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G D Lowe

Publications and source records attributed to G D Lowe.

At least 73 records · Page 4Linked to original sources
PubMed1999

Repeated-dose pharmacodynamics of clopidogrel in healthy subjects.

The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.

Administration, Oral↗
PubMed1999

Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist.

The safety and pharmacodynamic compatibility of clopidogrel with medications commonly used in patients with atherosclerosis, such as, a beta-adrenergic receptor antagonist (atenolol) and a calcium uptake inhibitor (nifedipine) were assessed. Atenolol and nifedipine interactions with clopidogrel were studied in patients with peripheral arterial obstructive disease taking a well-established regimen of nifedipine (N group of 6 patients) and in patients with coronary artery disease taking a well-established regimen of either atenolol (A group of 8 patients) or of atenolol and nifedipine (AN group of 8 patients). The study was conducted as a double-blind, randomized, crossover comparison of clopidogrel, 75 mg once daily, and placebo treatment for 7 days, with a 14-day washout between treatments. Pharmacodynamic interactions between atenolol and nifedipine, either alone or in combination, and clopidogrel were assessed primarily on the clinical control of angina or hypertension and, secondarily, by comparing the extent of inhibition of ADP (5 microM)-induced platelet aggregation achieved between the 3 groups. The mean number of anginal episodes per patient during the placebo week was 1.50, 9.0 and 11.5 in the A, N and AN groups, respectively; during the week of clopidogrel treatment, it was 1.39, 7.3 and 9.0, respectively, indicating no change in occurrence. Likewise, review of the use of nitrates (long or short acting) did not suggest any major change in usage during any period of the study. ECGs did not change between the three recording times (at screening and at the end of each treatment period). Vital signs were also unchanged throughout. Percent inhibition of platelet aggregation on day 7 was 31% in the N group, 39% in the A group, 28% in the AN group, and 33% overall. In conclusion, the coadministration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine, or both. Clopidogrel retained its full antiplatelet effect, and there were no safety problems caused by the coadministration.

Adrenergic beta-Antagonists↗
PubMed1999

A longitudinal study of the relationships between haemostatic, lipid, and oestradiol changes during normal human pregnancy.

Increased activation of both blood coagulation and fibrinolysis occurs during normal pregnancy. The responsible mechanisms are unclear, but may include increases in both oestradiol and blood lipids. We, therefore, studied the associations between fasting serum oestradiol, plasma cholesterol and triglyceride, and Factor VII activity, PAI activity, t-PA antigen, fibrin D-dimer, and vWF antigen in 10 women, each sampled on 6 occasions between 10 weeks and 35 weeks during normal pregnancy. Strong and similar individual correlations were observed between increases in FVII, PAI, t-PA and D-dimer (but not vWF) and increases in both oestradiol and triglyceride. Associations between increments in plasma cholesterol and haemostatic factors (except for FVII), were somewhat weaker. We, therefore, suggest that oestradiol-induced hypertriglyceridaemia may be a cause of elevations in plasma Factor VII activity, PAI and t-PA, and fibrin turnover (D-dimer) during normal pregnancy, but is poorly related to the increase in vWF antigen.

Adult↗
PubMed1998

Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study.

BACKGROUND: Several hemostatic and rheological factors have been associated with incident cardiovascular events. However, there have been no reports on the relationship of rheological factors with early atherosclerosis and very few on hemostatic factors. We therefore studied the relationship between these factors and carotid intima-media thickness (IMT). METHODS AND RESULTS: The Edinburgh Artery Study measured fibrinogen, tissue plasminogen activator (tPA), fibrin D-dimer, von Willebrand factor (vWF), blood and plasma viscosities, and hematocrit as part of its baseline examination during 1988-1989. At the 5-year follow-up, valid measurements of IMT had been recorded in 1106 men and women 60 to 80 years old. In men, blood viscosity (P< or =.001) and its major determinants, plasma viscosity, fibrinogen (both P< or =.01), and hematocrit (P< or =.05), were all linearly related to IMT. Furthermore, blood viscosity, fibrinogen (both P< or =.01), and plasma viscosity (P< or =.05) remained significantly associated on multivariate analysis. Correcting blood viscosity to a standard hematocrit of 45% had little effect on its association. In men, there was a significantly increased risk of having an IMT above versus below the upper quartile of its distribution (1.05 mm) for SD increases in blood viscosity (P< or =.01), fibrinogen, corrected blood viscosity, and plasma viscosity (all P< or =.05). With the exception of plasma viscosity, these risks were unaffected by adjustment for other common cardiovascular risk factors. No significant associations were found between any of the hemorheological factors and IMT in women or for tPA, fibrin D-dimer, or vWF in either sex. CONCLUSIONS: These findings suggest that in men, blood viscosity and its major determinants are associated not only with incident cardiovascular events but also with the early stages of atherosclerosis. This may be one explanation for the link between rheological factors and events.

Age Factors↗
PubMed1998

Effects of lipids and lipoproteins on thrombosis and rheology.

