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OBJECTIVE—To determine the proportion of the population, firstly, with cholesterol ⩾ 5.0 mmol/l and, secondly, with any cholesterol concentration, who might benefit from statin treatment for the following: secondary prevention of coronary heart disease (CHD); primary prevention at CHD risk 30%, 20%, 15%, and 6% over 10 years; and primary prevention at projected CHD risk 20% over 10 years (CHD risk at age 60 years if actual age

Intermittent claudication is a common condition of the elderly, occurring in 3 to 20% of individuals over the age of 65 years. Although local disease is usually benign, life expectancy in patients with intermittent claudication is reduced by approximately 10 years due to associated cardiovascular mortality. Several classes of drugs have been used in intermittent claudication, but clinical studies evaluating their efficacy leave much to be desired. Pentoxifylline (oxpentifylline), a rheological agent, and naftidrofuryl, an enhancer of aerobic metabolism, are the 2 most widely investigated and utilised drugs. The combined results of 10 placebo-controlled studies with pentoxifylline and 4 with naftidrofuryl estimate increases in claudication distances of 51 and 42%, respectively. How-† The views expressed in this article are those of the authors and should not be taken to represent the official view of the UK Medicines Control Agency. ever, due to publication bias, these figures are probably overestimates of the true benefit from treatment with these drugs. It is likely that any benefit from pentoxifylline or naftidrofuryl is small and of little clinical importance. The suggestion that naftidrofuryl has greater efficacy in older patients remains unproven. Other classes of drugs including vasodilators, antiplatelet drugs, anticoagulants and prostaglandins have not been shown to be effective. Only 2 approaches to the management of intermittent claudication have been shown convincingly to be of benefit: stopping smoking and exercising regularly.

Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients.The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method.The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin's beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years.Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.

1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.

One hundred and thirty five non-smoking hypertensive patients with ACE inhibitor cough confirmed by lisinopril rechallenge and placebo dechallenge were recruited into a double-blind random parallel-group comparison of losartan 50 mg, lisinopril 20 mg and hydrochlorothiazide 25 mg each given once daily for a maximum of 8 weeks. The aim of the study was to compare the incidence of cough with the angiotensin II antagonist losartan, the ACE inhibitor lisinopril and the hydrochlorothiazide in hypertensive patients with previous ACE inhibitor cough. Cough detected by self-administered questionnaire was the primary end-point, and cough frequency by visual analogue scale a secondary end-point. The incidence of cough with losartan (29%) was lower than that for lisinopril (72%, P0.01) and similar to that for hydrochlorothiazide (34%). Cough frequency by visual analogue scale was lower for losartan than lisinopril (P0.01) and similar to that for hydrochlorothiazide. The specific selective AT1 angiotensin II receptor antagonist losartan is significantly less likely than lisinopril to cause cough in patients who previously have had ACE inhibitor cough. ACE inhibitor cough is likely to be related to non-specific kininase II inhibition.

There is a strong association between cigarette smoking and accelerated hypertension. In mild hypertension smoking cigarettes has a distinct pressor effect and caffeine a small but more prolonged pressor action. Coffee and cigarette smoking together have an additive effect on blood pressure (BP). We have examined the interaction of cigarette smoking and drinking coffee on the BP of six patients who presented with accelerated hypertension (mean BP 240/140 mm Hg) and were heavy smokers and caffeine users. After initial control of the BP, the effects of smoking alone, coffee plus smoking, and placebo were examined in a balanced cross-over study. Baseline BP averaged 154/91 mm Hg and remained stable for 90 min after abstention from smoking and caffeine (placebo). Cigarette smoking without caffeine caused a modest rise in BP (mean 9/8 mm Hg), but the combination of coffee plus cigarette smoking caused a progressive increase in BP to an average 21/17 mm Hg (P0.05/P0.002) higher than placebo values. The effect of coffee was significantly additive to that of smoking alone. Smoking plus coffee ingestion shifted the BP from acceptable (155/94 mm Hg) to poor control (175/107 mm Hg). This pressor effect was observed despite treatment, and with amounts of caffeine and cigarettes which were in no way unusual for these patients. We propose that the association of cigarette smoking with accelerated hypertension may reflect an extreme pressor effect of combined smoking and caffeine use in some patients.

