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A randomised double-blind parallel group study was performed to compare the clinical efficacy of bepridil, a new calcium slow channel blocker, with that of propranolol and placebo in patients with chronic stable angina of effort. Efficacy was assessed objectively by dynamic exercise testing using an upright bicycle ergometer and subjectively by patient documentation of anginal frequency and nitrate consumption. The administration of bepridil resulted in a significant improvement in physical work capacity expressed as calculated maximal oxygen uptake (Vo2 max) and exercise time. This was associated with subjective improvement in terms of reduced anginal frequency. Despite baseline differences in exercise performance and anginal frequency between the three treatment groups, the beneficial effects of bepridil were statistically significant when compared to propranolol. Although minor electrocardiographic changes were noted, no adverse effects were evident when bepridil was prescribed in doses of up to 400 mg/day over a 10 week period. [ABSTRACT FROM AUTHOR]

The clinical response to felodipine, in addition to a beta-blocker, was evaluated and compared with placebo in this double-blind cross-over study. Twenty patients with exertional angina pectoris completed the study. Felodipine reduced the number of angina attacks and the Glyceryl Trinitrate (GTN) consumption. The median exercise capacity was increased 33% after 4 weeks' felodipine treatment compared with placebo. At maximal exercise, systolic blood pressure and rate pressure product were reduced by felodipine while no change was seen in heart rate or ST-depression. Felodipine reduced both supine and erect blood pressure. The mean supine blood pressure at rest was 138/82 mm Hg after four weeks' placebo treatment compared with 114/71 mmHg after felodipine 5-10 mg b.i.d. Felodipine has overall a modest but significant anti-anginal benefit when combined with a beta-blocker.

1. Changes in left ventricular structure and function were assessed by echocardiography in 22 patients before and after 9 months blood pressure control. 2. Nine patients had normal baseline echocardiograms (group 1) and 13 had echocardiographic evidence of left ventricular hypertrophy (group 2). 3. Group 2 patients demonstrated significant reductions in posterior wall thickness (P < 0.01), septal wall thickness (P < 0.025) and left ventricular mass (P < 0.005). Only six of the 13 patients showed a reduction of greater than or equal to 3 mm in posterior wall thickness. The remainder showed no alteration or only a slight non-significant reduction. 4. The regression of voltage in some patients but not in others did not appear to be related to initial blood pressure, the extent of the fall in blood pressure or duration of follow-up. It was not possible to say whether any specific therapy was beneficial to regression since most of the patients were on multiple therapy.

The effect of the cardioselective beta-adrenoreceptor blocking compound, metoprolol, was compared with methyldopa in the long-term management of hypertension. Thirty patients given metoprolol and twenty-six given methyldopa were treated for 2 years. The maximum dose of metoprolol was 200 mg twice daily (average 308 mg) and of methyldopa 1,000 mg twice daily (average 1,120 mg). Blood pressure was similar at entry to the study (metoprolol 177/110 mmHg and methyldopa 181/111 mmHg). After 2 years of treatment the blood pressure levels were again similar (metoprolol 149/91 mmHg and methyldopa 148/91 mmHg). Erect pressures were lower in the methyldopa group, but there was no difference between supine and erect blood pressure levels in those on metoprolol. At an exercise load of 300 and 600 kpm the increase in systolic pressure was significantly less in the metoprolol group. The proportional increase in systolic and diastolic pressure in response to a standardized stress situation was reduced by treatment with metroprolol but not by methyldopa. Tolerance to therapy did not develop in either group. The main difference between metoprolol and methyldopa was in the incidence and severity of side effects. Four patients were withdrawn from the metoprolol group. Seventeen were withdrawn from the methyldopa mainly because of side effects including drowsiness, depression, skin rash, and impotence. Six patients on metoprolol and seventeen on methyldopa continued on therapy although side effects were present. It is concluded that metoprolol and methyldopa lower blood pressure to the same extent, but metoprolol is advantageous because of a lower incidence of side effects.

