1063
generation from human neutrophils and mast cells in vitro, human nasal passages, and guineapig airways in vivo. We thank ICI Pharmaceuticals for drugs and financial support.
REFERENCES 1. Samuelsson B, Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983; 220: 568-75. 2. Barnes NC, Piper PJ, Costello JF. Comparative effects of inhaled leukotriene C4, leukotriene D4 and histamine in normal human subjects. Thorax 1984; 39: 500-04. 3. Quanjer PH. Standardised lung function testing. Bull Eur Physiopathol Respir 1983; 19 (suppl 5): 1-10. 4. Barnes N, Evans J, Zakrzewski J, Piper PN, Costello J. Studies of leukotriene antagonists and synthesis inhibitors in man. Black J, Armour C, eds. Mechanisms in asthma; pharmacology, physiology and management. New York: Alan R Liss, 1988: 393-403. 5. Cloud MC, Enas GC, Kemp J, et al. A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis 1989; 140: 1336-39. 6. Fleisch JH, Rinkema LE, Swanson-Dean D, et al. LY171,883,
4 h after ICI 204,219 nebulised salbutamol.
FEV, for
(.)or placebo (0)
and after
between 1 h and 4 h after the dose, with a maximum increase of 8% (2-14%) above baseline at 3-5 h. There was a similar percentage increase in sGaw from baseline on active treatment, but it did not achieve significance. FEV, after salbutamol was significantly greater on active treatment than on placebo (26 [16-36] vs 18 [11-26]% above baseline; p 0-005). The differences in FEV and sGaw after nebulised salbutamol between ICI 204,219 and placebo days were similar to those seen at 4 h just before salbutamol. Patients tolerated ICI 204,219 well without any symptoms or biochemical or haematological changes.
Thus, the cysteinyl-leukotriene receptor antagonist ICI 204,219 partially relieved bronchoconstriction at rest in patients with chronic asthma. The increase in FEV1 persisted after nebulised salbutamol, suggesting that the bronchodilatory effect was additive. No previous studies with cysteinyl-leukotriene antagonists have shown significant bronchodilatory action in asthma. One study on the effect of the antagonist L 648,0514 on bronchoconstriction showed a non-significant increase in sGaw and another reported a slight rise in FEV in patients with chronic asthma after 6 weeks’ treatment with LY 171,883.5This compound has other properties, such as phosphodiesterase inhibition6 which may contribute to the bronchodilatory effect. Two other cysteinyl-leukotriene antagonists, L 649,923’ and LY 171,883,8 did not improve baseline airway function in asthma. ICI 204,219 is the most potent cysteinyl-leukotriene antagonist yet studied in man; it shifts the inhaled leukotriene DQ dose response curve to the right by a 100 fold change in concentration.9 It binds specifically to the cysteinyl-leukotriene receptor and shows minimal binding to many other receptors. 10 The significant bronchodilatory effect we observed is likely to be due to the greater potency of ICI 204,219. The differences in post-salbutamol airway function between ICI 204,219 and placebo were similar to those seen just before salbutamol inhalation, suggesting an additive bronchodilatory effect. We did not produce a formal dose response curve to inhaled salbutamol, but the bronchodilatation achieved with the dose used was probably near maximum. The effectiveness of ICI 204,219 suggests that there is persistent generation of cysteinyl-leukotrienes in asthmatic subjects despite treatment with inhaled corticosteroids. This suggestion is supported by evidence that corticosteroids are ineffective in suppressing leukotriene
1-2-hydroxy-3-propyl-4-4
4-(1H-tetrazol-5-yl)
butoxy
phenyl
ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Ther 1985; 233: 148-57. 7. Britton JR, Hanley SP, Tattersfield AE. The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma. J Allergy Clin Immunol 1987; 79: 811-16. 8. Fuller RW, Black PN, Dollery CT. Effect of the oral leukotriene D4 9.
antagonist LY.171883 on inhaled and intradermal antigen and LTD4 in atopic subjects. J Clin Allergy Immunol 1989; 83: 939-44. Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT. Inhibition of leukotriene D-induced bronchoconstriction in normal subjects by the oral LTE4 receptor antagonist ICI 204,219. Am Rev Respir Dis 1990;
141: 988-902. 10. Krell RD, Aharony D, Buckner CK, et al. The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist. Am Rev Respir Dis 1990; 141: 978-87.
ADDRESS: Department of Thoracic Medicine, London Chest Hospital, Bonner Road, London E29JX, UK (K. P. Hui, MRCPI, N. C. Barnes, MRCP). Correspondence to Dr Neil C. Barnes.
Hyperinsulinaemia in thyrotoxic hypokalaemic periodic paralysis
To test the hypothesis that there is an abnormal serum insulin response to a carbohydrate load in
thyrotoxic hypokalaemic periodic paralysis (THPP), 18 men with THPP and 15 with uncomplicated thyrotoxicosis were studied during an oral glucose tolerance test. The THPP group had significantly higher fasting insulin concentrations (27·6 [3·6] vs 13·4 [1·8] mU/l; p
generation from human neutrophils and mast cells in vitro, human nasal passages, and guineapig airways in vivo. We thank ICI Pharmaceuticals for drugs and financial support.