Hyperventilation is an important feature of panic disorder, and an association has been reported between panic disorder and hypertension. We have examined the effect of hyperventilation on the blood pressure (BP) of healthy subjects. Twenty six subjects were randomised in a balanced two-period cross-over study to compare the effects of hyperventilation with that of normal breathing on sitting BP, heart rate and the electrocardiogram. Each study phase lasted 40 min, with 15 min of baseline observation, 5 min of hyperventilation or normal breathing, and 20 min of continued observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P0.01), diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P0.05), mean arterial pressure by 10.0 mm Hg (95% CI 3.3-16.7, P0.01) and heart rate by 36 beats/min (95% CI 31-44, P0.01). The changes in diastolic and mean arterial pressure correlated significantly with the total volume of air expired during hyperventilation (r = 0.57, p0.01 and r = 0.50 P0.01, respectively), but not with the change in expired carbon dioxide. In the electrocardiogram, T wave changes occurred in the inferior leads in 10 of 26 subjects, but there were no significant changes in other measurements. Hyperventilation significantly increased the BP of healthy subjects, and the role of hyperventilation in the link between panic disorder and hypertension deserves further study.

To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic).An international, multicentre, randomized double-blind, parallel-group controlled trial.Outpatient clinics at 20 tertiary care medical centres in 11 countries.One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study.After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks.Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale.The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide.The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

Summary A 43 year old man with inoperable aortic coarctation and severe hypertension requiring near maximal anti-hypertensive treatment was admitted in severe heart failure. After 2 weeks of treatment the heart failure and blood pressure were incompletely controlled and angiotensin converting enzyme (ACE) inhibitor was started. Serum creatinine was normal before starting the ACE inhibitor and on discharge from hospital. The patient was re-admitted a week later with gross fluid retention and in renal failure. In the absence of alternative causes, a diagnosis of ACE inhibitor-induced renal failure was made and treatment was stopped. The patient required haemodialysis for 2 days and within 1 week the renal function had reverted to normal and has remained so for 1 year. We propose that the renal haemodynamics in severe aortic coarctation are similar to those in bilateral severe renal artery stenosis and advise caution in the use of ACE inhibitors for adults with aortic coarctation.

To compare low-dose thiazides to beta-blockers, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and alpha-blockers for simplicity, tolerability, efficacy, safety and cost-effectiveness as first-line treatment for hypertension.Review of short-term comparative studies, and the outcome of long-term trials with vascular complications of hypertension as endpoints. SIMPLICITY: Among the advantages of thiazides are a flat dose-response; no dose titration; effectiveness when used once a day; no first-dose hypotension; and few contra-indications.Thiazides are the best tolerated agents in patients over the age of 60 years and in younger women. They sometimes cause gout and impotence in younger men, in whom beta-blockers are equally acceptable first-line therapy.Thiazide-based regimens have consistently reduced vascular complications of hypertension, the real measure of efficacy. There is little evidence that regimens based on other drugs are effective in this sense.Concerns that thiazide-induced biochemical changes cause coronary events are baseless. An overview of outcome trials shows that thiazide-based treatment reduces coronary events significantly, and the reduction is not significantly different from that predicted by epidemiological data. Thiazide-based therapy has also reduced coronary events significantly and substantially in elderly patients with isolated systolic hypertension.Low-dose thiazide treatment needs minimal monitoring, and has proved most cost-effective in formal analyses.Low-dose thiazide treatment is a clear first-line choice for patients aged over 60 years and younger women, except those with diabetes or gout. In younger men there is little to choose between thiazides and beta-blockers.

OBJECTIVE--To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication. DESIGN--Randomised controlled double blind four way crossover trial. SETTING--Royal Hallamshire Hospital, Sheffield. SUBJECTS--49 patients (40 men) aged 39-70 with chronic stable intermittent claudication. INTERVENTIONS--Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments. MAIN OUTCOME MEASURES--Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales. RESULTS--Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes. CONCLUSIONS--There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.