The computer-analysed 3 orthogonal lead system ("3-lead ECG") provides a rapid and consistent interpretation of the electrocardiogram. In 102 patients undergoing selective coronary arteriography, the ability of such a system to predict the presence of absence of coronary artery disease and the site of myocardial ischaemia was compared with that of the conventional scalar electrocardiogram interpreted by cardiologists ("12-lead ECG"). Each system predicted the site of myocardial ischaemia with equal accuracy. The 3-lead ECG was a more sensitive index (3-lead ECG sensitivity=77%; 12-lead ECG sensitivity=70%) but less specific (3-lead ECG specificity=74%; 12-lead ECG specificity=78%). In coronary artery disease, the predictive "index of merit" for the 3-lead ECG was 0-51, compared with 0-48 for the 12-lead ECG. These results provide further justification for the routine use of the 3 orthogonal lead electrocardiogram.

Plasma lipoprotein concentrations in 64 untreated adult onset diabetics were compared to the lipoprotein levels found in non diabetics. No significant difference was found. The relationship of the fasting plasma triglyceride concentration to the plasma immunoreaction insulin response to 50 g glucose orally was investigated. Using correlation analysis a significant and insulin response in the non diabetics but not in the diabetics.

The variation of the diagnostic value of stress Tl-201 scintigraphy with prevalence of coronary heart disease (CHD) in the population has been investigated using Bayesian reasoning. From scintigraphic and arteriographic data obtained in 100 consecutive patients presenting with chest pain, the sensitivity of stress Tl-201 scintigraphy for the detection of significant CHD was 90% and the specificity was 88%. From Bayes' Theorem, the posterior probability of having CHD for a given test result was calculated for prevalences of CHD ranging from 1% to 99%. The discriminant value of stress Tl-201 scintigraphy was best when the prevalence of CHD lay between 30% and 70% and maximum for a prevalence of 52%. Thus, stress Tl-201 scintigraphy would be an unsuitable diagnostic test where the prior probability of CHD is low, e.g., population screening programmes, and would add little where the clinical probability of having CHD is already high. However, where the prior probability of having CHD is intermediate stress Tl-201 scintigraphy may provide valuable diagnostic information.

1. The adequacy of the control of essential hypertension during exercise was studied in patients whose resting blood pressure had been controlled for 1 year with either metoprolol or methyldopa. 2. Systolic blood pressure increased with exercise in both groups, the increase being significantly less in the metoprolol group than in the methyldopa group.

Plasma fibrinogen and platelet-aggregates (method of Wu and Hoak) were measured in 21 patients with familial Type II hyperlipoproteinemia and 21 matched control subjects. Patients with hyperlipoproteinaemia had increased levels of fibrinogen and platelet-aggregates (p less than 0.01). Young patients with hyperlipoproteinaemia had prematurely high fibrinogen levels, and the normal rise in fibrinogen during adult life was abolished. There were no statistically significant correlations within the patient group between fibrinogen, platelet-aggregates, and plasma lipids. High fibrinogen and platelet-aggregate levels may play a part in the development of the premature arterial disease associated with Type II hyperlipoproteinaemia, or may be markers of arterial injury.

Fourteen patients with hyperlipoproteinaemia and peripheral vascular disease have been investigated to determine the effect on limb blood flow of hypolipidaemic therapy. Satisfactory lowering of serum lipoprotein levels was achieved in the treated group. There was a significant deterioration in peak reactive blood flow measurements in the placebo group compared with the treated group. Treatment of hyperlipoproteinaemia may, therefore, be of value in preventing the progression of peripheral atherosclerosis.

The systolic time intervals; total electro-mechanical systole (QS2), left ventricular ejection time (LVET), pre-ejection period (PEP), and ratio of PEP/LVET were measured from external readings in twenty hyperthyroid and fifteen hypothyroid patients. The hyperthyroid subjects showed shortening of the PEP and reduction in the PEP/LVET. The hypothyroid group showed lengthening of the PEP, shortening of the LVET and increased PEP/LVET. These changes returned towards normal in ten patients rendered euthyroid with appropriate therapy. The value of these measurements to predict the thyroid status was examined in a mixed group of seventy-four patients. There was close agreement between diagnosis predicted from systolic time intervals and that made independently from clinical and biochemical assessment, suggesting that the systolic time intervals may have been a useful place in the clinical assessment of thyroid patients.

