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Inhalation of a potassium channel activator, cromakalim, is well tolerated in healthy volunteers
1045
I
P.tu.420
Effect of intravenous
Gray, S.J., Rolan, P. and Posner, Dept. of Clinical Pharmacology,
Wellcome Research L.&oratories,
J.
Beckenham, Kent, BR3 3BS. U.K.
Local axon reflexes may play an important role in the pathophysiology of asthma. The enkeph&n adogue 443C81 [Tyr-DArg-Gly-Phe(4-NO&Pro-NH,] inhibits peripheral AS- and C-afferent nerve activity, but is almost devoid of CNS effects. Bronchial challenge by isocapnic hyperventilation of cold, dry air induces bronchoconstriction in susceptible subjects by a mechanism that is thought to involve neural reflexes. Therefore, we examined the effect of intravenous (i.v.) 443C81 on the response to cold air challenge in susceptible healthy volunteers to determine whether 443C81 might inhibit neural reflexes in the lung. Using a randomised, balanced, double-blind, cross-over design, 6 male volunteers received; (i) 443C81 i.v. 180 pg/kg/h for 2h, (ii) 443C81 i.v. 90 I.rg/kg/h for 2h or (iii) saline i.v. for 2h, with an interval of 7 days between occasions. FEV, (forced expiratory volume after 1 set), FVC (forced vital capacity), PEF (peak expiratory flow) and Vsop (expiratory flow at 30% remaining FVC) were recorded at the end of each infusion (MacSpiro Bronchial Challenge Analyser; Collingwood Measurement Ltd.). Subjects then inhaled cold, dry air by isocapnic hyperventilation for 3 min at a minute ventilation of 20 X FEV, (Jaeger RHES). Lung function (FEV,, PEF and I&,) and visual analogue scales for chest symptoms were recorded 5, 10 and 15 min post-challenge. Data were analysed by ANOVA. Compared with saline both doses of 443C81 induced a small (2.6-3.68) yet significant (p = 0.028) increase in pre-challenge FEV,, but had no effect on the bronchoconstriction induced by cold air. 443C81 reduced symptoms of shortness of breath 10 min post-challenge (p = 0.027), and urge to cough 5 and 10 min post-challenge (p = 0.017 and 0.042, respectively) and the magnitude of these effects was dose-related. All subjects experienced dry mouth during infusion of 443C81. and reduced secretion of saliva and mucus was apparent during and after the cold challenge. 443C81 may ha-ge slight bronchodilator activity when given by i.v. infusion to healthy volunteers, but it had no effect on the bronchoconstriction induced by cold air challenge, despite attenuation of some symptoms of the challenge. T’his lack of effect of 443C81 against cold air-induced bronchoconstriction could be attributable to the use of an inappropriate challenge model or study population, or to failure of the drug to reach the requisite receptors after i.v. administration. Reduced urge to cough following cr;ld air challenge may be due to direct inhibition of C-afferent nerves, which can mediate cough, or to the apparerrt anti-secretory effects of 443C81.
__.._ ;-.x1.421
III
Inhalation of a potassium charm in he Williams, Beecham Pharmaceuticals
tivator, mom volunteers
A.J., Verden, P. and Lavencier,
E.
Research Division, Biosciences Research Centre, Great Burgh. Epsom. Surrey, U.K.
Cromakalim, a potassium channel activator, inhibits histamine induced bronchoconstriction in healthy volunteers (Baird et al., 1988) and nocturnal bronchoconstriction in patients with nocturnal asthma (Williams et al., 198% The drug, therefore, has potential in the treatment of asthma and we have studied the effects, in healthy volunteers, of administering cromakalim by inhalation. Cromakalim or placebo were administered by inhaling nebuhred solutions generated by an ultrasonic nebulizer. Five groups of 4 volunteers received single doses of cromakahm, given according to an open study design, with stepwise increases in doses being given on separate study days to each successive group
of vohmteers. me doses administered were 0.05, 0.15,0.3,0.6, and 0.8 mg of cromakalim. A further 6 volunteers then received 1 mg of cromakalim and placebo according to a randomized, double blind crossover protocol with a one week
interval between dosing days. The following parameters were measured at intervals beforz aud for 24 hours after dosing: quantitative 12 lead electrocardiogram (ECG, Schiller), cardiac output and stroke volume by impedance cardiography (BoMed), erect and supine pulse and blood pressure using an automatic measuring device (Kontron) and arterial oxygen saturation using a pulse oximeter (Kontron). A continuous 2 lead ECG was recorded on tape for 24 hours after drug administration and subsequently analysed by a computerized method (Medilog). Clinical Chemistry and haematological screens and urinalysis were performed before and 24 hours after drug dosing and any symptoms reported by the volunteers were recorded on diary cards. No changes were found, compzed to pm-dose baseline values, in any of the measured parameters at any time point after dosing with cromakalim. Addi~!onally, iu the double blind phase of the study no differences were found between placebo and 1 mg cromakalim for any of the parameters measured. ‘Table 1 shows the results from cardiovascular monitoring and SaO, 15 minutes after placebo and X mg cro-Y&U&I. Quantitative measurements of the ECG showed no effect at any time point after cromakalim or difference between 1 mg cromakalim and placebo on heart rate, PQ interval, QRS duration, ST level, T wave height or QTc. No abnormalities were found on analysis of the 24 hour ECG tapes. The same 2 patients reported headache after both placebo and 1 mg cromakalim but no other symptoms were reported by the volunteers. Conclusion: Cromakalim, a potassium channel activator can be inhaled safely in doses up to 1 mg in healthy volunteers without effects on the cardiovascular system or ECG, Table 1 V&es (SEM) of Supine Cardiovascular Measurements and SaO, 15 minutes after 1 mg Cromakalim or Placebo
Blood pressure (mmHg)
Dw (b.p.m.?