The prevalence and severity of cough during long-term enalapril treatment were examined by comparing a cohort of 136 hypertensive patients who started treatment with enalapril with consecutive age and sex-matched patients who commenced nifedipine therapy during the same period. Cough and other symptoms were assessed by a questionnaire designed to avoid bias towards reporting cough. After a mean of 27 months' treatment patients on enalapril had an excess of persistent cough (16 per cent, 95 per cent CI 7-25, p less than 0.01), voice change (14 per cent, 95 per cent CI 2-27, p less than 0.05) and sore throat (10 per cent, 95 per cent CI -0.1 to 20.3 per cent, p less than 0.01) when compared to nifedipine-treated patients. The cough was usually dry, moderate or severe, paroxysmal, and troublesome at night. Cough tended to be more common in women (23 per cent vs. 7.2 per cent), non-smokers, and at higher doses of enalapril, but was not related to age, duration of treatment, or chronic respiratory disease. Dry cough commonly persists as a troublesome side-effect during long-term enalapril treatment, and is often associated with voice change and sore throat.

In a cohort of 136 hypertensive patients started consecutively on enalapril the incidence of persistent dry cough by life-table analysis was 14.6% (95% CI 10.2-19.0%). The incidence in women (19.2%; 95% CI 11.3-27.1%) was twice that in men (9.7%; 95% CI 6.6-12.8%). Dry cough was unrelated to age, smoking habit, renal function, or the dose and duration of enalapril treatment. In one half of patients who developed cough enalapril had to be stopped. The incidence of withdrawal due to cough was 6.0% (95% CI 4.5-7.5%), and cough was by far the most common reason for discontinuing enalapril treatment. Reviewing previous studies of enalapril-induced cough, it is evident that postmarketing surveillance studies have grossly underestimated the incidence and importance of this side-effect. Surveys in hospital clinics have slightly underestimated the true incidence through failure to use life-table methods of analysis.

Summary The association between haemospermia and hypertension was examined in a case-control study comparing 5 hypertensive patients with haemospermia to 20 age-matched hypertensive men. Patients with haemospermia had much higher blood pressures than hypertensive controls (200/131 mmHg vs 147/90 mmHg; P < 0.0005/P < 0.0001), higher left ventricular voltage on ECG (P < 0.02), and higher concentrations of serum creatinine, proteinuria and renovascular disease (all P = 0.06 vs controls). Haemospermia is associated with severe uncontrolled hypertension. It is not, however, associated with hypertension per se, as the prevalence of hypertension in published series of patients with haemospermia is no higher than that expected in the general population. Men presenting with haemospermia should have their blood pressure measured carefully as they may require antihypertensive treatment urgently.

1 Consecutive medical inpatients expected to benefit from a theophyllinate were treated with sustained-release aminophylline in a protocol conforming with ordinary practice. Of 16 patients, five had toxicity with aminophylline 450 mg daily, and a further three with 900 mg daily. Toxicity was serious in three patients. 2 Toxicity was significantly less common in cigarette smokers, and was related to higher plasma theophylline concentrations. However, there was a large overlap between concentrations associated with toxicity (as low as 9 micrograms/ml) and the accepted therapeutic range (5-20 micrograms/ml). Most patients with toxicity had theophylline levels within the therapeutic range. 3 For the same dose of aminophylline there was sevenfold variation between patients in plasma theophylline, with higher concentrations in non-smokers, infrequent alcohol users, older patients, those with left ventricular failure and those with lower serum transaminases. There variables could not be separated completely because of the small number of observations. 4 A nomogram for aminophylline dosage or monitoring of serum theophylline levels would have prevented little of the toxicity observed in these patients, although these measures would ensure that therapeutic concentrations were attained, and might prevent life-threatening toxicity.

