Placebo-controlled comparison of candoxatril, an orally active neutral endopeptidase inhibitor, and captopril in patients with chronic heart failure.

AIMS: To compare the effects on exercise capacity of the neutral endopeptidase inhibitor candoxatril, and the angiotensin converting enzyme inhibitor captopril, in patients with mild to moderate heart failure. METHODS: In this multi-centre double-blind placebo controlled study, 60 patients with NYHA Class I-III heart failure were randomised to candoxatril 200 mg b.d. (n = 22), captopril 25-50 mg b.d. (n = 23) or placebo (n = 15). Treadmill exercise tests were carried out weekly during a 5-week single-blind placebo run-in phase until a stable baseline was achieved, and repeated at 4 weekly intervals during the 12-week double-blind treatment phase. RESULTS: Nine patients withdrew from the study--four candoxatril and five captopril. The placebo-adjusted increase in exercise duration after 12 weeks was 56 s (95% CI, -26 to +137 s; P = 0.12) with candoxatril and 37 s (-43 to + 117 s; P = 0.29) with captopril. CONCLUSIONS: Both candoxatril and captopril were well tolerated and treadmill exercise duration appeared to increase during 12 weeks of therapy but this did not achieve statistical significance. This study tentatively suggests that in patients with heart failure, neutral endopeptidase inhibition may provide similar symptomatic benefits to angiotensin converting enzyme inhibition.

Quinapril in chronic heart failure.

Angiotensin converting enzyme inhibitors are now firmly established in the treatment of patients with chronic heart failure (CHF). Their beneficial acute and chronic hemodynamic effects are not associated with reflex tachycardia or drug tolerance. Angiotensin converting enzyme inhibitors produce symptomatic improvement and improve exercise capacity in all grades of heart failure. They also improve the prognosis of patients with severe heart failure. Quinapril is a recently introduced, nonsulfhydryl ACE inhibitor, whose intermediate half-life makes it well-suited for the treatment of patients with CHF. The acute and chronic hemodynamic effects of quinapril are similar to those of other ACE inhibitors. In a large, multicenter, randomized, placebo-controlled study of 225 patients with mild to moderate CHF, 10 to 40 mg/day quinapril significantly improved clinical status and exercise capacity in a dose-related manner. The incidence of side effects did not differ significantly from that of placebo. The initial studies with quinapril are promising and warrant further clinical investigation of this compound.

The atriopeptidase inhibitor UK 69,578 increases atrial natriuretic factor and causes a natriuresis in normal humans.

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.

Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure.

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.

Transoesophageal echocardiographic assessment of primum, secundum and sinus venosus atrial septal defects.

We compared the ability of transthoracic and transoesophageal echocardiography to determine the presence and site of an atrial septal defect and associated anomalous pulmonary venous connexions in 13 school age children (aged 5 to 15 years) and 12 adults (aged 25 to 68 years). Transthoracic echocardiography detected atrial septal defects in 12 children and 6 adults. Transoesophageal echocardiography confirmed the position of 16 (13 secundum, 3 primum) of these 18 defects but altered the diagnosis from a secundum defect to a sinus venosus defect in one and from a sinus venosus defect to a high secundum defect in another. In addition to these 18, transoesophageal echocardiography diagnosed a defect in 5 adults (3 secundum and 2 sinus venosus defects) and 1 child (secundum defect). In an adult with inconclusive transthoracic findings, transoesophageal echocardiography enabled clear visualisation of the atrial septum and excluded an atrial septal defect. Transoesophageal echocardiography showed anomalous attachment of a pulmonary vein into the region of a sinus venosus defect (n = 3) but did not show anomalous connexions to the superior caval vein (n = 3) or the inferior caval vein (n = 1). Transoesophageal echocardiography provides a reliable method of diagnosing or excluding an atrial septal defect in patients with inconclusive transthoracic findings and is of particular diagnostic value in sinus venosus defects.

Myocardial infarction following the combined recreational use of Viagra and cannabis.

