 ml cetirizine (5 and 10 mg/ml) given through a Wright nebuliser was compared with that of placebo in a double blind trial. The fall in FEV1 after exercise was reduced after both concentrations of cetirizine by 15.2% of baseline after 5 mg/ml and by 10.2% after 10 mg/ml, compared with 23.7% after placebo. In two patients cetirizine had no effect. In a further study cetirizine (10 mg/ml) given by inhalation displaced the geometric mean PC20 histamine 13.1 fold to the right by comparison with placebo. The reason for the difference between the effects of oral and of inhaled cetirizine on exercise asthma is not clear but may be related to differences in local concentration in the airway.