Summary It has been proposed that idiopathic retroperitoneal fibrosis may be a consequence of ‘healed’ retroperitoneal lesions of systemic Weber-Christian disease. However ureteric obstruction which is the hallmark of idiopathic retroperitoneal fibrosis, has not been described in systemic Weber-Christian disease. We report a patient with systemic Weber-Christian disease who, during a relapse, developed bilateral ureteric obstruction which resolved when the Weber-Christian disease remitted. The radiological appearances were consistent with a diagnosis of idiopathic retroperitoneal fibrosis, but the clinical course was slightly atypical in that the ureteric obstruction resolved completely and rapidly. Ureteric obstruction can complicate systemic Weber-Christian disease and this observation gives support to the hypothesis that idiopathic retroperitoneal fibrosis is related to systemic Weber-Christian disease.

The true incidence of the lupus syndrome induced by hydralazine was determined in a longitudinal study of 281 patients consecutively starting hydralazine for hypertension over a 51 month period. Data on the duration of treatment and the maximum dose achieved were examined using life table analysis. After three years' treatment with hydralazine the incidence of the lupus syndrome was 6.7% (95% confidence limits 3.2-10.2%). The incidence was dose dependent, with no cases recorded in patients taking 50 mg daily and incidences of 5.4% with 100 mg daily and of 10.4% with 200 mg daily. The incidence was higher in women (11.6%) than in men (2.8%). In women taking 200 mg daily the three year incidence was 19.4%. Hydralazine is an effective antihypertensive drug that has come to be used in restricted dosage (not more than 200 mg daily) because of its risk of inducing the lupus syndrome. This study shows that the true incidence of the syndrome is still unacceptably high even when the drug is prescribed according to current recommendations.

There is a correlation between body weight or obesity and blood pressure in the population, and most hypertensive patients are overweight. Weight reduction of 6 kg or more reduces blood pressure by an average of 15/9 mmHg even if the ideal body weight is not attained, and this is not explained by changes in salt intake or by measurement artefact due to the fat arm. Some form of calorie restriction is the mainstay of managing obesity in hypertensive patients, and those referred to a dietitian lose significantly more weight tham those given a diet sheet by a doctor or given no specific advice. About 50% of patients referred to a dietitian reduce their body weight by 6 kg or more. There is a tendency to regain weight in the long-term, but after four years more than one third of patients remain at least 6 kg below their initial weight. Men seem to lose relatively little weight whether or not they are referred to a dietitian, whereas women referred to a dietitian achieve substantial and sustained weight loss.

Treatment of 6 healthy adult men with a beta-blocker, timolol, resulted in a rise in serum phosphate which was maintained for the 5 days of therapy. This rise was accompanied by a transient fall in urine phosphate and a rise in the tubular maximum for phosphate reabsorption per unit glomerular filtration rate (TmPO4/GFR). No change in circulating parathyroid hormone or growth hormone could be demonstrated.

Summary In hypertensive patients single doses of ketanserin 40 mg prolonged the corrected QT interval (QTc) for at least 8 hours, with a maximal increase of 35 ms (P less than 0.001, n = 6) after 2 hours. During chronic dosing (20 and 40 mg b.d.) the QTc was further prolonged, by 46 and 45 ms respectively. QTc prolongation after treatment with a mean dose of 73 mg/day for 7 weeks (n = 26) was significantly related to body weight (r = -0.58, P less than 0.01), and to the dose of ketanserin corrected for body weight (r = 0.63, P less than 0.01), but not to plasma concentrations of ketanserin, ketanserinol, potassium or calcium. High doses of ketanserin (mean dose 167 mg/day, n = 9) increased the QTc by 40 ms (P less than 0.001), with prolongation of up to 80 ms in individual patients. Treatment with ketanserin at doses proposed for clinical use (40-80 mg/day) may carry a risk of ventricular arrhythmias.

Summary Two cases of gastrointestinal bleeding in patients being treated with continuous-release aminophylline tablets are reported.

