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Objectives To compare blood pressure control during 7 days of drug omission in patients taking bendroflumethiazide 2.5 mg, nifedipine LA 30 mg or enalapril 20 mg once daily and, secondarily, to measure patient compliance. Methods Twenty-four patients with hypertension were assigned, in a random crossover fashion, to a sequence of bendroflumethiazide, nifedipine LA and enalapril, each for 4 weeks, followed by a 1-week period of dose omission. The patients measured their own blood pressure daily using an Omron 705CP monitor. Differences in blood pressure from baseline (mean blood pressure during week 4 on treatment) and the week of dose omission were compared between the three drugs. Patient compliance was measured using pill counts and the Medication Event Monitoring System. Results Bendroflumethiazide maintained blood pressure control during drug omission for longer than enalapril or nifedipine LA. The magnitudes of the increase in systolic blood pressure (SBP) between baseline and day 7 off treatment were 7.0, 12.2 and 9.7 mmHg for bendrofiumethiazide, nifedipine LA and enalapril, respectively. For diastolic blood pressure (DBP), the values were 2.9, 5.3 and 7.3 mmHg for bendroflumethiazide, nifedipine LA and enalapril, respectively. Differences in SBP between bendroflumethiazide and the comparator drugs occurred at day 2 off treatment. Differences in DBP between bendroflumethiazide and nifedipine were apparent on days 2 and 3 off treatment. Differences in DBP between bendroflumethiazide and enalapril were apparent on days 2, 3, 4 and 5 off treatment. Patient compliance throughout the study was high in terms of both taking the medication when required and omitting the medication when required. Conclusions Bendroflumethiazide maintained blood pressure control during a period of drug omission better than nifedipine or enalapril.

Background: Patients with chronic cardiac failure (CCF) have abnormal vascular responses. Bradykinin (BK) is thought to contribute to the vasodilator effects of ACE inhibitors, but the effect of BK itself in patients with CCF has not been examined. Methods: We studied the responses to infused BK at 10, 30 and 100 pmol min−1 in patients with CCF (n-10) and controls (n-10). The slope of the dose-response curve was used for comparisons between the groups. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results: Following BK, vasodilatation was observed in both groups as the slopes were positive in all, but the difference between the groups was not significant (P-0.77). The study was repeated with the co-administration of 4 μmol min−1 of NG-monomethyl l-arginine (l-NMMA). The vasodilator response to BK was reduced in both groups, and the effect was somewhat greater in the patient group (P-0.23). The vasodilator response to the endothelium-independent vasodilator sodium nitroprusside was slightly less in the patient group (P-0.08). The patients only then underwent repeat infusion of BK before and after a single oral dose of captopril 12.5 mg or placebo. Following captopril, the vasodilator response to BK was unchanged when compared to placebo (difference between slopes, P-0.53). Conclusions: BK produces dose-dependent vasodilatation in both patients with CCF and controls; there was no difference in the responses, which were antagonised by l-NMMA and therefore in part NO (endothelium)-dependent. The responses were also unchanged after administration of an ACE inhibitor (captopril).

BACKGROUND—Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM—To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS—22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS—Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p

The haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular blood flow leads to microvascular sclerosis and disturbed autoregulation. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide that contributes to basal vascular tone. Impairment of the vasoconstrictor response to ET-1 could result in hyperperfusion and subsequent microvascular damage. The purpose of this study was to determine whether vascular responses to ET-1 are impaired in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes). Ten patients with type 2 diabetes and nine control subjects underwent brachial artery cannulation. Forearm blood flow was measured using strain-gauge venous occlusion plethysmography. ET-1 in three doses of 5, 10, and 20 pmol/min and 0.9% saline placebo was infused in a balanced double-blind randomised manner. Vascular smooth muscle function also was assessed using sodium nitroprusside. Control subjects showed vasoconstriction to ET-1 of 5 (p0.05), 10 (p0.05), and 20 pmol/min (p0.01). In the diabetic group, there was no significant response to ET-1 at 5 pmol/min (p0.05); however, significant vasoconstriction developed at 10 and 20 pmol/min (p0.01). There was a significant difference in response to ET-1 at 5 pmol/min between the diabetic and control groups (p0.05). Responses to sodium nitroprusside were similar in both groups (p0.05). Patients with type 2 diabetes have a blunted vasoconstrictor response to ET-1 despite preserved vascular smooth muscle function.

