THE CARDIOVASCULAR EFFECTS OF ICI 118,587: A β 1 ‐ADRENOCEPTOR PARTIAL AGONIST

1. The effects of selective beta‐adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1‐selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2‐adrenoceptors (pindolol) were each given for 3 weeks in a randomised double‐blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run‐in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta‐ adrenoceptor antagonism was determined by the inhibition of exercise‐ induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1‐5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2‐adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.

Section: Introductionmentioning

confidence: 99%

Selective beta‐adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects [see comments]

Tomlinson¹,

Cruickshank²,

Hayes³

et al. 1990

“…In dogs the effects of ICI 118,587 on heart rate were studied during varying levels of cardiac sympathetic stimulation. At low frequencies of stimulation, ICI 118,587 increased heart rate and at high frequencies antagonism occurred with a reduction in heart rate in comparison with controls (Nuttall & Snow, 1982). An earlier study of the effects of intravenously administered ICI 118,587 on heart rate during exercise on a bicycle ergometer showed a reduction in heart rate at high workloads but the effects at rest were less clear (Harry et al, 1981) although a positive inotropic effect has been demonstrated in this situation (Marlow et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, when sympathetic activity was low ICI 118,587 increased heart rate and when sympathetic tone was high, it acted as an antagonist (Nuttall & Snow, 1982).…”

Section: Introductionmentioning

confidence: 99%

The effects of ICI 118,587 and atenolol on the responses to exercise and on breathlessness in healthy subjects.

O'Neill¹,

Morton²,

Sharman³

et al. 1984

1 The effects of ICI 118,587 and atenolol on the responses to submaximal exercise and on breathlessness were studied in six healthy subjects. Atenolol reduced heart rate at rest and during exercise whereas ICI 118,587 increased resting heart rate but caused a small reduction in the highest heart rate achieved during exercise. 2 Neither ICI 118,587 nor atenolol significantly changed minute ventilation or oxygen uptake either at rest or during exercise. There were no effects on bronchomotor tone. 3 The assessment of breathlessness was validated for the subjects participating in the study. Atenolol increased the intensity of breathlessness in relation either to ventilation or to oxygen uptake. This effect was not secondary to a change in bronchomotor tone but was possibly related to changes in pulmonary haemodynamics. On the other hand, the relationships of breathlessness to ventilation or to oxygen uptake were unchanged by ICI 118,587. The effects of ICI 118,587 on exercise tolerance and dyspnoea in patients with impaired cardiac function should now be determined.

“…In the elderly, diuretics may cause serious hypokalaemia and/or hyponatraemia in about 20% of patients (McLennan, 1988 (Nuttall & Snow, 1982). This provides an appropriate balance between a constant level of mild agonist activity at rest and during exercise, thereby supporting myocardial performance, and protecting the failing heart from an excessive stimulatory cardiac response, e.g.…”

Section: Introductionmentioning

confidence: 99%

Xamoterol, a beta 1‐adrenoceptor partial agonist: review of the clinical efficacy in heart failure.

Marlow

1989

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587), a beta 1‐ adrenoceptor partial agonist, improves both systolic and diastolic function in heart failure patients. 2. Double‐blind, randomised studies comparing xamoterol with placebo showed that the beneficial haemodynamic effects of xamoterol produced significant improvements in exercise capacity and symptoms in patients with mild to moderate heart failure. These studies formed the basis for a large European multicentre study programme which recruited over 1000 patients, randomised to xamoterol (200 mg twice daily, n = 617), digoxin (0.125 mg twice daily, n = 135) or placebo (n = 300) for 3 months. 3. Efficacy was assessed by measuring exercise capacity and symptoms. The xamoterol group improved exercise capacity by 37% compared with an 18% improvement in the placebo group. Differences in the symptom scores measured by visual analogue scales and Likert scores indicated significant improvements by xamoterol in the cardinal symptoms of heart failure, dyspnoea and fatigue. 4. Analyses of data from subsets of patients in the study showed that elderly patients, patients on no other heart failure therapy and patients with cardiomegaly all had similar improvements in exercise and symptoms to those seen in the whole study population. In the subset which included digoxin treatment, xamoterol produced significantly greater improvements in exercise capacity than digoxin (33% vs 17%, P less than 0.05) and was associated with fewer side‐effects. 5. Xamoterol is therefore a promising addition to heart failure therapies currently available.