Data showing a linear relationship between spironolactone dose and the levels of canrenone in plasma and urine are presented to support the use of canrenone levels as a measure of the bioavailability of spironolactone. The bioavailability of a selected batch of spironolactone 25 mg tablets was compared to that of an oral aqueous suspension of spironolactone in a separate balanced cross-over study involving 10 healthy subjects. The tablets were equivalent to suspension as regards area under the plasma concentration-time curve and total urinary excretion of canrenone, the prinicipal unconjugated metabolite of spironolactone. Peak plasma concentrations of canrenone were higher, and were attained significantly earlier, after treatment with spironolactone in suspension. The results indicate that spironolactone was absorbed more rapidly from the suspension, but that the total absorption did not differ between the two formulations.

In general medical patients presenting with suspected deep vein thrombosis routine use of x ray venography was associated with a large fall in the proportion of patients with a final diagnosis of deep vein thrombosis, from 83% to 25% (p less than 0.001), and with an appreciable shortening of hospital stay, from 13.6 to 7.2 days. The diagnosis of deep vein thrombosis was rejected in only 4% of patients when a venogram was not performed, and it is estimated that two patients were treated with anticoagulants unnecessarily for every patient treated correctly. The risk, expense, and inconvenience of unnecessary anticoagulant treatment far exceeds the risk, expense, and inconvenience of performing venograms routinely. The common practice of misdiagnosing deep vein thrombosis clinically should be abandoned.

Non-gouty arthritis is quite common in hypertensive populations and there have been suggestions that drugs used to treat hypertension may be the cause. This possibility has been investigated in a case-control study. We identified 127 hypertensive patients with arthritis other than gout and matched them for age and sex to 254 hypertensive controls who did not have arthritis. Use of antihypertensive drugs was similar in cases and controls for all patients, and for those with undiagnosed arthritis. There was no significant excess use of any type of antihypertensive drug by cases with arthritis. These findings do not support the hypothesis that drug treatment for hypertension commonly causes arthritis. It is more likely that hypertension and arthritis occur together frequently because non-steroidal anti-inflammatory drugs raise blood pressure, and because both problems are common in middle-age.

Summary A case of ventricular tachycardia occurring after intravenous injection of sodium iothalamate (Conray 420) into a patient taking prenylamine is described. Both of these drugs may cause prolongation of the corrected QT interval and the mechanisms of this potentially fatal drug interaction are discussed.

The development of methods to allow the quantitative comparison of aldosterone antagonists in healthy men is reviewed. Pharmacological action is measured against a background of mineralocorticoid excess, induced either by administration of exogenous mineralocorticoid (usually aldosterone or fludrocortisone), or by stimulation of endogenous mineralocorticoid using salt restriction, diuretic administration, or a combination of the two. Use of fludrocortisone as the exogenous mineralocorticoid has proved convenient and useful, but the influence of aldosterone antagonists on potassium metabolism has proved somewhat inconstant in this experimental model. Repeated administration of a medium-potency diuretic appears to provide a clinically relevant situation in which the effect of aldosterone antagonists on potassium metabolism can be assessed. We describe these experimental methods in detail, discuss their applications, and make some suggestions for further research.

Antihypertensive efficacy and tolerability of the dihydropyridine calcium antagonist nisoldipine were examined in a double-blind, placebo-controlled study. Twenty patients with hypertension (greater than 140/95 mmHg) uncontrolled by bendrofluazide plus atenolol were randomly allocated to receive nisoldipine, 10-20 mg daily, or placebo for six weeks. Nisoldipine, compared with placebo, lowered blood pressure (BP) by 31/21 mmHg (P less than 0.02/P less than 0.002) after two weeks. Thereafter its antihypertensive effect declined to 20/9 mmHg (NS/NS) at four weeks and 8/3 mmHg at six weeks (NS/NS). Compared with placebo, the rise in BP with nisoldipine during the last four weeks of the trial was highly significant (P less than 0.005). During this period BP rose by 14/11 mmHg (P less than 0.05/P less than 0.02) in the nisoldipine group so the apparent loss of effect was not attributable to a fall of BP in the placebo group. Compliance, as assessed by tablet counts, was satisfactory and nisoldipine treatment did not cause significant weight gain. The drug was not well tolerated and three patients withdrew from treatment because of side-effects. Tolerance to the antihypertensive effect of nisoldipine appears to develop rapidly and further studies should be performed to confirm this, and evaluate the mechanism.