In view of accumulating evidence of vascular pathology in Alzheimer’s disease (AD), we tested the hypothesis that AD patients have impaired endothelial function. This was assessed using the technique of strain-gauge venous occlusion plethysmography, which measures forearm blood flow (FBF). Intra-arterial (brachial) infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) was used to assess local endothelial dependent and independent responses, respectively. There was no difference in the basal FBF of patients and controls. ACh and SNP caused dose-related increases in FBF from baseline, but no difference was recorded between the AD and control group. This study provides no evidence of endothelial dysfunction in the systemic circulation of patients with AD.

To compare enalapril 20 mg once daily with 10 mg twice daily in terms of blood pressure reduction and patient compliance.Cross-over study of patients randomly assigned to a sequence of enalapril 20 mg once daily or 10 mg twice daily in three 4-week periods following a 4-week placebo run-in.General practices in the greater Belfast and Lisburn area in Northern Ireland.Twenty-five hypertensive patients who had a mean diastolic blood pressure of between 90 and 110 mm Hg after receiving placebo for 4 weeks.Reduction in blood pressure and estimation of patient compliance.Patient compliance was superior on the once daily regimen. However, the twice daily regimen was associated with a greater blood pressure reduction which almost reached statistical significance at the 5% level.Enalapril 20 mg should be prescribed as 10 mg twice daily and measures taken to improve patient compliance.

Use non-pharmacological measures in all hypertensive and borderline hypertensive people. Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP)/=160 mm Hg or sustained diastolic BP/=100 mm Hg. Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of/=15% according to the Joint British Societies CHD risk assessment programme/risk chart. In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained/=140 mm Hg or diastolic BP is sustained/=90 mm Hg. In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP140 mm Hg and diastolic BP85 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is150/90 mm Hg. Despite best practice, these levels will be difficult to achieve in some hypertensive people. In diabetic hypertensive people, optimal BP targets are; systolic BP140 mm Hg and diastolic BP80 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is140/90 mm Hg. Despite best practice, these levels will be difficult to achieve in some people with diabetes and hypertension. In the absence of contraindications or compelling indications for other antihypertensive agents, low dose thiazide diuretics or beta-blockers are preferred as first-line therapy for the majority of hypertensive people. In the absence of compelling indications for beta-blockade, diuretics or long acting dihydropyridine calcium antagonists are preferred to beta-blockers in older subjects. Compelling indications and contraindications for all antihypertensive drug classes are specified. For most hypertensives, a combination of antihypertensive drugs will be required to achieve the recommended targets for blood pressure control. Other drugs that reduce cardiovascular risk must also be considered. These include aspirin for secondary prevention of cardiovascular disease, and primary prevention in treated hypertensive subjects over the age of 50 years who have a 10-year CHD risk/=15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol/=5 mmol/L and established vascular disease, or 10-year CHD risk/=30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects. Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy). Suggestions for the implementation and audit of these guidelines in primary care are provided.

Summary Aims Familial aggregation of diabetes and nephropathy has been observed in several populations. Various interpretations have included underlying genetic mechanisms possibly mediated by a predisposition to hypertension. Endothelial dysfunction is now recognized as central to these conditions and offers a unifying mechanism to explain the disease aggregation. To test this hypothesis, we have examined endothelial function in healthy subjects at differing risks for diabetic nephropathy. Methods Endothelial function was assessed in 12 healthy offspring (nine male (M)/three female (F); age 25.8 ± 1.2 years, mean ± sem) of parents with Type 1 diabetes mellitus (DM) and end-stage renal disease compared with 12 control offspring (9 M/3 F; age 26.3 ± 1.3 years) of parents with long duration (> 20 years) Type 1 DM but without evidence of nephropathy. Forearm blood flow responses to brachial artery infusion of acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), noradrenaline and the competitive inhibitor of basal nitric oxide release NG-monomethyl- l-arginine were assessed using venous occlusion plethysmography. Results There were no significant differences between the groups in von Willebrand factor, fasting plasma glucose (4.2 ± 0.1 vs. 4.0 ± 0.2 mmol/l) or in 24-h ambulatory blood pressure. Similarly, the groups did not differ in vasodilation to acetylcholine (P = 0.75) and sodium nitroprusside (P = 0.79) or in vasoconstriction to noradrenaline (P = 0.45) and NG-monomethyl- l-arginine (P = 0.30). Conclusion These data do not support a role for endothelial dysfunction in the familial aggregation of diabetic nephropathy. Diabet. Med. 16, 298–303 (1999)

Objective—To study underlying vascular responses in chronic heart failure in patients without ACE inhibitor treatment, and to compare them with age matched controls. Design—Forearm blood flow was studied using venous occlusion plethysmography in patients with chronic heart failure (n = 12) and matched controls (n = 13), after infusion of L-NMMA (a nitric oxide synthase inhibitor), glyceryl trinitrate (an endothelium independent vasodilator), and serotonin (an endothelium dependent vasodilator). Results—L-NMMA produced significant vasoconstriction in normal subjects (forearm blood flow reduced by 24%), but not in patients (6%; difference between groups p