The apolipoprotein A concentration in the plasma of ten healthy human subjects was measured immunologically on three occasions at monthly intervals and the following results recorded. 1. There was no difference between fasting and non-fasting apoprotein A concentrations. 2. Apoliportein A levels were higher in females than in males (p less than 0.001). 3. The correlation coefficient calculated for high density lipoprotein cholesterol and apolipoprotein A was 0.62. 4. The apoprotein values varied widely between subjects and ther were considerable concentration differences from month to month in the plasma of each individual.

Procainamide was given to 20 patients with normal renal function as an i.v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6 +/- 27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0 +/- 0.8 h, compared to a mean of 3.4 +/- 0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75 +/- 0.9 h in fast acetylators, and 4.4 +/- 2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose.

In the past decade a number of new antiarrhythmic drugs ahve been introduced. They have been extensively used in the acute phase of myocardial infarction. Few, if any, long-term comparative trials of these newer agents have been reported. Most of these newer agents have been shown to be able to reduce the frequency of ventricular arrhythmias but not the mortality rate. Beta blockers and some antiplatelet adhesive drugs, however, have reduced the mortality rate following myocardial infarction. There is a need for long-term properly stratified trials of these effective agents.

Lipoprotein typing was undertaken in apparently healthy women (419) and men (103) in whom measurements of fasting total cholesterol, triglycerides, and cholesterol content of the major lipoprotein fractions were made. In the female group (30 to 59 years) there was a significant rise in total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides with age. Using total cholesterol and triglyceride levels for classification, type II hyperlipoproteinaemia was present in 1 per cent and type IV in 6-7 per cent. When LDL cholesterol levels were also considered, type II occurred in 9-8 per cent ( 8-4% type IIA and 1-4% type IIB). In the male group ( 40 to 59 years) there was no increase in cholesterol or triglyceride levels with age: II per cent had type IV hyperlipoproteinaemia and none had a type II abnormality. When LDL cholesterol levels were also considered, type II occurred in 3 per cent ( 2% type IIA and 1% IIB). The apparent increase in LDL cholesterol frequency of type IIA abnormality in women could be merely the consequence of arbitrary selection of upper limits of normality for LDL cholesterol, but may signify improved detection of a high risk group.

Marked alterations in levels of circulating thyroid hormone were found in patients undergoing cardiopulmonary bypass with a rise in the free thyroxine and a fall in the free triiodothyronine levels. Studies using thyrotropin-releasing hormone during bypass demonstrated a blunted response to this stimulus. This reduced response is related to changes in thyroid hormone levels and it is suggested that bypass surgery may have a direct inhibitory action on thyroid-stimulating hormone release at the hypothalamo-pituitary level. The potential significance of these hormonal changes is discussed.

1 Using a standardized form of mental stress, 21 patients with idiopathic hypertension were investigated before and after treatment with placebo (n=8), propranolol (n=7) or methyldopa (n=6). 2 Blood pressure was satisfactorily controlled in the propranolol and methyldopa groups but only the propranolol group showed modification of the pressor response to stress testing. 3 These results suggest that propranolol may provide more uniform control of blood pressure than methyldopa in patients with essential hypertension.

1. A standardized method of objectively measuring performance during simulated car driving is described. 2. The effect of a single dose of propranolol and metoprolol were compared with placebo in two groups of patients with untreated essential hypertension. 3. Performance was similar after beta-adrenoreceptor-blocking agents or placebo. 4. Blood pressure response to stress persisted after administration of the blocking agents.

Continuous wave Doppler echocardiography was used to study 41 adults with clinically suspected aortic stenosis undergoing cardiac catheterisation. Non-invasive assessment of the severity of stenosis was made before catheterisation using electrocardiograms, chest radiographs, and cross sectional echocardiography in addition to clinical examination and assessment modified, where appropriate, by the result of the Doppler examination. Catheterisation gradients were obtained in 33 patients and correlated well with those obtained by Doppler examination particularly when simultaneous recordings were obtained. All patients with surgically significant stenoses were identified by non-invasive assessment including Doppler examination and overestimation was not found in any patient with a less than significant stenosis. Thus surgery can be recommended in patients with aortic stenosis without the need for previous cardiac catheterisation.

