Safety and pharmacokinetics of ioversol in healthy volunteers.

Ioversol 320, a new nonionic iodinated contrast medium, was injected intravenously into 24 healthy male volunteers using saline as a control. Physical examination, vital signs, electrocardiogram, biochemical and hematological data were recorded before and at intervals after injection. No significant changes were observed. Seventeen volunteers reported no side effects; six volunteers had mild transitory symptoms considered to be related to the contrast medium. The authors conclude that broader clinical trials can be safely conducted to determine safety and tolerability of ioversol.

Acute haemodynamic effects of different doses of alifedrine in congestive heart failure.

The haemodynamic effects of single oral doses of alifedrine 40 mg, 50 mg, 60 mg and placebo were compared in 30 patients with mild to moderate heart failure. Individual patients received either alifedrine 60 mg and placebo (15 patients) or alifedrine 40 mg and 50 mg (15 patients). All doses of alifedrine produced qualitatively similar haemodynamic responses, with maximum changes between 90 and 180 min after drug administration. The cardiac index was increased by +39%, +57%, and +50% by 40 mg, 50 mg and 60 mg, respectively. The increases were due to rises in stroke volume index (SVI) and in heart rate of +15%, +20% and +23%. Mean arterial blood pressure fell in a dose-related fashion, with a maximum fall of 11% by 120 min after 60 mg. The systemic vascular resistance index (SVRI) fell by 28%, 39% and 41%, and pulmonary vascular resistance index (PVRI) by 32%, 44% and 32% after 40 mg, 50 mg and 60 mg, respectively. The optimum dose appears to be 40 mg, which caused very little fall in blood pressure or increase in heart rate, yet significantly improved cardiac output. Alifedrine may have a place in the treatment of heart failure as an oral by active, positive inotropic agent.

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity.

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris.

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.

Detection of high risk coronary artery disease by thallium imaging.

One hundred and three patients who underwent coronary arteriography were studied by thallium imaging and the results analysed by Bayesian principles to assess the usefulness of semiquantitative stress thallium imaging for predicting the presence or absence of multivessel coronary disease. Significant disease was found in 80 patients, of whom 77 had abnormal thallium scans (sensitivity 96%). Thallium images were normal in 15 of 23 patients with no significant disease (specificity 65%). Multiple thallium segmental defects were found to be 90% sensitive and 65% specific for multivessel coronary artery disease and were present in 80% of patients with left main stem disease and in 93% of patients with triple vessel disease. A single thallium defect or normal scan excluded multivessel, left main, and triple vessel disease with 81%, 94%, and 91% predictive accuracy respectively. By Bayesian analysis the predictive accuracy for excluding multivessel disease was greater than 90% in patients with a pretest probability of multivessel disease of less than or equal to 40%. Coronary arteriography to exclude multivessel disease is therefore unnecessary in a high proportion of patients with known or suspected coronary artery disease.

Clinical trial of flupirtine maleate in patients with migraine.

A double-blind randomized parallel group trial was carried out in two centres to study the drug treatment of acute attacks of migraine. One group of 20 patients was treated with oral doses of 100 mg flupirtine maleate and another group of 20 patients with doses of 1 g paracetamol. In all cases, doses were taken as required up to a maximum of 4 doses per day for 5 days. The total consumption of analgesics was very similar in the two groups (flupirtine group 6.65 +/- 1.14 doses, paracetamol group 6.85 +/- 1.05 doses), as was the incidence of nausea and/or vomiting on each day of the attack. Despite an initial pain level on the first day of the migraine attack which was significantly higher in the flupirtine group, there were trends for flupirtine patients to show subsequently lower pain scores and to suffer less restriction of working ability and confinement to bed. Symptoms and possible side-effects were minor and infrequent in both treatment groups. Four symptoms were reported by 4 patients during flupirtine treatment and 7 symptoms by 5 patients during paracetamol treatment.

Comparative clinical trial of bemetizide/triamterene and cyclopenthiazide/potassium chloride combinations in patients with mild to moderate hypertension.

A double-blind trial was carried out to compare the combination of 25 mg bemetizide plus 50 mg triamterene ('Hypertane') and 0.25 mg cyclopenthiazide plus 600 mg potassium chloride ('Navidrex' K) in the treatment of mild to moderate essential hypertension. Two well matched groups of patients were treated for periods of 6 weeks with one or other of the drugs under test. There were 2-week placebo run-in and run-out periods. Blood pressure and laboratory investigations were performed every 2 weeks during the trial period. Both treatments resulted in similar overall statistically significant reductions in blood pressure during the trial. With bemetizide/triamterene, mean lying blood pressure decreased by 11.1/11.2 mmHg and mean standing blood pressure by 15.9/10.3 mmHg; with cyclopenthiazide/potassium chloride the corresponding reductions were 14.9/12.1 mmHg and 9.1/11.7 mmHg. The fact that some of the observed overall reduction seen with both drugs was due to 'placebo effect' is discussed but the clinical importance of overall changes is stressed. There were no significant differences between changes in blood pressure with the two treatments. Biochemical changes were those expected with thiazide diuretics. However, the decrease in potassium and increases in urea and uric acid levels were less with bemetizide/triamterene than with cyclopenthiazide/potassium chloride. Clinical tolerance of both treatments was good.