The aim of the study was to investigate endothelium-dependent vasodilator responses in the forearm vasculature of patients with systemic vasculitis. We studied 10 patients with systemic vasculitis and 16 healthy control subjects using forearm venous occlusion plethysmography to assess changes in forearm blood flow in response to acetylcholine (ACh). NG-monomethyl-L-arginine (L-NMMA), was also used to assess the contribution of endothelium derived relaxing factor/nitric oxide (EDRF/NO) to the vasodilator responses to acetylcholine. A significantly greater vasodilator response to ACh was seen in the patient group at all doses infused (p < 0.01). After pre-infusion of L-NMMA, the differences in ACh dilator responses were no longer significant. There was a greater magnitude of inhibition of ACh responses by L-NMMA in the patient group. The enhanced vasodilator response to ACh observed was in part abolished by L-NMMA, suggesting that EDRF/NO is produced in excess in systemic vasculitis. The precise role played by EDRF/NO in the pathogenesis of systemic vasculitis requires further study.

Following oral administration of only one dose of lithium (e.g. just prior to a clinic blood test), plasma concentrations rise quickly and may appear to be in the therapeutic steady state range for several hours. At the clinic, therefore, noncompliance may go undetected. It has been suggested that measurements of erythrocyte lithium concentrations (Le) may be more useful than plasma lithium concentrations (Lp) in detecting patient non-compliance. This was investigated by comparing the pharmacokinetics of lithium in plasma and erythrocytes after a single 800 mg dose of lithium carbonate and during constant dosing around steady state. Twelve healthy male volunteers took part in the study and took 800 mg of lithium carbonate (Priadel) for 28 days. Le and Lp ranges were determined around steady state using data obtained from eight volunteers known to be compliant. Compliance was measured using electronic monitoring. Both erythrocyte and plasma lithium concentrations reached values comparable to steady state after a single oral dose. This suggests that Le measurements are no better than Lp measurements when attempting to identify noncompliant patients who only dose shortly before a blood test.

In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA1c concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8±2.9 vs 27.3±3.5 μmol · kg-1 · min-1, p< 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8±3.6 vs 27.3±3.5 μmol · kg-1 · min-1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 ±0.5 vs 10.2±0.3 μol · kg-1 · min-1 p < 0.05) and suppressed to a lesser extent following insulin (4.0±0.7 vs 2.0±0.4 μ±mol · kg-1 · min-1, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline (11.7±0.5 vs 10.6±0.4 μmol · kg-1 · min-1, p

Oxidative damage due to free radical production is increased in uraemic patients and has been suggested as a possible factor contributing to the anaemia of chronic renal failure (CRF) and the pathogenesis of atherosclerosis. Oxidative stress was assessed in 40 patients with CRF maintained by either haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) and in 18 healthy controls. Lipid peroxidation (assessed as malondialdehyde, MDA), total glutathione (TG), antioxidant enzyme (glutathione reductase (GSHRx), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD)) activity and antioxidant associated trace metal (selenium, copper, zinc) levels were studied. Erythrocyte membrane fluidity was examined using the fluorescent probe 1,6 diphenyl-1,3,5-hexatriene (DPH). The results indicate increased levels of oxidative stress and altered erythrocyte membrane fluidity in patients treated with CAPD compared with controls and patients treated with HD. Only minor changes were observed in patients treated with HD. Altered free radical activity, oxidative stress and altered erythrocyte membrane fluidity observed in patients with CRF may contribute to the increase in vascular disease in such patients and to the anaemia of CRF.

Objective: To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. Design: Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. Setting: Outpatient clinics serving the greater Belfast area. Subjects: 16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. Main outcome measures: Systolic and diastolic blood pressure and peripheral and hepatic insulin action. Results: One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) μmol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) μmol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg202.8 (1.5) μmol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) μmol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline. Conclusions: Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, how dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.

The endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-L-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p less than 0.01 for all doses). NG monomethyl-L-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p less than 0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p less than 0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.