The operation on and subsequent course of 88 patients with valve replacements using Björk-Shiley tilting disc prostheses has been reviewed in terms of mortality, clinical results, and valve function. The follow-up period varied between 6 months and 2 years. The hospital mortality was 17% and late mortality 8%. Of those who left hospital, 75% returned to full normal activity and required less (or no) drug therapy other than maintenance anticoagulation. There was one transient embolic episode. Significant intravascular haemolysis does not occur with this prosthesis.

Hyperuricaemia and hyperlipidaemia (elevated fasting plasma cholesterol or triglycerides) were frequently found in 219 males and 63 females with peripheral vascular disease (PVD). The subjects were divided into sexes and the uric acid, cholesterol and triglyceride concentration adjusted for the effects of age and obesity by multiple regression analysis. Followig this no significant relationship was found between uric acid and cholesterol or triglyceride. When the males with PVD were divided into lipoprotein types it was found that those who were normo-lipoproteinaemics or who had type IV hyperlipoproteinaemia (HLP) had a significantly higher mean uric acid level. The other types had a mean uric acid concentration similar to that found in 25 healthy normolipoproteinaemic males. The discrepancy between this result and the lack of correlation between uric acid and triglyceride noted above is presumably due to the complex effects of age and obesity. In the females no significant increase in the mean uric acid concentration was found in any of the lipoprotein groups.

1 The cardiovascular effects of the beta-adrenoceptor blocking drugs, propranolol and acebutolol, on regional coronary blood flow and left ventricular function have been investigated in the conscious dog with developing myocardial infarction. 2 Propranolol (1 to 1.5 mg/kg) or acebutolol (4 to 5 mg/kg) were administered intravenously 2 to 3 h after occlusion of the left anterior descending coronary artery. 3 Propranolol or acebutolol administration resulted in a relative increase in flow to the ischaemic area of the myocardium, particularly to the subendocardium. 4 Propranolol produced a greater reduction in heart rate and myocardial contractility than acebutolol. 5 These results demonstrate that beta-adrenoceptor blocking drugs reduce myocardial oxygen consumption and increase coronary flow to the ischaemic area of the myocardium after coronary artery occlusion in the conscious dog.

The week-to-week, inter- and intraobserver variation in left ventricular echocardiographic measurements has been studied in 10 normal male volunteers and in five patients with stable valvular disease. A two-way analysis of variance showed no statistically significant variation either from week to week or between observers. Furthermore the within observer variation was minimal. Calculation of the coefficient of variation allowed confidence limits to be applied to each of the six ventricular measurements, thus providing ranges of variation in follow-up studies using M-mode echocardiography.

Lipoprotein analyses were performed in 133 male patients and were correlated with the coronary arteriographic findings. The prevalence of hyperlipoproteinaemia was significantly higher in those patients with coronary artery disease (P less than 0-02). In addition, the more extensive the degree of coronary artery pathology the higher were the plasma concentrations of total cholesterol, triglyceride, and low density lipoprotein (LDL) cholesterol. Hyperlipoproteinaemia was more prevalent in the younger patients with coronary artery disease (P less than 0-02).

Ten patients in sinus rhythm with symptomatic cardiac failure participated in a study investigating the value of digitalis at rest and during dynamic exercise. A haemodynamic profile and left ventricular ejection fraction were measured before treatment, after intravenous ouabain, and after six weeks of maintenance treatment with digoxin. There was no significant change in the haemodynamic profile or in the left ventricular ejection fraction at rest after either glycoside. During exercise there was a significant reduction in left ventricular filling pressure from 39 +/- 3 mm Hg to 34 +/- 3 mm Hg (p less than 0.05) after ouabain and to 33 +/- 3 mm Hg (p less than 0.02) after digoxin. Cardiac index improved from 33 +/- 0.3 1/min/m2 to 4.0 +/- 0.4 l/min/m2 (p less than 0.01) after ouabain and to 3.8 +/- 0.4 l/min/m2 (p less than 0.01) after digoxin. During exercise stroke volume index and stroke work index also improved significantly with both glycosides. This was accompanied by an increase in left ventricular ejection fraction from 29 +/- 2% to 36 +/- 3% (p less than 0.05) after ouabain and digoxin. In this study both intravenous ouabain and maintenance treatment with oral digoxin exerted a modest positive inotropic effect in patients with cardiac failure in sinus rhythm. The haemodynamic benefit, however, was manifest only during exertion.