Cromakahm. 1 mg Placebo
58 (4.0) c;q.(2.7)
systolic
Diastolic
Cardiac output (L/min)
Stroke volume (ml)
SaO, @)
125 (5.4) 128 (4.5)
79.0 (4.5) 79.3 (2.4)
6.6 (0.5) 5.5 (0.4)
116 (11.4) 104 (10.3)
95.8 (0.4) 96.5 (0.6)
ederenees Baird A., Hamilton T.. Richards D., Tasker T., and Williams A., 1988, Cromakalim, inhibits histamine-induced bronchoconstriction in healthy volunteers. Br. J. Clin. Pharmac. 25, 114. Williams A., Hopkirk A., Vyse T., Chiew V. and Lee T., 1989, Inhibition of nocturnal asthma by relaxation of airway smooth muscle with a potassium channel activator. Am. Rev. Resp. Dis. 139, 140.
u
P.tu.423
re
si
Eienburg,
D.C., Boblitt,
D.L. and Schiefer,
K.A.
Department oj Phcrmacology, Coliege of Pharmacy, University of Houston, Houston, Texas 77204-W 5, U.S.A.
Recent investigations in this laboratory have indicated that chronic infusion of epinephrine results in significant alterations in stimulus-induced neurotransmitter overflow as a result of alterations in the inhibitory influence of prejunctional alpha-adrenoceptors on sympathetic nerves in the rat kidney (Schwartz and Eikenburg, 1988). Similarly, it has been reported that the stimulus-induced overflow of neurotransmitter as well as the influence of prejunctional adrenoceptors and uptake mechanisms change markedly with age in some tissue s, eg. heart (Daly et al., 1988). In light of the potential functional significance of such changes in the rat kidney, the present study was undertaken to examine
I
P.tu.420
Effect of intravenous
Gray, S.J., Rolan, P. and Posner, Dept. of Clinical Pharmacology,
Wellcome Research L.&oratories,
J.
Beckenham, Kent, BR3 3BS. U.K.
Local axon reflexes may play an important role in the pathophysiology of asthma. The enkeph&n adogue 443C81 [Tyr-DArg-Gly-Phe(4-NO&Pro-NH,] inhibits peripheral AS- and C-afferent nerve activity, but is almost devoid of CNS effects. Bronchial challenge by isocapnic hyperventilation of cold, dry air induces bronchoconstriction in susceptible subjects by a mechanism that is thought to involve neural reflexes. Therefore, we examined the effect of intravenous (i.v.) 443C81 on the response to cold air challenge in susceptible healthy volunteers to determine whether 443C81 might inhibit neural reflexes in the lung. Using a randomised, balanced, double-blind, cross-over design, 6 male volunteers received; (i) 443C81 i.v. 180 pg/kg/h for 2h, (ii) 443C81 i.v. 90 I.rg/kg/h for 2h or (iii) saline i.v. for 2h, with an interval of 7 days between occasions. FEV, (forced expiratory volume after 1 set), FVC (forced vital capacity), PEF (peak expiratory flow) and Vsop (expiratory flow at 30% remaining FVC) were recorded at the end of each infusion (MacSpiro Bronchial Challenge Analyser; Collingwood Measurement Ltd.). Subjects then inhaled cold, dry air by isocapnic hyperventilation for 3 min at a minute ventilation of 20 X FEV, (Jaeger RHES). Lung function (FEV,, PEF and I&,) and visual analogue scales for chest symptoms were recorded 5, 10 and 15 min post-challenge. Data were analysed by ANOVA. Compared with saline both doses of 443C81 induced a small (2.6-3.68) yet significant (p = 0.028) increase in pre-challenge FEV,, but had no effect on the bronchoconstriction induced by cold air. 443C81 reduced symptoms of shortness of breath 10 min post-challenge (p = 0.027), and urge to cough 5 and 10 min post-challenge (p = 0.017 and 0.042, respectively) and the magnitude of these effects was dose-related. All subjects experienced dry mouth during infusion of 443C81. and reduced secretion of saliva and mucus was apparent during and after the cold challenge. 443C81 may ha-ge slight bronchodilator activity when given by i.v. infusion to healthy volunteers, but it had no effect on the bronchoconstriction induced by cold air challenge, despite attenuation of some symptoms of the challenge. T’his lack of effect of 443C81 against cold air-induced bronchoconstriction could be attributable to the use of an inappropriate challenge model or study population, or to failure of the drug to reach the requisite receptors after i.v. administration. Reduced urge to cough following cr;ld air challenge may be due to direct inhibition of C-afferent nerves, which can mediate cough, or to the apparerrt anti-secretory effects of 443C81.