Digoxin is one of the most frequently prescribed drugs, particularly in the elderly population where there is an increased prevalence of atrial fibrillation and cardiac failure. The drug has a narrow therapeutic range and has gained a reputation for producing adverse effects in older patients. The more frail elderly patients with coexistent disease, often taking other treatments, are more at risk from digoxin toxicity due to inappropriate dosing, noncompliance, or increased sensitivity to digoxin resulting from pharmacokinetic or pharmacodynamic interactions. Application of basic pharmacological principles may be helpful in anticipating these problems. Elderly patients more commonly receive digoxin than younger patients, which in part accounts for the higher rates of toxicity in this group. Numerous components contribute to the development of toxicity, and diagnosis of toxicity is difficult in this age group. The measurement of serum concentrations can contribute to the clinical diagnosis. A major problem is the accurate diagnosis of digoxin toxicity which may have numerous nonspecific clinical manifestations, many of which are related to coexisting disease in elderly patients. This diagnostic imprecision is well recognised but has been helped by the introduction of serum digoxin measurement. However, reliance on serum concentrations should not replace clinical judgement, since these do not always correlate with toxicity. The apparently decreasing incidence of toxicity over recent years probably reflects several factors: the improvement in digoxin formulations, awareness of digoxin pharmacology, utilisation of serum concentrations, and the realisation that digoxin withdrawal is a viable proposition in elderly patients. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin overdose, especially in the elderly population.

Aims To determine the role of nitric oxide (NO) in forearm reactive hyperaemia in healthy human subjects. Methods Ten healthy subjects aged 19–34 years underwent brachial artery cannulation. Forearm circulatory arrest was achieved by means of an upper arm cuff inflated to 200 mmHg for 5 min. The blood flow responses during reactive hyperaemia were measured using venous occlusion plethysmography following a 10 min intra-arterial influsion of 8 μmol min−1N-monomethyl l-arginine (-NMMA) and following matching placebo administered in random order. Results were analysed by repeated measures anova and t-tests. Results -NMMA resulted in a significant reduction of basal forearm blood flow indicating inhibition of basal NO release (P=0.005). There was no significant difference between the blood flow responses during reactive hyperaemia following -NMMA and placebo (P=0.97). Conclusions Nitric oxide production does not make a significant contribution to the vasodilatation associated with reactive hyperaemia in the human forearm.

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.

Vasodilation to acetylcholine is mediated at least in part by endothelium-derived hyperpolarising factor (EDHF) which causes membrane hyperpolarisation by activating potassium channels. It is however uncertain which potassium channel mediates this effect. The aim of this study was to determine the role of the potassium-ATP (K(+)-ATP) channel in mediating endothelium-dependent vascular responses to acetylcholine.In 10 healthy volunteers acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside as a control assessing endothelium-independent vasodilatation were infused into the non-dominant brachial artery. Forearm blood flow (FBF) in response to each dose was measured by strain-gauge venous occlusion plethysmography. The K(+)-ATP channel blocker glipizide (2.5 mg) was then administered orally. After 45 min the infusions with FBF measurements were repeated.Acetylcholine (P0.01) and sodium nitroprusside (P0.01) both caused an increase in FBF. There was no significant difference in vascular responses to acetylcholine (P0.05) or sodium nitroprusside (P0.05) following K(+)-ATP channel blockade.The K(+)-ATP channel does not modulate forearm arteriolar endothelium-dependent responses in healthy volunteers and therefore does not play a role in membrane hyperpolarisation.

The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure.After a single dose of 100 mg, Cmax of the parent compound (2.52 mg.l-1) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (Cmax 8.4 vs 3.21 mg.l-1). No adverse effects were observed.It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity.

The involvement of cyclooxygenase-derived substances in the forearm arteriolar responses to serotonin was determined in 10 healthy male volunteers. Serotonin was infused in five incremental doses (0.003-30 micrograms min-1) for 2 min each into the brachial artery of the non-dominant forearm. Forearm blood flow (FBF) responses to each dose were measured by strain-gauge venous occlusion plethysmography. The cyclooxygenase inhibitor indomethacin (100 mg) was administered orally following the serotonin infusions. After 90 min the serotonin infusions were repeated and FBF responses measured. Serotonin caused a biphasic response with vasodilatation occurring at low doses (0.003-3 micrograms min-1, P < 0.01) and vasoconstriction occurring at the highest dose (P < 0.01). There was no significant difference in vascular response to serotonin following cyclooxygenase inhibition. In conclusion, cyclooxygenase products are not involved in the forearm vascular responses to serotonin in healthy human subjects.

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml−1 · min−1) and were analyzed using repeated measures analysis of variance and Dunnett's test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml−1 · min−1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P0.001). Diabetic subjects, however, showed no significant response (P0.05). There was a significant difference between the diabetic and control groups (P0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.