REFERENCES 1. Samuelsson B, Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983; 220: 568-75. 2. Barnes NC, Piper PJ, Costello JF. Comparative effects of inhaled leukotriene C4, leukotriene D4 and histamine in normal human subjects. Thorax 1984; 39: 500-04. 3. Quanjer PH. Standardised lung function testing. Bull Eur Physiopathol Respir 1983; 19 (suppl 5): 1-10. 4. Barnes N, Evans J, Zakrzewski J, Piper PN, Costello J. Studies of leukotriene antagonists and synthesis inhibitors in man. Black J, Armour C, eds. Mechanisms in asthma; pharmacology, physiology and management. New York: Alan R Liss, 1988: 393-403. 5. Cloud MC, Enas GC, Kemp J, et al. A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma. Am Rev Respir Dis 1989; 140: 1336-39. 6. Fleisch JH, Rinkema LE, Swanson-Dean D, et al. LY171,883,
4 h after ICI 204,219 nebulised salbutamol.
FEV, for
(.)or placebo (0)
and after
between 1 h and 4 h after the dose, with a maximum increase of 8% (2-14%) above baseline at 3-5 h. There was a similar percentage increase in sGaw from baseline on active treatment, but it did not achieve significance. FEV, after salbutamol was significantly greater on active treatment than on placebo (26 [16-36] vs 18 [11-26]% above baseline; p 0-005). The differences in FEV and sGaw after nebulised salbutamol between ICI 204,219 and placebo days were similar to those seen at 4 h just before salbutamol. Patients tolerated ICI 204,219 well without any symptoms or biochemical or haematological changes.
Thus, the cysteinyl-leukotriene receptor antagonist ICI 204,219 partially relieved bronchoconstriction at rest in patients with chronic asthma. The increase in FEV1 persisted after nebulised salbutamol, suggesting that the bronchodilatory effect was additive. No previous studies with cysteinyl-leukotriene antagonists have shown significant bronchodilatory action in asthma. One study on the effect of the antagonist L 648,0514 on bronchoconstriction showed a non-significant increase in sGaw and another reported a slight rise in FEV in patients with chronic asthma after 6 weeks’ treatment with LY 171,883.5This compound has other properties, such as phosphodiesterase inhibition6 which may contribute to the bronchodilatory effect. Two other cysteinyl-leukotriene antagonists, L 649,923’ and LY 171,883,8 did not improve baseline airway function in asthma. ICI 204,219 is the most potent cysteinyl-leukotriene antagonist yet studied in man; it shifts the inhaled leukotriene DQ dose response curve to the right by a 100 fold change in concentration.9 It binds specifically to the cysteinyl-leukotriene receptor and shows minimal binding to many other receptors. 10 The significant bronchodilatory effect we observed is likely to be due to the greater potency of ICI 204,219. The differences in post-salbutamol airway function between ICI 204,219 and placebo were similar to those seen just before salbutamol inhalation, suggesting an additive bronchodilatory effect. We did not produce a formal dose response curve to inhaled salbutamol, but the bronchodilatation achieved with the dose used was probably near maximum. The effectiveness of ICI 204,219 suggests that there is persistent generation of cysteinyl-leukotrienes in asthmatic subjects despite treatment with inhaled corticosteroids. This suggestion is supported by evidence that corticosteroids are ineffective in suppressing leukotriene
1-2-hydroxy-3-propyl-4-4
4-(1H-tetrazol-5-yl)
butoxy
phenyl
ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Ther 1985; 233: 148-57. 7. Britton JR, Hanley SP, Tattersfield AE. The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma. J Allergy Clin Immunol 1987; 79: 811-16. 8. Fuller RW, Black PN, Dollery CT. Effect of the oral leukotriene D4 9.
antagonist LY.171883 on inhaled and intradermal antigen and LTD4 in atopic subjects. J Clin Allergy Immunol 1989; 83: 939-44. Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT. Inhibition of leukotriene D-induced bronchoconstriction in normal subjects by the oral LTE4 receptor antagonist ICI 204,219. Am Rev Respir Dis 1990;
141: 988-902. 10. Krell RD, Aharony D, Buckner CK, et al. The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist. Am Rev Respir Dis 1990; 141: 978-87.
ADDRESS: Department of Thoracic Medicine, London Chest Hospital, Bonner Road, London E29JX, UK (K. P. Hui, MRCPI, N. C. Barnes, MRCP). Correspondence to Dr Neil C. Barnes.
Hyperinsulinaemia in thyrotoxic hypokalaemic periodic paralysis
To test the hypothesis that there is an abnormal serum insulin response to a carbohydrate load in
thyrotoxic hypokalaemic periodic paralysis (THPP), 18 men with THPP and 15 with uncomplicated thyrotoxicosis were studied during an oral glucose tolerance test. The THPP group had significantly higher fasting insulin concentrations (27·6 [3·6] vs 13·4 [1·8] mU/l; p