__.._ ;-.x1.421
III
Inhalation of a potassium charm in he Williams, Beecham Pharmaceuticals
tivator, mom volunteers
A.J., Verden, P. and Lavencier,
E.
Research Division, Biosciences Research Centre, Great Burgh. Epsom. Surrey, U.K.
Cromakalim, a potassium channel activator, inhibits histamine induced bronchoconstriction in healthy volunteers (Baird et al., 1988) and nocturnal bronchoconstriction in patients with nocturnal asthma (Williams et al., 198% The drug, therefore, has potential in the treatment of asthma and we have studied the effects, in healthy volunteers, of administering cromakalim by inhalation. Cromakalim or placebo were administered by inhaling nebuhred solutions generated by an ultrasonic nebulizer. Five groups of 4 volunteers received single doses of cromakahm, given according to an open study design, with stepwise increases in doses being given on separate study days to each successive group
of vohmteers. me doses administered were 0.05, 0.15,0.3,0.6, and 0.8 mg of cromakalim. A further 6 volunteers then received 1 mg of cromakalim and placebo according to a randomized, double blind crossover protocol with a one week
interval between dosing days. The following parameters were measured at intervals beforz aud for 24 hours after dosing: quantitative 12 lead electrocardiogram (ECG, Schiller), cardiac output and stroke volume by impedance cardiography (BoMed), erect and supine pulse and blood pressure using an automatic measuring device (Kontron) and arterial oxygen saturation using a pulse oximeter (Kontron). A continuous 2 lead ECG was recorded on tape for 24 hours after drug administration and subsequently analysed by a computerized method (Medilog). Clinical Chemistry and haematological screens and urinalysis were performed before and 24 hours after drug dosing and any symptoms reported by the volunteers were recorded on diary cards. No changes were found, compzed to pm-dose baseline values, in any of the measured parameters at any time point after dosing with cromakalim. Addi~!onally, iu the double blind phase of the study no differences were found between placebo and 1 mg cromakalim for any of the parameters measured. ‘Table 1 shows the results from cardiovascular monitoring and SaO, 15 minutes after placebo and X mg cro-Y&U&I. Quantitative measurements of the ECG showed no effect at any time point after cromakalim or difference between 1 mg cromakalim and placebo on heart rate, PQ interval, QRS duration, ST level, T wave height or QTc. No abnormalities were found on analysis of the 24 hour ECG tapes. The same 2 patients reported headache after both placebo and 1 mg cromakalim but no other symptoms were reported by the volunteers. Conclusion: Cromakalim, a potassium channel activator can be inhaled safely in doses up to 1 mg in healthy volunteers without effects on the cardiovascular system or ECG, Table 1 V&es (SEM) of Supine Cardiovascular Measurements and SaO, 15 minutes after 1 mg Cromakalim or Placebo
Blood pressure (mmHg)
Dw (b.p.m.?
Cromakahm. 1 mg Placebo
58 (4.0) c;q.(2.7)
systolic
Diastolic
Cardiac output (L/min)
Stroke volume (ml)
SaO, @)
125 (5.4) 128 (4.5)
79.0 (4.5) 79.3 (2.4)
6.6 (0.5) 5.5 (0.4)
116 (11.4) 104 (10.3)
95.8 (0.4) 96.5 (0.6)
ederenees Baird A., Hamilton T.. Richards D., Tasker T., and Williams A., 1988, Cromakalim, inhibits histamine-induced bronchoconstriction in healthy volunteers. Br. J. Clin. Pharmac. 25, 114. Williams A., Hopkirk A., Vyse T., Chiew V. and Lee T., 1989, Inhibition of nocturnal asthma by relaxation of airway smooth muscle with a potassium channel activator. Am. Rev. Resp. Dis. 139, 140.
u
P.tu.423
re
si
Eienburg,
D.C., Boblitt,
D.L. and Schiefer,
K.A.
Department oj Phcrmacology, Coliege of Pharmacy, University of Houston, Houston, Texas 77204-W 5, U.S.A.
Recent investigations in this laboratory have indicated that chronic infusion of epinephrine results in significant alterations in stimulus-induced neurotransmitter overflow as a result of alterations in the inhibitory influence of prejunctional alpha-adrenoceptors on sympathetic nerves in the rat kidney (Schwartz and Eikenburg, 1988). Similarly, it has been reported that the stimulus-induced overflow of neurotransmitter as well as the influence of prejunctional adrenoceptors and uptake mechanisms change markedly with age in some tissue s, eg. heart (Daly et al., 1988). In light of the potential functional significance of such changes in the rat kidney, the present study was undertaken to examine