OBJECTIVE--To determine the use of new drugs in one United Kingdom region. DESIGN--Examination of data on prescribing of angiotensin converting enzyme inhibitors, new broad spectrum antibiotics, and H2 receptor antagonists. Calculation of number of defined daily doses prescribed each month. SETTING--All general practices in Northern Ireland. MAIN OUTCOME MEASURES--Drug use index and market share of each drug. RESULTS--During 1988-91 prescribing of angiotensin converting enzyme inhibitors increased by 126%, of H2 receptor antagonists by 46%, and of new antibiotics by 207%. The first drug on the market usually retained the largest market share. Use of oral antibiotics increased threefold irrespective of the reporting policy of the general practitioners' local laboratory. CONCLUSIONS--The increase in prescribing of these drugs seems to be greater than can be accounted for by an increase in patients with specific indications for these drugs. This suggests that the profession has not instituted effective checks to ensure that the legitimate promotion of new products does not lead to inappropriate and wasteful use.

BACKGROUND--An association between hypertension and obstructive sleep apnoea (OSA) has been found by some researchers but remains controversial. Since such an association would have important implications for the investigation and management of hypertension, the rate of nocturnal hypoxaemic episodes has been compared in hypertensive and normotensive men. METHODS--The study was carried out in the community in Belfast and its environs. Thirty four men with mild to moderate hypertension aged 40-64 years were identified from general practice and a hypertension clinic. Normotensive men, matched for age and body mass index, were selected from a community survey. Subjects answered a sleep questionnaire and underwent overnight pulse oximetry at home. Computer analysis of the results gave the number and magnitude of dips in oxygen saturation (SaO2 dips, 4% or greater). RESULTS--The median number of SaO2 dips/hour for hypertensives was 2.0, and for normotensives was 0.8. Lowest SaO2 and mean SaO2 levels were significantly lower in the hypertensive group. Only one subject had a rate of SaO2 dips/hour greater than five and symptoms suggestive of OSA. CONCLUSIONS--Both hypertensive and normotensive men had relatively few episodes of nocturnal hypoxaemia. The small increase in the rate of SaO2 dips in hypertensive subjects has not yet been fully explained. These results imply that OSA is not common in hypertensive subjects and is unlikely to be an important cause of hypertension.

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.

A mild to moderate elevation of the total homocysteine concentration (tHcy) is now recognized as a risk factor for vascular disease. It is also associated with endothelial dysfunction in middle-aged and elderly individuals without overt atherosclerotic vascular disease. This is important, as endothelial dysfunction is a well recognized early and potentially reversible marker of the atherosclerotic process. We investigated whether mild hyperhomocysteinaemia was associated with endothelial dysfunction in otherwise healthy young males. We compared endothelial function, by measuring forearm blood flow, in 17 males with mild hyperhomocysteinaemia (defined as tHcy10 micromol/l) and 14 controls with low tHcy (defined as5 micromol/l). Forearm blood flow was measured in response to the intra-arterial infusion of acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response). Responses to the vasoactive substances were expressed as the area under the curve of the change in forearm blood flow from baseline. Data are given as mean (95% confidence interval). The two groups were well matched for age, body mass index, pulse rate and blood pressure. tHcy was significantly different between the groups [12.3 (10.4-14.2) micromol/l compared with 4.9 (4.6-5.1) micromol/l; P0.001]. Concentrations of vitamin B(12) and folate were significantly higher in the control group. There was no difference in basal forearm blood flow between the group with mild hyperhomocysteinaemia and the controls, and both the endothelial-dependent [37.5 (26.2-38.8) and 35.3 (26.1-44.4) arbitrary units respectively] and -independent [26.1 (22.2-29.9) and 25.9 (21.0-30.8) units respectively] responses were not significantly different between the groups. Thus the present study demonstrates that, in healthy adults, mild elevation of tHcy was not associated with impaired endothelial-dependent vasodilation. These data suggest an age effect with regard to homocysteine and endothelial dysfunction. The development of vascular disease in individuals with hyperhomocysteinaemia may only result with higher concentrations or after prolonged exposure.