Recent reports of treatment of massive digoxin overdosage have emphasized the success of medical therapy. This report describes a fatal outcome to this problem despite aggressive medical management, including pervenous cardiac pacing and draws attention to deficiencies in current treatment of a serious problem.

This study on 4 type II hyperlipoproteinaemic subjects examines the effects of pharmacologic doses (8 g twice daily) of the bile acid sequestrant cholestyramine on the plasma distribution and chemical composition of the high density lipoprotein subfractions, HDL2 and HDL3, and describes the influence of the drug on the metabolism of the major HDL aporoteins, apolipoprotein A-I and A-II. Cholestyramine lowered plasma low density lipoprotein cholesterol (32%; P less than 0.05) without affecting the level of that lipid in very low density or high density lipoproteins. However, the plasma HDL2/HDL3 ratio and apolipoprotein A-I concentration rose significantly on treatment, while apolipoprotein A-II remained unchanged. The rise in apolipoprotein A-I derived from an increase in its synthetic rate and produced a relative enrichment of the protein with respect to apolipoprotein A-II in both HDL subfractions. These results demonstrate the cholestyramine treatment affects HDL metabolism in a way which, according to current concepts, may prove beneficial to the recipient.

The analytical characterization, by GC-MS, of individual compounds in mixtures of steroids, such as occur frequently in biological extracts, is difficult because of the close similarities in structure and properties of many components. The improved separating power of capillary (open-tubular) columns alleviates the problem, but does not solve it fully: for example, the coincidence of retention times of two different compounds may still be virtually complete. Comparative analyses on two distinctively different phases afford one valuable application of selectivity, but may not always be feasible when costly columns are required. Comparative analyses of the sample, before and after effecting its modification by well-defined reactions, are inexpensive and are particularly when selective transformations are used. The use of the microbial enzyme cholesterol oxidase as a selective oxidant for 3 beta-hydroxysteroids (chiefly limited to 4-ene, 5-ene and 5 alpha-types) is illustrated for a model mixture of androstanols related to the boar pheromone (5 alpha, 16-androsten-3 alpha-ol). Retention regularities and changes in mass spectra enhance the reliability of identifications. An exploratory application of cholesterol oxidase in the analysis of minor "polar" sterols in human serum is reported. Most of the known minor sterols are good substrates for the enzyme, and their transformation products yield distinctive GC-MS data, as exemplified for the 7 alpha- and 7 beta-hydroxycholesterols. Another convenient and versatile selective reagent is methaneboronic acid, which yields cyclic esters of suitably constituted diols. These derivatives have shorter retention times (on "non-polar" phases) than the di-TMS ethers, chiefly by virtue of their much lower molecular weights. The mass spectra of cyclic boronates generally show clear molecular ions, also fragmentations that complement the information obtainable from the di-TMS ethers. These features are illustrated for a group of diols and triols of the 5 alpha-pregnane series.

BRL 26921 is the p- anisoyl derivative of the primary streptokinase-human plasminogen complex in which the acyl group is specifically located at the catalytic centre of the enzyme. Doses of BRL 26921 ranging from 5 mg to 25 mg were given intravenously or into a coronary artery to 12 patients with acute myocardial infarction. The complex was well tolerated and produced no serious bleeding. Coronary artery reperfusion was demonstrated angiographically in three patients. In most patients, fibrinogen, plasminogen, alpha 2 antiplasmin and alpha 2 macroglobulin levels fell and the level of fibrinogen degradation products increased acutely post treatment indicating systemic fibrinolytic activation. The degree of this activation was variable but was profound in some. It appeared to be dose related and modified by the presence of streptokinase antibodies. BRL 26921 appears less "selectively" thrombolytic in patients than had been expected from animal models.