Summary The antihypertensive effect of the selective serotonin antagonist ketanserin was examined in a double-blind, placebo-controlled, parallel group study in 20 patients with essential hypertension. After 7 weeks treatment with ketanserin (mean dose 71 mg/d) there was a significant fall of both systolic and diastolic blood pressure, as compared to placebo, with a peak effect of 19.1/9.1 mmHg lying (P < 0.01/P < 0.01), and 16.5/11.3 mmHg standing (P < 0.01/P < 0.01); twice daily dosage appeared satisfactory. Subjective side effects were similar in the ketanserin and placebo groups. Ketanserin is an effective antihypertensive drug of moderate potency when given twice daily, with no orthostatic effect.

Hydralazine, labetalol, methyldopa, minoxidil, prazosin and placebo were compared when added to atenolol 100 mg and bendrofluazide 5 mg daily in hypertensive patients inadequately controlled by the beta-blocker/diuretic combination. Atenolol was withdrawn in those allocated to labetalol and minoxidil was given only to men. The order of acceptability was: placebo, hydralazine, prazosin, methyldopa, minoxidil, labetalol. All the active agents were more effective than placebo. Minoxidil was more effective than the other active drugs, which had similar potency to one another. Hydralazine was the most generally suitable third drug, with prazosin a close second. Minoxidil was effective in the milder hypertensives, but in the present regimen caused fluid retention in those with more severe hypertension. Labetalol probably should be introduced at lower dose (150 mg daily) even as replacement for full doses of a previously administered beta-blocker.

A retrospective survey of serum potassium measurements in a blood pressure clinic provided evidence that potassium supplements averaging 24 mmol daily were effective in elevating serum potassium concentration and reducing the incidence of hypokalaemia in diuretic-treated hypertensives. In patients treated with bendrofluazide the serum potassium concentration was related to the dose of diuretic, but not to age, sex, body weight, supine blood pressure or serum creatinine. There was no evidence that drugs other than diuretics or potassium (including beta-adrenergic blockers) had a clinically significant influence on serum potassium. The major part of the variation in serum potassium between patients could not be explained by the variables examined.

Factors predisposing to diuretic-induced acute gout were investigated in a case-control study. Seventy hypertensive patients with acute gout occurring during diuretic treatment were identified and matched for age and sex to 140 hypertensive controls who took diuretics but did not develop gout. Gout was related more strongly to the use of loop diuretics than thiazides, with 30% of cases taking a loop diuretic compared to 14% of controls (P less than 0.01). In a sub-group of men who took a thiazide and no other diuretic, gout was significantly associated with obesity (odds ratio 3.7, 95% confidence interval 1.4, 9.1) and high alcohol intake (odds ratio 3.3, 95% confidence interval 1.1, 9.8). In these patients, 23% of gout was attributable to obesity and 16% to high alcohol consumption. Approximately 40% of acute gout might have been prevented by avoiding thiazides in those 20% of men who weighed more than 90 kg and/or consumed more than 56 units of alcohol per week.

24 hour infusion of iloprost was compared with placebo infusion in 19 patients with stable intermittent claudication using a double blind, balanced crossover design. Despite significant inhibition of platelet aggregation to ADP and collagen (p less than 0.001) and the typical cardiovascular and gastrointestinal side effects, there was no significant effect on treadmill exercise times at any time up to 6 weeks after infusion. The 95% confidence limits indicated that an improvement of more than 25% was unlikely to occur. No significant changes in B thromboglobulin, platelet aggregate ratio, bleeding time, whole blood viscosity and euglobulin clot lysis time were demonstrated.