OBJECTIVE: Low birth weight has been associated with hyperlipidemia, hypertension, diabetes, and coronary heart disease in adult life, but the precise mechanism is debated. The endothelium is thought to play a pivotal role in each of the above conditions with abnormalities being detectable before the development of overt disease. To investigate the possibility that endothelium has a role in mediating the excessive risk of adult vascular disease associated with low birth weight, endothelial function was assessed in young healthy adults who were either of low or normal birth weight at term. RESEARCH DESIGN AND METHODS: Twelve low birth weight (2.2 +/- 0.05 kg, mean +/- SEM) subjects (six men/six women; age 28 +/- 0.2 years) and twelve age- and sex-matched normal birth weight (3.3 +/- 0.07 kg) control subjects were studied. The L-arginine-nitric oxide pathway was assessed in the forearm vascular bed by using venous occlusion plethysmography during intra-arterial brachial infusion of acetylcholine, sodium nitroprusside, norepinephrine, and NG-monomethyl-L-arginine (L-NMMA). Von Willebrand factor, a noninvasive marker of endothelial dysfunction, was also measured. Comparisons were made using Student's t test. RESULTS: Von Willebrand factor was significantly elevated in low birth weight compared with normal birth weight subjects (136.9 +/- 12.7 vs. 95.6 +/- 9.5%; P = 0.016). The groups did not differ in the responses to acetylcholine (P = 0.76), sodium nitroprusside (P = 0.84), norepinephrine (P = 0.21), or L-NMMA (P = 0.35). CONCLUSIONS: The finding of elevated von Willebrand factor in low birth weight subjects is suggestive of endothelial cell injury but does not appear to be associated with dysfunction of the L-arginine-nitric oxide pathway.

This article summarises the new British Hypertension Society guidelines for management of hypertension, which have been published in full.1 Since the previous guidelines 2 3 much new evidence has emerged on optimal blood pressure targets4; management of hypertension in diabetic patients4–7; treatment of isolated systolic hypertension8; comparison of the antihypertensive efficacy and tolerability of different drug classes9–11; the role of non-pharmacological measures for prevention 12 13 and treatment of hypertension14; and additional benefits associated with the use of aspirin and statins. Of concern is that national surveys continue to reveal incomplete detection, treatment, and control of hypertension.15 Furthermore, treated hypertensive patients still die prematurely from cardiovascular disease.16 These guidelines aim to present the best currently available evidence on hypertension management and their implementation. #### Summary points Use non-pharmacological measures in all hypertensive and borderline hypertensive people Initiate antihypertensive drug treatment in people with sustained systolic blood pressure ≥160 mm Hg or sustained diastolic blood pressure ≥100 mm Hg Decide on treatment in people with sustained systolic blood pressure between 140 and 159 mm Hg or sustained diastolic blood pressure between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease, diabetes, or a 10 year coronary heart disease risk ≥15% according to the Joint British Societies coronary heart disease risk assessment programme or risk chart Optimal blood pressure treatment targets are systolic blood pressure

There is considerable evidence that endothelium-dependent nitric oxide (NO)-mediated vasodilatation in response to acetylcholine is impaired in essential hypertension, whereas the endothelium-independent response to sodium nitroprusside is normal. More limited data have suggested that there is also reduced vasoconstriction in response to N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of basal NO release. As it is not known whether endothelial dysfunction in hypertension, if indeed present, is a cause or consequence of the condition, we have studied the normotensive offspring of parents with essential hypertension. Both basal and stimulated vascular responses were examined in 12 normotensive offspring [mean age (+/-S.E.M.) 26.1+/-1.4 years] of parents with essential hypertension and compared with those in 12 age-matched offspring (mean age 25.6+/-1.1 years) of normotensive subjects. Forearm blood flow was measured simultaneously in both arms by venous occlusion plethysmography, both at baseline and during intra-arterial brachial infusion of increasing doses of acetylcholine, sodium nitroprusside, noradrenaline and L-NMMA. There were no significant differences between the groups in the responses to acetylcholine, sodium nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to L-NMMA was significantly blunted in the offspring of hypertensive parents compared with that in the offspring of normotensive parents (P=0.005). Thus endothelial dysfunction, as demonstrated by impaired basal production of NO, is present in subjects at high risk of essential hypertension, and does not occur simply as a consequence of the condition.

Objective To compare 2.5 mg bendrofluazide daily (the standard antihypertensive dose), 1.25 mg bendrofluazide daily and 2.5 mg bendrofluazide on alternate days, in terms of reduction of blood pressure, patient compliance and adverse effect profile. Design A single-blind parallel group trial of patients who were randomly assigned to 16 weeks' treatment with bendrofluazide at doses of 2.5 mg daily, 1.25 mg daily and 2.5 mg every other day after a 4-week placebo run-in period. Setting General practices in the greater Belfast and Lisburn area in Northern Ireland. Patients Ninety-three patients with newly diagnosed or previously diagnosed hypertension, who had a mean diastolic blood pressure of 90-110 mmHg after receiving placebo for 4 weeks. Main outcome measures Reduction in blood pressure, patient compliance and changes in biochemical variables. Results Sitting systolic and diastolic blood pressures in members of all three groups were significantly lowered with respect to baseline (P< 0.01) with no differences among groups. Overall mean compliance was 97%. No clear relation between dose and biochemical changes was apparent Conclusions Bendrofluazide at doses of 1.25 mg daily or 2.5 mg every other day reduces blood pressure as effectively as does the conventional 2.5 mg daily regimen.

