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Biomedical subjects

C T Dollery

Publications and source records attributed to C T Dollery.

At least 19 recordsLinked to original sources
PubMed1999

Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators.

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

Aged↗
PubMed1997

Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint. METHODS: All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat. FINDINGS: At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14%; p = 0.22). INTERPRETATION: Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Aged↗
PubMed1997

Urinary leukotriene E4 levels in patients with atopic dermatitis.

Leukotriene synthesis may be increased in a variety of inflammatory diseases. Urinary leukotriene E4 is a stable metabolite of leukotrienes C4 and D4 which has previously been found to be increased in exacerbations of severe asthma and after antigen inhalation. Levels of urinary LTE4 in seven patients during and after a severe flare of atopic dermatitis were measured by high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Mean urinary LTE4 levels (+/- SEM) were not increased during (16.7 +/- 3.7 pg/mumol) or after (16.9 +/- 4.8 mumol) the acute exacerbation of atopic dermatitis when compared with the normal range (mean = 23.8 [95% confidence interval 19.9-28.2] pg/mumol creatinine). These findings do not provide evidence of cysteine leukotriene involvement in the pathogenesis of atopic dermatitis.

Acute Disease↗
PubMed1995

Alcohol intake and cardiovascular mortality in hypertensive patients: report from the Department of Health Hypertension Care Computing Project.

OBJECTIVE: To determine the benefits and risks of drinking alcohol in treated hypertensives. DESIGN: A prospective study of 6,369 hypertensives (3,161 men) attending primarily hospital clinics in the UK. METHODS: Relative risks both for drinkers compared with non-drinkers and for level of alcohol consumption were calculated for mortality from ischaemic heart disease, stroke, non-circulatory and all causes. RESULTS: At presentation 76% of the men and 48% of the women reported recent alcohol consumption. Compared with drinkers, non-drinkers were older, less likely to smoke and had a higher untreated blood pressure. After adjustment for confounding factors, male drinkers had a reduced risk of stroke mortality and possibly of ischaemic heart disease mortality. Similar results were observed in women for stroke mortality but not for ischaemic heart disease mortality. The trend remained after adjustment for previous cardiovascular disease. In men the lowest risk of ischaemic heart disease mortality occurred at intakes of > 21 units per week and stroke mortality was lowest at 1-10 units per week. Men consuming > 21 units per week had a twofold higher non-circulatory mortality. Total mortality was lowest in men who drank 1-10 units per week. Similar effects of alcohol on cardiovascular mortality were observed in women. CONCLUSIONS: Alcohol intake may reduce stroke mortality in treated hypertensives. Ischaemic heart disease mortality in men may also be reduced, especially at higher intakes ( > 21 units per week). The beneficial effects were offset by increasing incidence of non-circulatory causes of death. Alcohol consumption of 1-10 units per week was associated with the lowest mortality in men.

Adolescent↗
PubMed1993

Potent leukotriene D4 receptor antagonist ICI 204,219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction.

ICI 204,219 is a potent and specific leukotriene D4 receptor antagonist that blocks both the early and late responses to allergen challenge in humans when given orally at a dose of 40 mg. Here we report our findings with an inhaled formulation of ICI 204,219 against allergen-induced bronchoconstriction. A group of 10 atopic subjects (mean age 25.6 +/- 4.2; 6 females; FEV1 > 90% of predicted; on inhaled beta 2-agonists only) were studied on 2 separate days 2 to 3 wk apart. In a randomized placebo-controlled trial they inhaled eight puffs of a standard metered dose inhaler containing either ICI 204,219 (200 micrograms/puff, total dose 1,600 micrograms) or propellant alone. They underwent bronchial allergen challenge 30 min later using a single concentration of allergen previously shown to lower the FEV1 by > or = 15%. FEV1 was monitored hourly for 10 h, and urine was collected for LTE4 determination. Inhalation of ICI 204,219 was well tolerated, with no adverse clinical or biochemical effects. There was no significant effect of ICI 204,219 inhalation on basal airway caliber (change in FEV1 30 min after inhalation was -149 +/- 67 ml after placebo versus 3 +/- 38 ml after ICI 204,219; p = 0.08). The early response to allergen was significantly inhibited by ICI 204,219 (the maximum fall in FEV1 was -21.2 +/- 6.1% after ICI 204,219 compared with -38.8 +/- 6.5% on placebo; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Antihypertensive therapy in elderly patients with isolated systolic hypertension: third progress report of the Syst-Eur trial.