Sildenafil citrate (Viagra, Pfizer, Inc., New York, N.Y.) is widely prescribed as a treatment for male erectile dysfunction. It is metabolized predominantly by the cytochrome P450 3A4 hepatic microsomal isoenzyme and effects can, therefore, be potentiated by such inhibitors. The vasodilatory effects of Viagra necessitate caution in its use in patients with cardiovascular disease and it is contraindicated in patients receiving nitrates. Previous literature has drawn attention to Viagra use and myocardial infarction. This paper reports the case of a young man who presented with a myocardial infarction after taking Viagra in combination with cannabis, a known inhibitor of the cytochrome P450 3A4 isoenzyme.

Confirmation by Doppler echocardiography of valvular regurgitation in a horse with a ruptured chorda tendinea of the mitral valve.

Regurgitation of blood through the left atrioventricular valve owing to the rupture of one of the chordae tendineae of the valve was diagnosed in a horse with sudden-onset respiratory distress and a holosystolic cardiac murmur. Severe regurgitation was confirmed with Doppler echocardiography and prolapse of part of the valve leaflet was identified with B-mode ultrasonography. The rupture of one of the chordae tendineae of a right accessory cusp of the left atrioventricular valve was confirmed post mortem. Bronchiolitis, multifocal haemorrhages and haemorrhagic fibrous plaques were found in the pleura of the dorsocaudal segments of the lungs.

Transoesophageal echocardiographic assessment of mitral valve commissural morphology predicts outcome after balloon mitral valvotomy.

OBJECTIVE: To investigate the value of transoesophageal echocardiography in the assessment of commissural morphology and prediction of outcome after balloon mitral valvotomy (BMV). DESIGN: Prospective study. SETTING: Tertiary cardiac referral centre. PATIENTS: 72 consecutive patients (mean age 61.3 years, range 38-89 years) referred for BMV. INTERVENTIONS: Transoesophageal echocardiography was performed immediately before BMV and the mitral commissures were scanned systematically. Anterolateral and posteromedial commissures were scored individually according to whether non-calcified fusion was absent (0), partial (1), or extensive (2). Calcified commissures usually resist splitting and scored 0. Scores for each commissure were combined giving an overall commissure score for each valve of 0-4, higher scores reflecting increased likelihood of commissural splitting. Valve anatomy was also graded by the method of Wilkins et al, which does not include commissural assessment. MAIN OUTCOME MEASURES: Patients were divided into outcome groups: A (good) and B (suboptimal). "Good" was defined as final valve area > 1.5 cm2 with a > 25% increase in area and absence of severe mitral regurgitation judged by echocardiography. RESULTS: Valve area increased from a mean (SD) of 1.1 (0.28) cm2 to 1.8 (0.46) cm2. Commissure scores were higher in group A than in group B (p < 0.01), scores > or = 2 predicting a good outcome with positive and negative accuracy of 67% and 82%, respectively (p < 0.001). Commissure score was the strongest independent predictor of outcome. CONCLUSION: Transoesophageal echocardiographic assessment of commissural morphology predicts outcome after BMV, adding significantly to the Wilkins score.

Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial.

OBJECTIVES: To evaluate the effect of intensive lipid-lowering treatment on coronary artery calcification in a substudy of a trial recruiting patients with calcific aortic stenosis. METHODS: In a double blind randomised controlled trial, 102 patients with calcific aortic stenosis and coronary artery calcification were randomly assigned by the minimisation technique to atorvastatin 80 mg daily or matched placebo. Coronary artery calcification was assessed annually by helical computed tomography. RESULTS: 48 patients were randomly assigned to atorvastatin and 54 to placebo with a median follow up of 24 months (interquartile range 24-30). Baseline characteristics and coronary artery calcium scores were similar in both groups. Atorvastatin reduced serum low density lipoprotein cholesterol (-53%, p < 0.001) and C reactive protein (-49%, p < 0.001) concentrations whereas there was no change with placebo (-7% and 17%, p > 0.95 for both). The rate of change in coronary artery calcification was 26%/year (0.234 (SE 0.037) log arbitrary units (AU)/year; n = 39) in the atorvastatin group and 18%/year (0.167 (SE 0.034) log AU/year; n = 49) in the placebo group, with a geometric mean difference of 7%/year (95% confidence interval -3% to 18%, p = 0.18). Serum low density lipoprotein concentrations were not correlated with the rate of progression of coronary calcification (r = 0.05, p = 0.62). CONCLUSION: In contrast to previous observational studies, this randomised controlled trial has shown that, despite reducing systemic inflammation and halving serum low density lipoprotein cholesterol concentrations, statin treatment does not have a major effect on the rate of progression of coronary artery calcification.

Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.

OBJECTIVE: To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure. METHODS: Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study. RESULTS: Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05). CONCLUSIONS: While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.

Dextropropoxyphene overdose. Epidemiology, clinical presentation and management.

This paper comprehensively reviews the worldwide situation regarding acute overdosage of dextropropoxyphene (propoxyphene). The changing epidemiology of this type of poisoning over the last 20 years is described with discussion of concurrent trends and, in particular, the effects of different preventive measures adopted in various countries. The clinical pharmacology of dextropropoxyphene relevant to the clinical toxic effects resulting from acute overdosage is described, and the management is detailed. In particular, the importance of early diagnosis and treatment is stressed in view of the potentially lethal complications that may suddenly occur with this poisoning. Recommendations for the correct use of the specific narcotic antagonist, naloxone, are made, together with other intensive supportive measures. As dextropropoxyphene is frequently taken together with other toxic agents, the concomitant effects of alcohol and sedative drugs are described and the treatment of paracetamol (acetaminophen) in combination with dextropropoxyphene is emphasised. The most effective preventive measures for the future are suggested, but caution is advised regarding the prescription for 'at risk' patients of alternative analgesics, which may be no safer in overdosage.

Atrial natriuretic factor in chronic heart failure.

The pathophysiological role of atrial natriuretic factor in patients with chronic heart failure is still unclear. Plasma ANF levels are elevated in this condition, particularly in patients with severe left ventricular dysfunction and during acute exacerbations. Drug therapy, including diuretics, vasodilators and inotropes which reduce cardiac filling pressures also reduce plasma ANF levels. In the clinical setting the measurement of ANF levels may provide a useful means of assessing salt and water retention in patients with heart failure. Intravenous infusion of ANF to patients with heart failure causes a diuresis and natriuresis, a fall in filling pressures and possibly suppression of the renin-angiotensin aldosterone system. High bolus dosing with the peptide may reduce systemic vascular resistance resulting in hypotension, which markedly attenuates the renal effects. A new pharmacological approach in this area is the development of neutral endopeptidase inhibitors, which prolong the half-life of endogenous ANF and potentiate its effects. The therapeutic potential of ANF in heart failure has yet to be realised.

Diagnosis of mitral valve aneurysm by transoesophageal echocardiography.

In a patient with mitral valve aneurysm precordial echocardiography suggested a mistaken diagnosis of infective endocarditis. Transoesophageal echocardiographic examination established the correct diagnosis, which was subsequently confirmed at operation. Transoesophageal echocardiography gives better resolution of lesions associated with the mitral valve than precordial examination and may improve the diagnostic accuracy.

Severe coronary vasospasm associated with hyperthyroidism causing myocardial infarction.

A 48 year old woman presented with angina after an anterior myocardial infarction and was found to be hyperthyroid. Coronary angiography showed a stenosis of the left coronary os and a long, severe stenosis of the left anterior descending artery which was partially relieved by glyceryl trinitrate. Three months later, after radioactive iodine treatment had rendered her euthyroid, repeat coronary angiography showed entirely normal coronary arteries. This unusual case establishes an association between hyperthyroidism and coronary vasospasm resulting in myocardial infarction.

Association between liberalization of Scotland's liquor licensing laws and admissions for self poisoning in West Fife.

Data were collected prospectively on 2868 consecutive patients admitted for self poisoning between 1971 and 1982. Analysis showed a dramatic increase in the frequency of alcohol taken in association with self poisoning, in both sexes, after the liberalization of Scotland's liquor licensing laws. This increase, however, did not appear to affect the severity of overdoses or the outcome. Total admission rates for self poisoning increased with relaxation of the liquor licensing laws, and since overdoses associated with alcohol tend to occur at night these impose considerable strain on casualty departments and acute admitting units.