S. George Carruthers

Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

BACKGROUND Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Treatment of pruritus in primary biliary cirrhosis with rifampin

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity

Diurnal, day‐to‐day, intrasubject, and intersubject variability of responsiveness of dorsal hand veins to norepinephrine has been investigated in healthy young subjects through the use of a novel technique in which a linear variable differential transformer (LVDT) is placed directly over the vein. Under constant operating conditions, control vein diameter remained consistent. There is log dose responsiveness to norepinephrine infused directly into the hand vein. There was little diurnal, day‐to‐day, or intrasubject variability in the dose of norepinephrine required to induce 50% constriction of hand vein diameter. The responsiveness to norepinephrine of different veins in either hand was also consistent. However, there was wide intersubject variability, apparently unrelated to age, gender, or other subject characteristics. We conclude that the LVDT method is reproducible and reliable and offers a relatively noninvasive means of assessing the effects of disease and drugs on the human dorsal hand vein in vivo. The LVDT technique has been applied to study the rate of onset, magnitude of effect, dose responsiveness, and duration of action of intravenous dihydroergotamine, 0.1, 0.2, and 0.4 mg, on human dorsal hand veins. Despite systemic intravenous administration, there was an average delay in maximum response of 30 minutes to 1 hour. Venoconstriction was incomplete, with a maximum reduction of approximately 50% of vein diameter after each of the larger doses. There was no significant difference between the effects produced by 0.2 or 0.4 mg, which persisted for 6 hours after dosing.

Phenytoin-Theophylline Interaction

Theophylline (1,3-dimethylxanthine) is a constituent of numerous bronchodilator preparations and is widely used in the treatment of patients with obstructive airways disease. Its metabolism is comp...

The influence of age on dorsal hand vein responsiveness to norepinephrine

The influence of age on the responsiveness of dorsal hand vein α‐receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein α‐receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.

Genetic aspects of variability in superficial vein responsiveness to norepinephrine

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose‐related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady‐state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose‐concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of “tissue responsiveness” (i.e., vascular a‐adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.

Respiratory and cardiac effects of metoprolol and bevantolol in patients with asthma.

The effects on standing heart rate and respiratory function of two relatively selective β1‐adrenoceptor antagonists, metoprolol and bevantolol, were compared in a double‐blind, randomized, crossover study of 16 patients with asthma. After control observations on 2 separate days, the patients received approximately equivalent cardiac β‐adrenoceptor antagonist doses of metoprolol, 12.5, 25, 50, and 100 mg, and bevantolol, 18.75, 37.5, 75 and 150 mg, at intervals of 2 hours. Dosing was stopped if symptoms warranted or if there was a fall of ≥20% in the forced expiratory volume in 1 second. In general, the cumulative dosing regimen proved a safe and effective means of assessing bronchial responsiveness to these β‐blockers in asthma, but one patient had to be dropped from the study because of severe bronchoconstriction after the first dose. Of the 15 patients studied who were taking both drugs, seven patients were withdrawn prematurely. In these seven patients, the average maximum tolerated cumulative doses were 45.5 mg bevantolol and 26.8 mg metoprolol, doses that are much lower than those usually required for therapeutic activity. The respiratory response to either drug could not be predicted.

Measurement of partial agonist activity of pindolol

The partial agonist activity of pindolol was assessed by examining the action of cumulative doses on the heart rates of resting, standing, and exercising healthy men and by studying the interaction of pindolol with metoprolol, a beta blocker devoid of partial agonist activity. Pindolol did not affect resting or standing heart rates (RHR, SHR) but reduced the heart rate after vigorous exercise by approximately 25%. The flatter dose‐response curve of pindolol for exercise heart rate (EHR) has been reported for practolol and oxprenolol, which also exert partial agonist activity. After extremely large doses of pindolol there was no evidence of enhancement of agonist activity on RHR, nor was there any evidence of dominance of agonist activity over antagonist activity on EHR. Metoprolol did not alter RHR but reduced SHR by approximately 20% and EHR bx approximately 31%. The effects of pindolol on SHRs and EHRs were not enhanced by metoprolol, even though the drug bx itself induced greater reductions of both. The reduction of SHR bx metoprolol was reversed by pindolol. Pindolol appears to have greater affinity than metoprolol for atrial beta adrenoceptors in man.

Pindolol and propranolol in patients with angina pectoris and normal or near-normal ventricular function: Lack of influence of intrinsic sympathomimetic activity on global and segmental left ventricular function assessed by radionuclide ventriculography

To investigate the role of intrinsic sympathomimetic activity on left ventricular (LV) function during antianginal therapy with beta-adrenoreceptor antagonists, 23 patients with chronic, exercise-induced angina pectoris and normal or near normal LV function underwent radionuclide ventriculography at rest and during exercise, during 3 randomly allocated periods: (a) treatment with oral propranolol, a drug without intrinsic sympathomimetic activity, 40 to 80 mg 4 times a day; (2) treatment with pindolol, a drug with marked intrinsic sympathomimetic activity, 5 to 10 mg 2 times a day; and (3) a control period. During the control period, the LV ejection fraction decreased from rest (58.9 +/- 8.2%) to exercise (54.3 +/- 10.7%), and the wall motion score decreased from 0.57 +/- 1.08 at rest to 2.39 +/- 2.10 during exercise, p less than 0.001. After propranolol, the ejection fraction did not change significantly at rest (57.2 +/- 8.1%) but improved during exercise (56.8 +/- 11.8%), compared with control values. After pindolol, the ejection fraction did not change at rest (57.9 +/- 8.6%) but improved during exercise (56.9 +/- 8.1%), compared with control values. Similarly, the wall motion score after administration of both agents did not change significantly at rest, but improved during exercise (p less than 0.001). The number of anginal episodes, nitroglycerin tablets consumed, and magnitude of S-T segment depression decreased significantly with both pindolol and propranolol. With both drugs, a similar improvement in exercise tolerance and a similar decrease in exercise heart rate and blood pressure were obtained. It is concluded that pindolol and propranolol, beta-adrenoreceptor antagonists with and without intrinsic sympathomimetic activity, respectively, have similar effects on global and regional LV function in patients with angina pectoris, at doses producing equal suppression of exercise heart rate and similar antianginal effect.

Elevation of serum total cholesterol and triglyceride levels during amiodarone therapy

Over the last decade there has been increasing awareness that some cardiovascular medications may adversely affect serum cholesterol concentrations. It has been suggested previously that amiodarone may alter serum cholesterol, triglyceride and glucose concentrations, but no substantive data support this observation. During the course of a 1-year study of adverse effects in patients taking amiodarone, 21 patients with normal total serum cholesterol before entry in the study were prospectively investigated for changes in lipid metabolism. A statistically significant sustained rise of 17% in total serum cholesterol occurred from a baseline of 178 +/- 7 mg/dl (4.6 +/- 0.2 mmol/liter) to 208 +/- 9 mg/dl (5.4 +/- 0.2 mmol/liter). Ten of the patients developed elevations of cholesterol above the 75th percentile for their age and sex. This group experienced a sustained rise of 20% in mean cholesterol concentration from baseline, had statistically significant elevations of triglyceride concentrations and had higher glucose and desethylamiodarone concentrations than patients who did not develop elevations in cholesterol greater than the 75th percentile. It may be possible to predict these differences in response as early as 4 to 8 weeks after starting therapy. Because amiodarone is increasingly used in patients without ischemic heart disease or life-threatening arrhythmias, the potential atherogenic risk of these metabolic abnormalities merits further investigation.