We present a case of non-specific vasculitis presenting as a pyrexia of unknown origin to illustrate the diagnostic difficulty which can arise with this condition. The diagnostic event was central retinal artery occlusion and the disease was also associated with pyoderma gangrenosum. History, examination, investigations and management are discussed.

OBJECTIVE To determine whether combination of an angiotensin converting enzyme inhibitor with a high dose of thiazide diuretic avoids adverse metabolic consequences of thiazide diuretics. DESIGN Double-blind randomized crossover study of two 12-week treatment periods with captopril (up to 100 mg/day) either alone or in combination with 5 mg bendrofluazide given after a 6-week placebo run-in period. Treatment periods were separated by a 6-week placebo washout period. SETTING Outpatient clinics in greater Belfast. PATIENTS Fifteen white non-diabetic essential hypertensives (seven male) aged < 65 years recruited from general practices in greater Belfast. MAIN OUTCOME MEASURES Systolic and diastolic blood pressures and peripheral and hepatic insulin action. RESULTS Two patients failed to complete the study. Blood pressure was lowered (139/89+/-18/7 mmHg combination versus 160/97+/-21/7 mmHg captopril; P < 0.001). Fasting insulin level was raised (7.9+/-3.6 mU/l combination versus 6.2+/-3.2 mU/l baseline; P < 0.001). There were no differences between treatments for glucose, urate, cholesterol and triglyceride levels. Serum potassium level was lowered (3.8+/-0.4 mmol/l combination versus 4.2+/-0.4 mmol/l captopril, P < 0.05). Postabsorptive endogenous glucose production was raised (10.8+/-1.7 micromol/kg per min combination versus 10.0+/-1.5 micromol/kg per min captopril; P < 0.01) and was greater than baseline (9.7+/-2.1 micromol/kg per min, P < 0.05). Suppression of glucose production by insulin was similar with both treatments. Exogenous glucose infusion rates required to maintain euglycaemia did not differ (32.4+/-7.6 micromol/kg per min captopril, 32.7+/-6.2 micromol/kg per min combination, 31.5+/-7.2 micromol/kg per min baseline). CONCLUSIONS Combination therapy increased glucose production (compared with captopril alone), indicating hepatic insulin resistance. It cannot be assumed that combined preparations with angiotensin converting enzyme inhibitors will ameliorate adverse effects of high doses of thiazide diuretics on insulin action.

The aim of the study was to investigate endothelium-dependent vasodilator responses in the forearm vasculature of patients with systemic vasculitis. We studied 10 patients with systemic vasculitis and 16 healthy control subjects using forearm venous occlusion plethysmography to assess changes in forearm blood flow in response to acetylcholine (ACh). NG-monomethyl-L-arginine (L-NMMA), was also used to assess the contribution of endothelium derived relaxing factor/nitric oxide (EDRF/NO) to the vasodilator responses to acetylcholine. A significantly greater vasodilator response to ACh was seen in the patient group at all doses infused (p0.01). After pre-infusion of L-NMMA, the differences in ACh dilator responses were no longer significant. There was a greater magnitude of inhibition of ACh responses by L-NMMA in the patient group. The enhanced vasodilator response to ACh observed was in part abolished by L-NMMA, suggesting that EDRF/NO is produced in excess in systemic vasculitis. The precise role played by EDRF/NO in the pathogenesis of systemic vasculitis requires further study.

Given the clear evidence that reducing blood pressure decreases the vascular complications of hypertension, loss of efficacy represents the principal complication of noncompliance with antihypertensive therapy. Withdrawal symptoms are also important and occur after abruptly stopping beta-blockers and centrally-acting antihypertensive drugs. Very few studies have been conducted to assess the impact of missing 1 or 2 doses of an antihypertensive agent on short term control of blood pressure. A high trough to peak ratio (> 50%) for a once-daily medication suggests a long duration of action. However, methodological problems in the design of the studies to determine trough to peak ratios make comparisons between various medications very difficult. In general, however, stopping a drug with a low through to peak ratio is more likely to result in loss of antihypertensive effect than a drug with a high ratio. Poor compliance in dose-escalating studies with antihypertensive agents may have resulted in excessively high dose recommendations in clinical trials.