Studies of the haemodynamic effects of creatine phosphate in man.

1 The haemodynamic effects of intravenous creatine phosphate 1000 mg have been studied. 2 During the first 60 min following drug administration heart rate and blood pressure did not change but cardiac output fell significantly by approximately 18%. Calculated total peripheral resistance showed a corresponding significant rise, the maximum increase being approximately 24%. All these changes were beginning to diminish within 90 min after the injection. 3 Total limb blood flow measured in both arm and leg (using venous occlusion strain-gauge plethysmography) showed no appreciable changes following injection of creatine phosphate. 4 There was a progressive reduction in leg muscle blood flow (Xe133 clearance method) following injection which was statistically significant with respect to the initial level and reached a minimum (46% reduction) 50 min after the injection. 5 Skin blood flow, estimated by infra-red photoplethysmography, showed changes complementary to those seen with muscle flow. There was a progressive and significant rise to a peak (73% increase) 30 min after the injection. 6 No adverse reactions to the injections were noted. 7 Reduced cardiac output in the absence of altered total limb blood flow presumably reflects a reduction in visceral blood flow, which was not measured in this study. Within the limbs, creatine phosphate appears to result in a redistribution of blood flow from muscle to skin. Thus, these preliminary results suggest that intravenous creatine phosphate could be clinically useful in situations where short term improvement in skin blood flow would be advantageous and that further controlled studies would be justified.

A study of the antihypertensive action of xipamide using ambulatory intra-arterial monitoring.

1 The antihypertensive activity of the diuretic xipamide has been studied in 18 patients with mild/moderate essential hypertension using the technique of continuous ambulatory intra-arterial blood pressure recording. Full data from 48 h blood pressure recordings before and after treatment were available from 13 patients. 2 After a mean period of 3 months' treatment with xipamide 20 mg once daily, both systolic and diastolic blood pressure were markedly reduced throughout the whole 24 h day, the reductions of systolic being statistically significant throughout the whole period, and of diastolic for 19 out of the 24 hourly periods measured. There was no postural hypotension seen during treatment and there was a conspicuous lack of side effects. 3 Xipamide would appear to be as effective as many beta-adrenoceptor blockers but without their side effects and produces a better control of blood pressure throughout the whole day and night.

A double-blind controlled trial of mianserin and amitriptyline in depression.

A double-blind trial was carried out in 47 patients with depression to compare the effectiveness of 30 mg mianserin, 60 mg mianserin and 50 mg sustained-release amitriptyline, each given as a single dose at night over a period of 4 weeks. Hamilton Rating Scale scores showed significant, progressive improvement from Week 1 with all three regimens. Although the differences between the groups were not significant, the greatest improvement occurred after 60 mg mianserin daily and the order of effectiveness was consistent for various Hamilton Rating Scale items. Patient self-assessment, using visual analogue scales, gave similar results to the Hamilton Rating Scale with significant, progressive improvement in all groups. Once again, a consistent order of effectiveness was evident with most of the items, the greatest improvement being noted with 60 mg mianserin daily and the least with 30 mg mianserin daily. There was a considerable reduction in the number of reports of symptoms recorded before the trial during treatment in all groups. The only increase in symptoms possible drug-related was of blurred vision in patients receiving amitriptyline.

An effective conscious animal model of atrial fibrillation.

In 11 fully conscious dogs with chronically implanted spicardial electrodes, 50 Hz sine-wave electrical stimulation of the left atrium reliably and repeatedly produced an arrhythmia which was indistinguishable from atrial fibrillation in terms of its ECG appearance, the statistical properties of the ventricular response and responses to a number of pharmacological agents. In five of the 11 preparations this arrhythmia consistently persisted for periods in excess of 10 min following the cessation of stimulation, indicating an intrinsic cardiac basis for the arrhythmia and suggesting that it is true atrial fibrillation. A close correlation between the ventricular response to this arrhythmia and the degree of atrioventricular conductivity, together with the observation that dramatic changes can occur in ventricular responses without corresponding changes in atrial activity, suggest that the ventricular response is mainly a function of the atrio-ventricular conducting system. The experimental model described is useful for the study of both short and long term drug action no atrial fibrillation and for the evaluation of methods used therapeutically in attempts to terminate episodes of paroxysmal atrial fibrillation.