The Syst-Eur trial is a randomised, double-blind, placebo-controlled trial that examines the hypothesis that antihypertensive treatment can prevent or delay cardiovascular complications in elderly patients (> 60 years) with isolated systolic hypertension. On March, 1st 1993 a total of 1395 patients with a sitting systolic blood pressure on placebo averaging 160-219 mmHg and a diastolic blood pressure < 95 mmHg were randomised into this trial. The placebo and active treatment groups were similar at randomisation with respect to age (72 +/- 7 years, mean +/- SD), percentage of women (68%), percentage of patients with cardiovascular complications (30%) and sitting blood pressures (175 +/- 12/85 +/- 6 mmHg). The fall in sitting systolic and diastolic blood pressures from baseline to 2 years was significantly more pronounced (p < 0.001) in the actively treated (-22 +/- 18/-6 +/- 9 mmHg) as compared with the placebo treated Syst-Eur patients (-10 +/- 20/-1 +/- 9 mmHg). Active treatment consists of nitrendipine if necessary associated with a converting-enzyme inhibitor and a thiazide. Whether treatment with these antihypertensive agents results in a clinically meaningful reduction of cardiovascular morbidity and mortality is the subject of investigation in this trial.

Aged↗
PubMed1993

Meta-iodobenzylguanidine (MIBG) scanning in the diagnosis of phaeochromocytoma.

During the period 1984-90, meta-iodobenzylguanidine (MIBG) scans were performed in 23 patients with suspected phaeochromocytoma seen at the Hammersmith Hospital. Sixteen patients had a histologically proven phaeochromocytoma and in 14 of these patients the tumour was demonstrated by abnormal uptake of MIBG. Seven patients did not have a phaeochromocytoma and in all of these the MIBG scan was negative. These findings gave the procedure a sensitivity of 87.5% with a specificity of 100%; positive and negative predictive values were 100% and 77.7%, respectively. MIBG scanning is an extremely valuable technique in the management of patients with suspected phaeochromocytoma but is best employed to localise a tumour which has been confirmed biochemically.

3-Iodobenzylguanidine↗
PubMed1992

The identity of IgE receptors (Fc epsilon RII) that mediate cellular activation of human macrophages: evidence against a role for CD23.

There is now compelling evidence that macrophages bind IgE, and are involved in several IgE-dependent responses. The CD23 antigen mediates a mitogenic response in "primed" B-lymphocytes, although its expression is not confined to B cells, and CD23 is inducably expressed in many cells including macrophages. CD23 is also known to bind IgE, a property that leads to inhibition of the mitogenic response in B cells. In the present review, the possibility that CD23 mediates IgE-dependent responses in macrophages has been re-examined, and it is proposed that the functional receptor for IgE on macrophages may be quite separate from the CD23 antigen.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects.

The effects of a highly selective leukotriene D4 receptor antagonist, ICI 204.219, on allergen-induced bronchoconstriction and changes in airway reactivity were evaluated in a double-blind, placebo-controlled, crossover trial. Ten atopic subjects were selected for the study on the basis of an immediate fall in forced expiratory volume in 1 s (FEV1) of at least 15% and a least a doubling dose fall in their PC20-histamine (the concentration of histamine needed to reduce FEV1 by 20%) after antigen challenge. Baseline PC20-histamine was determined before the ingestion of a single oral 40 mg dose of ICI 204.219 or matched placebo. 2 h later subjects were challenged with aerosolised allergen; FEV1 was measured for the next 6 h then PC20-histamine was remeasured. Two subjects did not complete the study for reasons not related to the trial medication. ICI 204.219 significantly attenuated the early and late phase bronchoconstriction to inhaled allergen (mean treatment difference in area under the FEV1-time curves 2529 [95% Cl 1085-3972] delta %FEV1.min; p less than 0.005: and 3537 [528-6545] delta %FEV1.min; p less than 0.03) and suppressed the allergen-induced increase in non-specific bronchial reactivity (mean treatment difference 1.03 [0.34-1.71] doubling dilutions of histamine; p less than 0.01). These findings suggest that ICI 204.219 may be a disease-modifying agent in asthma. Further studies are under way to evaluate its clinical efficacy.

Administration, Inhalation↗
PubMed1991

The effects of two centrally-acting anti-hypertensive drugs on the quality of life.