The effects of celiprolol 200 mg or 400 mg once daily on blood pressure (BP), serum lipids, plasma fibrinogen and airways function was compared with the effects of metoprolol 100 mg or 200 mg once daily in 171 patients with mild to moderate hypertension and coexistent hyperlipidaemia in a double-blind, multicentre study lasting 1 year. Significant decreases in systolic and diastolic blood pressure and heart rate were observed compared with baseline (DBP: celiprolol -13.3 mm Hg, P0.0001; metoprolol -14.3 mm Hg, P0.0001; SBP: celiprolol -18.2 mm Hg, P0.0001; metoprolol -20.5 mm Hg, P0.0001; heart rate celiprolol -4 beats/min, P0.003; metoprolol -12 beats/min, P0.0001). There was no difference between the effects of the two treatments on BP but celiprolol had less effect on heart rate than metoprolol, (celiprolol-metoprolol 7.3 beats/min, P = 0.0002). When compared with baseline values celiprolol significantly reduced serum low density lipoprotein cholesterol (LDL-C) (-5.8%, P = 0.0401) and produced a slight increase in high density lipoprotein cholesterol (HDL-C) which approached statistical significance (4.1%, P = 0.0659). Metoprolol significantly increased serum triglycerides (32%, P = 0.0001) and the total/HDL-C ratio (7.4%, P = 0.0192). Compared with metoprolol, celiprolol significantly reduced LDL-C (-7.3%, P = 0.0062), total cholesterol (-4.5%, P = 0.0085), apoliproprotein B (-10.1%, P = 0.0001), the apolipoprotein B/A1 ratio (-10.9%, P = 0.0001), the total cholesterol/HDL-C ratio (-10.8%, P = 0.0001) and triglycerides (-24.8%, P = 0.0001), and significantly increased HDL-C (6.0%, P = 0.0043).(ABSTRACT TRUNCATED AT 250 WORDS)

EDITOR, - Three letters1 comment on our article on the market penetration of new drugs in Northern Ireland.2 J P Griffin attacks our article as flawed in its conclusions without revealing the flaws.1 We did not state that it was “always the first medicine in the field which continues to be…the market leader.” We did not advocate that the search for better products in the same therapeutic class should not be pursued. We …

Decreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-L-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p < 0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies.(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.

The efficacy and safety profiles of lisinopril (10-40 mg) and enalapril (5-20 mg) were compared in 169 hypertensive patients during 12 weeks' treatment in a randomised double-blind parallel group study. BP was measured hourly for the first 8 hours following the first dose of lisinopril 10 mg and enalapril 5 mg. The peak reduction in sitting systolic and diastolic BP occurred approximately 6 hours post dose in both groups. At 8 hours post dose lisinopril had reduced sitting systolic and diastolic BP by 2.9 mmHg and 3.5 mmHg (P = 0.02) respectively, more than enalapril with similar results for standing BP. One patient on enalapril developed first dose postural hypotension. After 12 weeks' therapy lisinopril produced a greater decrease (P less than 0.05) in BP than enalapril. Sitting BP decreased by 25/15 mmHg on lisinopril and 17/12 mmHg with enalapril. Standing BP decreased by 24/14 mmHg compared with 16/10 mmHg on enalapril. Eighteen patients did not complete the study, 8 on lisinopril (6 adverse events, 1 uncontrolled BP, 1 protocol violator) and 10 on enalapril (8 adverse events, 1 uncontrolled BP, 1 protocol violator). Overall, the results indicated that while both drugs are well tolerated, the dose range of lisinopril 10-40 mg may produce a greater antihypertensive effect than enalapril 5-20 mg.

After an 8-week placebo period, 73 patients whose diastolic blood pressures were between 90 and 110 mmHg were randomly assigned to receive 125 micrograms (low dose) or 500 micrograms of cyclopenthiazide (standard dose) for a period of one year. Blood pressure was measured in the patient's home by the same observer at two-weekly intervals during an 8-week placebo run-in period, every 4 weeks for a further 12 weeks and at 24, 36 and 52 weeks thereafter. Serum potassium, urate, glucose, glycosylated haemoglobin, total and HDL cholesterol, and apolipoproteins were measured at the end of the placebo period and at 4, 8, 24 and 52 weeks of active treatment. Twelve of the 73 patients had an inadequate antihypertensive response--five on the higher dose and seven on the lower dose. One patient receiving 500 micrograms was withdrawn because of adverse effects. In the remaining 60 patients, systolic and diastolic blood pressures were significantly reduced when compared with pretreatment values in both treatment groups throughout the one year period. The decreases in blood pressure were not significantly different from each other (p greater than 0.65). Three patients on 500 micrograms required potassium supplements. Maximum decreases in the serum potassium of 0.52 mmol/l (500 micrograms dose) and 0.14 mmol/l (125 micrograms dose) were observed at 24 weeks of treatment in the remaining 57 patients. The differences between the two doses at this time were statistically significant (p less than 0.05), as were the increases in serum urate observed at 4, 8 and 24 weeks (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)