Adrenal axis suppression unrelated to the dynamics of dosing with beclomethasone monopropionate.

AIMS: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment. At high doses they can give rise to systemic side-effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression. This effect may depend on the delivery system, which in turn alters drug deposition and adsorption. We hypothesized that adrenal suppression depends on the rate of steroid absorption rather than the total steroid dose received. METHODS: Eight healthy adult males were recruited for a randomized double-blind placebo controlled trial. Adrenocortical suppression ability was demonstrated by a 30% suppression of early morning cortisol following 1 mg dexamethasone. Subjects then attended in the evening on two occasions receiving 500 microg of intravenous beclomethasone monopropionate (17-BMP) for either 15 min or 2 h. Overnight urinary cortisol : creatinine (C : C) ratio was measured before and after the infusion and an 08.00 h serum cortisol was measured following the infusion. RESULTS: Mean C : C pre and post 15 min infusion was 5.97 and 3.22 (P = 0.005). Mean C : C pre and post 2 h infusion was 6.31 and 4.15 (P = 0.004). Delta C : C and mean 08.00 h cortisol for 15 min and 2 h infusion was 2.74 and 2.16 and 425 nmol l(-1) and 400 nmol l(-1), respectively (P = NS). CONCLUSIONS: The rate of infusion of 17-BMP seemed to have little effect on the degree of adrenal suppression. Individual C : C ratios were reproducible. Differences in absorption of ICS are unlikely to explain observed differences in HPA axis suppression.

Opiate therapy in chronic cough.

RATIONALE: Cough is the most common complaint for which medical attention is sought, and chronic cough can be both physically and mentally debilitating. There is currently no evidence supporting the use of antitussives in chronic treatment-resistant cough. OBJECTIVES: We tested the hypothesis that morphine sulfate in the dose of 5 mg twice daily would bring about a reduction in cough frequency and severity in patients failing to respond to specific measures. METHODS: Patients recruited from the Hull Cough Clinic were enrolled into a randomized double-blind placebo-controlled study using 4 weeks of slow-release morphine sulfate and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to 10 mg twice daily. Cough was assessed using the Leicester Cough Questionnaire, daily symptom diary, and citric acid cough challenge. RESULTS: Twenty-seven patients completed the core study. A significant improvement of 3.2 points over baseline was noted on the Leicester Cough Questionnaire (p < 0.01). A rapid and highly significant reduction by 40% in daily cough scores was noted among patients on slow-release morphine sulfate (p < 0.01). Objective testing of the cough reflex using citric acid cough challenge tests did not show any significant changes. Eighteen patients continued into the extension study. Two-thirds of these patients opted to increase the morphine to 10 mg twice daily. At the end of 3 months, there was a similar improvement in cough between the 5- and 10-mg groups. CONCLUSION: Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily.

Expression and characterization of the intracellular vanilloid receptor (TRPV1) in bronchi from patients with chronic cough.

TRPV1 is a modulator of noxious stimuli known to be important in the cough reflex. We have compared the expression of TRPV1 in normal human airways and those from patients with chronic cough and found that there is up regulation in airways smooth muscle in disease. This increased expression appears to be intracellular and we have therefore examined the role of intracellular rat and human TRPV1 activity was found using intracellular calcium signalling with human intracellular TRPV1 being located in a thapsigargin insensitive compartment. Increase in TRPV1 activity may have a role in the airway hypersensitivity seen in chronic cough.

Nitric oxide synthase inhibition: therapeutic potential in asthma.

Nitric oxide (NO) is synthesized from L-arginine in the human respiratory tract by enzymes of the NO synthase (NOS) family. Levels of NO in exhaled air are increased in asthma, and measurement of exhaled NO has been advocated as a noninvasive tool to monitor the underlying inflammatory process. However, the relation of NO to disease pathophysiology is uncertain, and in particular the fundamental question of whether it should be viewed primarily as beneficial or harmful remains unanswered. Exogenously administered NO has both bronchodilator and bronchoprotective properties. Although it is unlikely that NO is an important regulator of basal airway tone, there is good evidence that endogenous NO release exerts a protective effect against various bronchoconstrictor stimuli. This response is thought to involve one or both of the constitutive NOS isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS). Therefore, inhibition of these enzymes is unlikely to be therapeutically useful in asthma and indeed may worsen disease control. On the other hand, the high concentrations of NO in asthma, which are believed to reflect upregulation of inducible NOS (iNOS) by proinflammatory cytokines, may produce various deleterious effects. These include increased vascular permeability, damage to the airway epithelium, and promotion of inflammatory cell infiltration. However, the possible effects of iNOS inhibition on allergic inflammation in asthma have not yet been described and studies in animal models have yielded inconsistent findings. Thus, the evidence to suggest that inhibition of iNOS would be a useful therapeutic strategy in asthma is limited at present. More definitive information will require studies combining agents that potently and specifically target individual NOS isoforms with direct measurement of inflammatory markers.