Abstract
BACKGROUND: Potassium (K+) channel activators, such as cromakalim, open ATP sensitive K+ channels and relax airway smooth muscle in vitro and inhibit induced bronchoconstriction in vivo in animals. The prolonged half life of cromakalim gives it potential as an oral bronchodilator. The effect of orally administered BRL 38227 (the active enantiomer of cromakalim), at doses of 0.125, 0.25, and 0.5 mg, on airway function and airway responsiveness to histamine and methacholine has been investigated in asthmatic patients. METHODS: Seventeen patients with asthma were studied in three separate randomised double blind, placebo controlled studies. In the first study eight patients with moderately severe asthma were given 0.125, 0.25, and 0.5 mg of BRL 38227 or placebo, and responses to histamine were assessed before and five hours after treatment. In the second study responses to methacholine were measured before and five hours after 0.125 and 0.5 mg of BRL 38227 or placebo were given to nine patients with mild asthma. In the third study the effect of 0.5 mg of BRL 38227 or placebo was assessed in eight patients with mild asthma. Responses to histamine were measured before treatment and two and five hours after treatment. To provide a positive control study eight subjects who had taken part in studies 1 and 3 were also given oral salbutamol (8 mg) in a placebo controlled, double blind study. Responses to histamine were assessed before and two hours after treatment. RESULTS: BRL 38227 did not cause significant bronchodilatation or changes in airway responsiveness in any of the studies. Headache was reported in 19 of 25 of patients receiving (in some cases twice) 0.5 mg of BRL 38227. By contrast, oral salbutamol gave significant protection against histamine challenge (geometric mean 2.23 doubling dilutions). CONCLUSIONS: After a single oral dose of BRL 38227 no beneficial effect on airway function was detected, despite a high incidence of side effects, which indicates that the orally administered K+ channel activator BRL 38227 may not be useful in the management of asthma.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allen S. L., Boyle J. P., Cortijo J., Foster R. W., Morgan G. P., Small R. C. Electrical and mechanical effects of BRL34915 in guinea-pig isolated trachealis. Br J Pharmacol. 1986 Oct;89(2):395–405. doi: 10.1111/j.1476-5381.1986.tb10273.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anderson S. D., Seale J. P., Rozea P., Bandler L., Theobald G., Lindsay D. A. Inhaled and oral salbutamol in exercise-induced asthma. Am Rev Respir Dis. 1976 Sep;114(3):493–500. doi: 10.1164/arrd.1976.114.3.493. [DOI] [PubMed] [Google Scholar]
- Arch J. R., Buckle D. R., Bumstead J., Clarke G. D., Taylor J. F., Taylor S. G. Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: comparison with nifedipine. Br J Pharmacol. 1988 Nov;95(3):763–770. doi: 10.1111/j.1476-5381.1988.tb11702.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Black J. L., Armour C. L., Johnson P. R., Alouan L. A., Barnes P. J. The action of a potassium channel activator, BRL 38227 (lemakalim), on human airway smooth muscle. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1384–1389. doi: 10.1164/ajrccm/142.6_Pt_1.1384. [DOI] [PubMed] [Google Scholar]
- Black J. L., Barnes P. J. Potassium channels and airway function: new therapeutic prospects. Thorax. 1990 Mar;45(3):213–218. doi: 10.1136/thx.45.3.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cook N. S. The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci. 1988 Jan;9(1):21–28. doi: 10.1016/0165-6147(88)90238-6. [DOI] [PubMed] [Google Scholar]
- Frech G. C., VanDongen A. M., Schuster G., Brown A. M., Joho R. H. A novel potassium channel with delayed rectifier properties isolated from rat brain by expression cloning. Nature. 1989 Aug 24;340(6235):642–645. doi: 10.1038/340642a0. [DOI] [PubMed] [Google Scholar]
- Nakao K., Okabe K., Kitamura K., Kuriyama H., Weston A. H. Characteristics of cromakalim-induced relaxations in the smooth muscle cells of guinea-pig mesenteric artery and vein. Br J Pharmacol. 1988 Nov;95(3):795–804. doi: 10.1111/j.1476-5381.1988.tb11707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pongs O. Molecular basis of potassium channel diversity. Pflugers Arch. 1989;414 (Suppl 1):S71–S75. doi: 10.1007/BF00582251. [DOI] [PubMed] [Google Scholar]
- Williams A. J., Lee T. H., Cochrane G. M., Hopkirk A., Vyse T., Chiew F., Lavender E., Richards D. H., Owen S., Stone P. Attenuation of nocturnal asthma by cromakalim. Lancet. 1990 Aug 11;336(8711):334–336. doi: 10.1016/0140-6736(90)91877-d. [DOI] [PubMed] [Google Scholar]