The prehospital management of acute myocardial infarction by general practitioners and emergency-treatment service physicians was analysed in 53 patients. The correct clinical diagnosis was made or suggested before admission in 47 patients. Only 25 patients received analgesics from the general practitioner, and 32 were still in pain and needed diamorphine on admission to hospital. Only one patient received antiarrythmic treatment. The findings suggest that, despite accurate clinical diagnosis of acute myocardial infarction, deficiencies exist in the prehospital phase of management and that education programmes are worth consideration.

Slow-release procainamide given 8-hourly is shown to produce plasma levels generally accepted as giving effective prophylaxis against ventricular dysrhythmias occurring after recent myocardial infarction. Patients can be classified into 'slow' and 'fast' acetylators of procainamide. Knowledge of acetylator status is helpful in determining the dose of procainamide necessary to attain effective steady-state plasma levels while avoiding toxic ones. Acetylator status cannot be assessed accurately using sulphadimidine when the patients are also taking procainamide.

Surveys of the apparently healthy working population of the West of Scotland have revealed a high prevalence of hyperlipoproteinaemia (HIP). In males, type IV occurred more frequently (12%) than in females (3.3%), although obesity played an important part in this finding. HLP also occurred frequently (61%) in survivors of myocardial infarction (type II 39%, type IV 22%) but less frequently in peripheral vascular disease (38%), although there was a higher prevalence in females (47%) than males (32%) largely due to an increased prevalence of type IIa (29.5% cf 7.5%). HLP did not appear to play a significant role in cerebrovascular disease.

Eighteen patients with idiopathic hypertension were studied to assess the anti-hypertensive control, both at rest and during exercise of increasing doses of hydrochlorothiazide, metoprolol and a combination of hydrochlorothiazide and metoprolol. Each active treatment period was given for four weeks with an intervening four week placebo period, with assessments made at 2 to 4 hours and 22 to 24 hours following tablet intake. The results show that the resting systolic and diastolic values for all active treatment periods were significantly different from placebo. During exercise, the systolic blood pressure levels were significantly reduced by all active treatments with the greatest overall reduction being achieved by either metoprolol or the metoprolol-hydrochlorothiazide combination. However, the exercise induced increase in systolic blood pressure was reduced by approximately 25% by both metoprolol and the combination product, when compared to placebo, but not by the diuretic alone.

A simple procedure has been devised to give virtually pure preparations of polymorphonuclear leucocytes. This has permitted study of the regulation of cholesterol biosynthesis at cell level. Freshly isolated cells from donors with various forms of hyperlipoproteinaemia have been shown to have very low levels of cholesterol synthesis, presumably due to high circulating levels of apoprotein-B in donor plasma [1]. The activity of the rate-limiting enzyme for cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, rapidly increases as the cells are incubated in lipoprotein-deficient medium, until, by 12 h, cells from patients heterozygous for familial type IIa hypercholesterolaemia are clearly distinguished from other hyperlipoproteinaemias. The possible significance of this finding is discussed in relation to the causation and treatment of atherosclerotic disease.

High density lipoprotein subfractions (HDL2 and HDL3) were separated from the plasma of 25 healthy volunteers (13 males, 12 females) rate zonal ultracentrifugation. The rotor elution profile, measured at 280 nm, was used with the specific extinction coefficient for each subfraction (HDL2, 0.60 +/- 0.11 mg protein/A280nm, HDL3, 0.86 +/- 0.10 mg protein/A280nm (n=25) to calculate their plasma concentration. Their protein and lipid composition were also determined by chemical analysis. Plasma lipids, lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein A-II and apolipoprotein B levels were measured in the same subjects and correlated with the HDL subfraction concentrations. HDL cholesterol and apolipoprotein A-I concentrations correlated significantly (p less than 0.01 and 0.02 respectively) with plasma HDL2, but not with HDL3. Indeed, the significantly higher levels of HDL cholesterol and apolipoprotein A-I in the female group could be attributed entirely to an increase in circulating HDL2. This data supports the proposal that the latter subfraction is the major contributor to the anti-atherogenic role of plasma HDL.