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Biomedical subjects

P Sever

Publications and source records attributed to P Sever.

At least 19 recordsLinked to original sources
PubMed1995

The heterogeneity of hypertension: why doesn't every patient respond to every antihypertensive drug?

Hypertension is a multifactorial disease, and there is growing evidence that implicates a range of environmental factors in its aetiology. These include dietary sodium, obesity, alcohol and stress. Additionally, several genetic abnormalities may predispose an individual to hypertension. The number of hypertensive phenotypes resulting from different environmental-genetic interactions may explain, therefore, why there is marked heterogeneity in response to treatment and why any single antihypertensive agent would be unlikely to control BP in more than 25-50% of patients. This is one rationale for combination therapies in which the component drugs affect different pathophysiological mechanisms.

Antihypertensive Agents↗
PubMed1994

Consistent responses of the human vascular smooth muscle cell in culture: implications for restenosis.

PURPOSE: The mechanisms whereby restenoses occur at discrete sites within the vasculature remain uncertain. We have recently reported that vascular smooth muscle cells (VSMC) derived from patients with graft stenoses are resistant to growth inhibition by heparin. In this study, we have examined whether VSMC proliferation rates and responses to inhibition by heparin vary according to the individual or the anatomic site of origin. METHODS: Long saphenous veins from seven patients were divided into proximal, middle, and distal portions, and VSMC were cultured separately from each. VSMC proliferation in response to 15% fetal calf serum +/- 100 micrograms/ml heparin was measured by counting triplicate samples at 0, 3, 7, 10, and 14 days. This experiment was repeated from the second to the sixth passage (n = 6) and for artery and vein pairs derived from four additional patients. RESULTS: Differences between vein segment cultures of individual veins were found not to differ significantly from experimental error for either proliferation or heparin inhibition and were not altered by repeated passage (ANOVA). There were, however, significant differences in sensitivity to heparin inhibition between patients (p = 0.02) (ANOVA). There were no significant differences between paired samples of artery and vein for either proliferation or heparin inhibition (Mann-Whitney test). CONCLUSIONS: VSMC growth characteristics reflect the individual patient and are maintained in cell culture.

Analysis of Variance↗
PubMed1994

Lipid profiles after the daily consumption of an oat-based cereal: a controlled crossover trial.

Water-soluble fiber has been reported to reduce serum cholesterol and consequently, oat bran, which has a high soluble-fiber content, has been recommended as part of a lipid-lowering diet. However, a recent small study of 20 volunteers with low mean serum cholesterol concentrations (4.8 mmol/L) demonstrated no lipid-lowering effect of oat bran. The present study investigated 64 volunteers with cholesterol concentrations much more typical of the UK population (6 mmol/L). Subjects were randomly allocated to receive either a normal-sized helping of an oat-based cereal or a cereal containing no oats for 4 wk and then crossed over to the alternative regimen for a further 4 wk. Small (2.23% and 4.55%) but significant (P < 0.04 and P < 0.05) reductions in total and low-density-lipoprotein cholesterol, respectively, were observed in association with the consumption of oat-based cereal. These data support the view that consumption of oat-based cereals may well contribute usefully to a lipid-lowering diet.

Cholesterol, HDL↗
PubMed1994

Growth inhibition of human vascular smooth muscle cells by fenofibrate: a possible therapy for restenosis.

OBJECTIVE: The aim was to assess the growth inhibitory effect of fibrates on human vascular smooth muscle cells. Restenosis is the most important factor limiting the long term success of invasive vascular interventions and there is as yet no effective preventive treatment. Platelet derived growth factor (PDGF) is considered to be an important growth promoting agent for vascular smooth muscle cells (VSMC) and fenofibric acid (a hypolipidaemic drug) has been reported to be a PDGF antagonist. METHODS: The effect of the fibrate drugs fenofibrate, clofibrate, bezafibrate, and gemfibrozil were examined on the proliferation of cultured human vascular smooth muscle cells derived from saphenous vein (n = 20) and graft stenoses (n = 7). RESULTS: Fenofibrate (100 microM) produced potent inhibition (48%) of VSMC proliferation at a concentration equivalent to that of its circulating metabolite fenofibric acid, but none of the other drugs produced any significant effect on growth. VSMC derived from graft stenoses were equally sensitive to inhibition as saphenous vein derived controls, in contrast to our previous work which reported that graft stenosis derived VSMC were resistant to growth inhibition by the physiological inhibitor heparin. The antiproliferative effect of fenofibrate was independent of inhibition of cellular cholesterol synthesis or toxicity. Fenofibrate inhibited VSMC growth induced by 15% fetal calf serum, PDGF, and basic fibroblast growth factor to a similar degree, indicating that it is not a specific PDGF antagonist. CONCLUSIONS: Fenofibrate is not a specific PDGF antagonist. Fenofibric acid, one of the principal metabolites of fenofibrate, did not produce any inhibition of growth, suggesting that oral administration of fenofibrate would not be efficacious. Fenofibrate is the first potent inhibitor to be described for VSMC derived from human myo-intimal hyperplastic lesions.

