SUMMARY The effects of xamoterol (200 mg twice a day) in 21 patients with left ventricular dysfunction were studied in a double blind, randomised, crossover, placebo controlled trial with treatment periods of four weeks. Most patients had moderate heart failure (New York Heart Association class II), all had ischaemic heart disease, a history of a myocardial infarction, and symptoms of dyspnoea on exertion. Patients were assessed in terms of exercise duration (bicycle ergometer), clinical signs of heart failure, symptoms and activities, and ejection fraction. Xamoterol increased exercise duration (mean (SD)) (from 445 (8) seconds to 484 (8) seconds) and ejection fraction (from (1 3)% to 46 6 (1 -3)%) and reduced the signs and symptoms of heart failure.The results of this study show that xamoterol is a safe and effective treatment for left ventricular dysfunction resulting from ischaemic heart disease.
The isolated spontaneously beating heart was used for comparing the effects of hypoxia and positive inotropic drugs on myocardial ultrastructure. Hypoxia gives a significant decrease in the volume fractions of mitochondrial cristae relative to the total mitochondrial volume (Vvmcristae) and a significant increase in the volume fraction of mitochondrial matrix relative to the total mitochondrial volume (Vvmmatrix), but changes in volume fractions of mitochondria (Vvmitochondria) and myofibrils (Vvmyofibrils) were absent. Significant changes in ultrastructure in hearts treated with dopamine (0.6 microM), dobutamine (90 nM), G-strofanthin (0.25 microM), xamoterol (32 nM) and isoprenaline (0.15 microM or 15 nM) were absent. Furthermore, myocardial effects in the isolated rabbit heart without exposure to any treatment showed a significantly decrease in oxygen consumption after 90 min. and a significant decrease in frequency of contractions after 120 min. perfusion time, but no change in contractility was seen. We conclude that this experimental model is useful in studies of positive inotropic drugs.
The long term effects of treatment with xamoterol in 14 patients aged 44-73 with mild to moderate heart failure as a result of ischaemic heart disease are reported. After 18 months' treatment with xamoterol, patients,were assessed in a. randomised double blind crossover comparison of xamoterol (200 mg twice a day) and placebo, each given for one month. Compared with placebo, xamoterol significantly increased exercise duration and work done on a bicycle ergometer and reduced the maximum exercise heart rate. Assessment of symptoms and activities at 12 months by visual analogue and Likert scales showed a trend towards the relief of symptoms of breathlessness and tiredness and an Improvement in activity. There was an improvement in the clinical signs of heart failure and no haemodynamic deterioration over a 12 month period as assessed by ejection fraction.The improvement in exercise tolerance, symptoms, and activities was sustaied for 18 months without side effects or development of tolerance.Chronic heart failure affects approximately 4% of the elderly population and is often a result of myocardial infarction.1 In the Framigham study 39% of the patients with chronic heart failure had coronary artery disease.2 In patients with ischaemic left ventricular dysfunction treatment with xamoterol (for up to 3 months) had a beneficial effect.'
The high prevalence of chronic congestive heart failure has encouraged the search for new orally active drugs. In the early stages of heart failure, when symptoms are confined to periods of work stress, the overriding objective of drug therapy is to improve cardiac contractile activity. As heart failure advances and vasoconstriction and increased activity of the neuroendocrine system results in salt and water retention, diuretics can be added. In the terminal stages of disease, the addition of angiotensin converting enzyme (ACE) inhibitors can be expected to benefit the patient (87).In 1948, Ahlquist (1) proposed the existence of two types of receptors in the adrenergic system, a-and P-receptors. Lands et al. (46) presented experimental evidence in 1967 that justified a subdivision of f3-adrenergic receptors into PI-and P,-adrenoceptors. In 1972, Furchgott described (31) the procedure for the characterization of a-and P-adrenoceptors. According to the earlier classification, the responses of the tissues could be classified as being mediated by either P,-or P,-adrenoceptors. Subsequently, PI-and P,-adrenoceptors have been found to coexist in various organs. For example, in the heart of some animals and in the human, we have both receptor types. The functional and pathophysiological roles of these receptors are not fully defined (4,(15)(16)(17)37,38,103).The pharmacological classification of P-adrenoceptors into PI-and &-subtypes has been based on the relative affinity of the receptors for the agonists and on the competition between selective antagonists and nonselective radiolabeled ligands. The P-adrenoceptors have been identified biochemically, and these two mammalian proteins possess identical molecular masses. The structures of PI-and P,-adrenoceptors have been proposed and their genes have been cloned. Recent data establish that the two receptors are products of different genes (30).When an agonist occupies the P-adrenoceptor, adenyl cyclase is activated through its interaction with the guanine nucleotide-binding regulatory proteins, G,. Cyclic AMP is an
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