Summary In a retrospective study, based on a biochemical survey of people aged 65 and over in a general practice, subjects taking a barbiturate preparation for indications other than epilepsy had a significantly lower serum calcium concentration than did those taking nitrazepam or diazepam. Ordinary doses of barbiturate may adversely affect vitamin D metabolism in the elderly.

Summary In 93 patients with hypertension uncontrolled by bendrofluazide 5 mg plus atenolol 100 mg daily, the effects of adding nifedipine (up to 60 mg/day, n = 31), prazosin (up to 20 mg/day, n = 31), or hydralazine (up to 200 mg/day, n = 31) were compared in a 6 month open random parallel group study. The three drugs did not differ significantly as regards antihypertensive effect, withdrawal rate, total number of side effects, or effect on serum biochemical variables. The pattern of side-effects differed. Headache, flushing and oedema were common with nifedipine, tiredness and drowsiness with prazosin, and headache with hydralazine. Nifedipine is an acceptable third-line antihypertensive drug which may have some advantage over hydralazine and prazosin.

Une observation: nombreux infarctus dans les os des extremites chez un malade de 19 ans atteint de septicemie a meningocoques avec coagulation intravasculaire disseminee

Patients with mild hypertension who habitually smoked cigarettes and consumed caffeine were examined after they abstained from caffeine and cigarettes overnight. Their mean blood pressure (147/89 mm Hg) was substantially lower than values recorded in the clinic (164/102 mm Hg) and remained so when they continued to abstain (149/94 mm Hg at two hours). Smoking two cigarettes (3.4 mg nicotine) elevated blood pressure by 10/8 mm Hg, but for only 15 minutes. Drinking coffee (200 mg caffeine) elevated blood pressure by up to 10/7 mm Hg between one and two hours. Combined coffee ingestion and cigarette smoking caused a sustained rise in blood pressure from 5 to 120 minutes to levels similar to those measured in the clinic (162/102 mm Hg at two hours). Similar results were obtained in thiazide-treated patients. The interaction of coffee and cigarettes on blood pressure, but not on pulse rate, was significant. The pressor effect of cigarette smoking and caffeine ingestion in combination may be important in the evaluation of patients with mild hypertension.

A possible association between treatment with methyldopa and the occurrence of renal stones was sought by retrospectively comparing 54 hypertensive patients with calculi detected by X-ray examination with a control group matched for age and sex. Treatment with methyldopa was equally frequent in both groups. There was a significant excess of methyldopa use in a subgroup of 16 patients with bilateral calculi, but the drug could be the primary cause of stone formation in, at most, four of these patients. If methyldopa does cause renal stones, it is probably an uncommon event, but precipitation of the drug from the urine may worsen a tendency to stone formation, which will lead to a higher incidence of bilateral calculi.

Summary Two patients developed profound hypotension approximately one hour after taking an initial oral dose of ketanserin 40 mg. The reaction appeared similar to that reported with prazosin, and may have been due to the alpha 1-adrenoceptor antagonist action of ketanserin. Both patients were taking regular beta-blocker therapy, which may exacerbate such a reaction.

The beta adrenergic blocking drug, timolol, tended to correct the hypokalemia of short-term bendrofluazide treatment in 6 healthy male subjects and although the effect was small it was significant. Timolol also reduced the rise in plasma aldosterone and urine potassium excretion following bendrofluazide and increased the urine sodium/potassium ratio. There was no evidence of a shift of potassium from the intracellular to the extracellular space.

Hyperuricaemia was present in 18 out of 73 men with untreated mild hypertension and was related significantly to alcohol intake, serum aspartate transaminase activity, and obesity. In the whole group the mean serum urate concentration correlated highly significantly with alcohol intake and activities of serum aspartate and alanine transferases but not with ponderal index, serum creatinine concentration, age, or blood pressure. Hypertension and hyperuricaemia are related at least in part through their common association with frequent alcohol use. A serum urate concentration exceeding 0.5 mmol/l (8--4 mg/100 ml) in a man with untreated hypertension is highly suggestive of heavy alcohol consumption. There was no evidence that hyperuricaemia had a deleterious effect on renal function.