Bezafibrate↗
PubMed1994

Effect of calcium channel blockers on the growth of human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses.

Vascular restenosis after invasive interventions is an important clinical problem for which no preventive pharmacologic therapy exists. Calcium channel blockers have been shown to inhibit myointimal hyperplasia in animal models of restenosis and in some small and flawed clinical coronary restenosis trials. We examined the inhibitory effect of amlodipine, verapamil, and diltiazem on the growth of cultured human vascular smooth muscle cells (VSMC) derived from saphenous vein (n = 20) and graft stenoses (n = 7), in 14-day proliferation assays and [methyl 3H]thymidine uptake studies. Amlodipine and verapamil produced significant inhibition (30%) of VSMC proliferation and DNA synthesis at 10 microM but not at 500 nM-1 microM. To our knowledge, this is the first study to examine the antiproliferative effect of calcium channel blockers in VSMC derived from human graft stenoses. Growth inhibition of VSMC from graft stenoses was not significantly different from that of control saphenous vein-derived cells. We conclude, therefore, that calcium channel blockers inhibit human VSMC proliferation in vitro, regardless of whether the cells were grown from graft stenoses or saphenous vein. However, the concentrations at which these calcium channel blockers elicit antiproliferative effects may not be attainable during therapeutic dosing in humans.

Amlodipine↗
PubMed1994

Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.

Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.

Adenine↗
PubMed1994

The Hypertension in the Very Elderly Trial (HYVET). Rationale, methodology and comparison with previous trials.

The Hypertension in the Very Elderly Trial (HYVET) is a multicentre, open, randomised, controlled trial. The aim of this trial is to investigate the effect of active treatment on stroke incidence in hypertensive patients over the age of 80 years. Secondary end-points include total cardiovascular mortality and morbidity. Entry criteria include a sustained sitting systolic blood pressure of 160 to 219mm Hg plus a sustained sitting diastolic pressure of 95 to 109mm Hg. Also required is a standing systolic blood pressure of at least 140mm Hg. Patients must give their informed consent, and be free of congestive heart failure requiring treatment, gout, renal failure or a recent cerebral haemorrhage. Patients are to be randomised to 3 groups-(i) no treatment; (ii) treatment with a diuretic [bendroflumethiazide (bendrofluazide)]; or (iii) treatment with an angiotensin converting enzyme (ACE) inhibitor (lisinopril). Starting dosage for bendroflumethiazide and lisinopril is 2.5 mg/day. In order to achieve goal sitting systolic and diastolic blood pressures (< 150/80 mm Hg), a doubling of the dosage is allowed. Furthermore, slow release diltiazem (120 mg/day increasing to 240 mg/day if required) may be added to the medication of the actively treated groups. These drugs have been chosen as inexpensive and appropriate representatives of their therapeutic classes. 700 patients in each group (a total of 2100) will be sufficient to detect a 40% difference in cerebrovascular events between no treatment and active treatment (alpha = 0.01, 1-beta = 0.90). These numbers will also detect a difference in total mortality of 25% and in cardiovascular mortality of 35%. The pilot phase of the trial has been started with support from the British Heart Foundation. Centres which are interested in taking part should contact C.J. Bulpitt or any of the other authors.

Aged↗
PubMed1993

Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society.