The objectives of this study were to compare the effects of two centrally-acting antihypertensive drugs on measures of quality of life in a three-month double-blind trial of hypertensive patients randomized to methyldopa (n = 79) or rilmenidine (n = 78). We studied men and women aged over 21 y attending eight hospital out-patient clinics in the United Kingdom. They had average diastolic blood pressures between 95 and 110 mm Hg and systolic pressures below 210 mm Hg after a 4-week placebo run-in period. The doses ranged from 1 to 2 mg daily of rilmenidine and 500 mg to 1 g of methyldopa. Hydrochlorothiazide (25 mg daily) was added after 8 weeks when the diastolic blood pressure remained at 90 mm Hg or more in 29% of patients on rilmenidine and 35% of those on methyldopa. Quality of life was assessed from self-completed questionnaires using standardized instruments. Both drugs reduced blood pressure, but at the end of the trial the fall in the methyldopa group (19.3/13.0 mm Hg) was significantly greater than in the rilmenidine group (13.2/10.0 mm Hg). Ten patients in the methyldopa group withdrew from the trial compared with three in the rilmenidine group, primarily because of adverse effects. In both groups there was a significant increase in the overall reporting of adverse effects. Reports of dry mouth increased on both drugs, and sleepiness on rilmenidine but not methyldopa. There was no significant difference between the drugs in the overall reporting of adverse effects or of individual adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization.

The Syst-Eur Trial is a concerted action of the European Community's Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure. To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10-40 mg/day), combined with enalapril (5-20 mg/day) and hydrochlorothiazide (12.5-25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and per-protocol comparison of the outcome in the 2 treatment groups. A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).

Aged↗
PubMed1991

Assessment of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, with intravenous clonidine.

The activity of MK-467, a new peripherally acting alpha 2-antagonist, was assessed in volunteers by a randomized, double-blind, crossover design. One hour after administration of either 15 mg or 30 mg MK-467 or placebo, 200 micrograms clonidine was given intravenously and observations were made for a further 8 hours. Clonidine reduced plasma norepinephrine levels to 79% +/- 7% of that of control 1 hour after infusion, an effect that was antagonized by low-dose MK-467 (p less than 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of MK-467 (p less than 0.01), although there was no significant difference between the 3 study days in the maximal clonidine-induced decrease in systolic pressure, diastolic pressure, or heart rate. Clonidine induced a peak increase in mean blood glucose of 13%, which was antagonized by both doses of MK-467 (p less than 0.05). Plasma insulin was suppressed by clonidine from 72 +/- 14 to 47 +/- 7 IU.L-1, an effect antagonised by both doses of MK-467 (p less than 0.05 in each case). MK-467 had no effect on clonidine-induced increased drowsiness, xerostomia, or increase in growth hormone secretion, which is consistent with it being a peripherally acting specific alpha 2-antagonist. The small effect of MK-467 on clonidine-induced changes in plasma glucose and insulin suggests that peripheral alpha 2-adrenergic receptors play only a minor role in normal glucose homeostasis.

Administration, Oral↗
PubMed1991

Clinical pharmacology of calcium antagonists.

There have been major advances in the understanding of the basic pharmacology of drugs acting upon voltage-dependent and receptor-activated calcium channels using patch-clamp techniques. The structure of the L channel is known and the (different) binding sites for various calcium antagonists have been identified using the methods of molecular biology. Although calcium slow-channel antagonists are very widely used in the treatment of hypertension, advances in the clinical pharmacology of angina and, to a lesser extent, cardiac arrhythmias, have not kept up with the basic research in molecular biology. All of the calcium antagonists in current use dilate arteries, and their therapeutic action largely depends on this property. There is evidence of differences in response between arteries and veins, and some degree of selectivity between vascular territories, but the goal of much more specific or localized vasodilation has not been achieved. The most prominent difference between the three main classes of antihypertensive drugs is the mild reflex increase of heart rate seen with the dihydropyridines and the bradycardia seen with verapamil. Most of the side effects of calcium antagonists are also based on vasodilatation, such as flushing and headache. The mild edema often seen with the dihydropyridines probably depends on the changes in capillary pressure brought about by arterial dilatation. Despite their undoubted efficacy as vasodilators, there are no studies thus far which allow any conclusions as to the long-term effect of calcium antagonists on the morbidity and mortality due to hypertension.

Calcium Channel Blockers↗
PubMed1991

Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1.

1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.

6-Ketoprostaglandin F1 alpha↗