Several important new issues have arisen in the management of patients with hypertension. A working party of the British Hypertension Society has therefore reviewed available intervention studies on anti-hypertensive treatment and made recommendations on blood pressure thresholds for intervention, on non-pharmacological and pharmacological treatments, and on treatment goals. This report also provides guidelines on blood pressure measurement, essential investigations, referrals for specialist advice, follow up, and stopping treatment.

Aged↗
PubMed1993

Abnormal growth regulation of vascular smooth muscle cells by heparin in patients with restenosis.

Proliferation of vascular smooth muscle cells (VSMC) underlies myointimal hyperplasia, which can lead to restenosis after angioplasty and vascular surgery. We propose that some individuals have an intrinsic capacity for this exaggerated response to vascular injury, partly through decreased sensitivity to the physiological growth inhibitor heparin. We investigated the effect of heparin on VSMC from restenotic lesions and from apparently normal vessels of the same patients, and VSMC from control patients undergoing primary bypass procedures. Cells from patients with restenosis (both restenotic lesion and undiseased vein) showed much lower sensitivity to growth inhibition by heparin than the controls (median inhibition 8 [95% Cl -2 to 25] vs 22 [15-44]%, p < 0.001); this finding suggests aberrant growth regulation in these cells.

Arterial Occlusive Diseases↗
PubMed1993

Cellular biology of human intimal hyperplastic stenosis.

Restenosis after angioplasty and vascular surgery remains a major unsolved clinical problem. Vascular smooth muscle cell (VSMC) hyperplasia is an invariable response, but in 20-50% of cases proceeds to compromise the vessel lumen. We sought to identify cellular characteristics of human VSMC which are associated with restenosis. Human VSMC were grown from 135 samples of vascular tissue derived from patients undergoing primary cardiovascular surgery and revision surgery for restenosis. Cells derived from normal vein and artery, atherosclerotic plaques and from stenotic lesions were studied for successful proliferation in cell culture. Furthermore, growth rates were measured in response to 15% foetal calf serum +/- inhibition with heparin (100 micrograms/ml). Significantly fewer cells from atherosclerotic plaques progress to the third passage in cell culture than those derived from stenoses and controls (p < 0.001, Chi square) and growth rates after the third passage could not be studied in these cells. Of cells that progress to this stage, growth rates do not differ between stenosis-derived and normal cells under standard conditions. VSMC from mature atherosclerotic plaques may have undergone senescent changes. Stenosis-derived cells do not grow more rapidly than normal cells, but are significantly less sensitive to heparin (p < 0.001, Mann-Witney test), which is a major physiological inhibitor of VSMC growth. Differences in biological characteristics of human VSMC, observed in cell culture, may provide important insights into human vascular disease.

Actins↗
PubMed1992

Management of elderly patients with sustained hypertension.

OBJECTIVE: To assess the clinical benefits of treating hypertension in elderly patients and to derive practical guidelines regarding indications, goals, and forms of treatment. DESIGN: Review of six published randomised trials. RESULTS: Active treatment of hypertension in elderly patients was associated with significant improvements in several indices of cardiovascular morbidity and mortality, particularly the incidence of fatal and non-fatal strokes. On the basis of the trial data, combined systolic and diastolic hypertension was defined as a sustained systolic pressure greater than 160 mmHg and diastolic pressure greater than 90 mmHg. There is convincing evidence that efforts should be made to reduce both systolic and diastolic pressures to below these levels in patients up to the age of 80 years. Isolated systolic hypertension was defined as a systolic pressure greater than 160 mmHg in the presence of a diastolic pressure less than 90 mmHg. Two trials reported benefit from the treatment of isolated systolic hypertension in patients up to the age of 80, and further trials are underway to support or refute this recommendation. Diuretics have an established role in the management of hypertension in elderly patients; beta adrenoceptor antagonists have given variable results, and the benefits are less impressive than with diuretic based regimens. Newer agents show promise in the treatment of elderly patients, particularly in the presence of coexisting disease, but their effects on morbidity and mortality have not been evaluated in large randomised trials. CONCLUSIONS: Diuretics rather than beta blockers are the treatment of choice for patients with uncomplicated hypertension, but combinations of drugs may be required in as many as 50% of patients.

Adrenergic beta-Antagonists↗
PubMed1992

Celiprolol.

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Antihypertensive Agents↗