Atherosclerotic plaque rupture and erosions precipitate thrombus formation and may lead to an acute ischemic syndrome. Lipids and lipoproteins modulate the expression and/or function of thrombotic, fibrinolytic and rheologic factors, and thereby influence hemostasis and potential tissue damage resulting from vascular injury. Triglyceride-enriched lipoproteins are accompanied by elevations in factor VII clotting activity, plasminogen activator inhibitor (PAI-1) and viscosity of blood and plasma. Low density lipoprotein (LDL) promotes platelet activation and tissue factor expression and LDL levels correlate with levels of vitamin K dependent coagulation factors and fibrinogen. Conversely, LDL inhibits tissue factor pathway inhibitor (TFPI) which limits activation of the extrinsic coagulation pathway. High density lipoprotein (HDL) has anti-atherothrombotic properties that result from inhibition of platelet and erythrocyte aggregation, reduced blood viscosity and suppression of tissue factor activity and PAI-1 activity and antigen levels. The effects of lipids and lipoproteins on hemostasis and rheology may have important implications for the clinical sequelae following plaque disruption and erosion.

Adult↗
PubMed1998

Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.

BACKGROUND AND AIMS: epidemiological studies suggest polyunsaturated fatty acids protect against the development of atherosclerosis. The aim of this study was to perform a randomized controlled trial of gamma-linolenic and eicosapentaenoic acids in patients with lower limb atherosclerosis. Main outcome measures were: cholesterol and lipoprotein concentrations; haemostatic and rheological variables; the ankle brachial pressure index; walking distance; and cardiovascular events and death. METHODS: 120 men and women with stable intermittent claudication were randomized to 2 years treatment with either a combination of gamma-linolenic and eicosapentaenoic acids, or placebo. RESULTS: 39 (65.0 cent) of those taking fatty acids and 36 (60.0 cent) of those taking placebo completed the trial. Lipid concentrations did not differ significantly during the trial. In those taking fatty acids, haematocrit was significantly higher than in the placebo group after 6 months (46.1 cent compared with 44.6 cent, P </= 0.01), and systolic blood pressure was significantly lower after 2 years (150|mmHg compared with 161.8|mmHg, </= 0.05). There was no difference in walking distance, but there was a small reduction in non-fatal coronary events in the fatty acid group (10 cent compared with 15 cent, P > 0.05). CONCLUSIONS: a combination of polyunsaturated fatty acids produced a statistically significant reduction in systolic blood pressure, but no other significant benefits on risk factors. The trend towards fewer coronary events in those taking fatty acids warrants further investigation.

Aged↗
PubMed1998

Smoking, hemorheologic factors, and progression of peripheral arterial disease in patients with claudication.

PURPOSE: The purpose of the current study was to determine whether hemostatic and rheologic factors are associated with the deterioration of peripheral arterial disease in patients with intermittent claudication and the influence of smoking and severity of underlying disease on these relationships. METHODS: We conducted a prospective cohort study with a 6-year follow-up period of a consecutive series of 607 patients with uncomplicated intermittent claudication. The study setting was the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. The main outcome measures were peripheral vascular intervention or onset of severe chronic leg ischemia (rest pain, ulceration, gangrene). RESULTS: A total of 210 patients died during follow-up. Two hundred three patients did not have a vascular event or deterioration of limb ischemia, 45 patients underwent a peripheral vascular intervention, and 64 progressed to severe chronic leg ischemia. Median levels (interquartile ranges) of whole blood viscosity were significantly higher in the vascular intervention group (3.75 mPa/sec; range, 3.38 to 4.13 mPa/sec) than in those who did not deteriorate 3.48 mPa/sec; range, 3.06 to 3.83 mPa/sec) (p < or = 0.05), and plasma von Willebrand factor was higher in those with severe chronic leg ischemia (154.0 IU/dl; range, 122.0 to 187.0 IU/dl) than in those who did not deteriorate (131.0 IU/dl; range, 106.0 to 165.0 IU/dl) (p < or = 0.01). After adjustment for age, sex, cigarette smoking, and ankle brachial pressure index, the levels of plasma fibrinogen and blood and plasma viscosities were each associated with an increased risk of vascular intervention (all p < or = 0.05). There were no significant associations between any of the hemorheologic factors and the risk of severe chronic leg ischemia on multivariate analyses. CONCLUSION: Elevations in rheologic factors may have important effects on further reduction of blood flow in the legs of patients with claudication and promote worsening ischemia and clinical progression of symptoms.

Blood Viscosity↗
PubMed1998

Complement activation by cellulose: investigation of the effects of time, area, flow rate, shear rate and temperature on C3a generation in vitro, using a parallel plate flow cell.

The development and utilization of a parallel plate flow system to study the blood response to flat sheet biomaterials, is described. Unlike most other parallel plate flow systems, which have been used to study cellular interactions with biomaterials, the controlled flow test cell described below employs the test materials on both sides of the channel through which the blood flows. The flow cell is used to conduct an investigation into the in vitro generation of C3a by a regenerated cellulose membrane, Cuprophan. The effects of experimental variables such as temperature, blood flow rate, contact area and wall shear rate on C3a generation by Cuprophan were studied. The results show that C3a generation by Cuprophan is lower at 12 degrees C than at 22 degrees C, which is in turn lower than C3a generation at 37 degrees C. Furthermore, a decrease in contact area, and increase in wall shear rate and blood flow rate, can produce a decrease in C3a concentration.

Journal Article↗
PubMed1998

The relative power of heat-precipitation nephelometric and clottable (Clauss) fibrinogen in the prediction of ischaemic heart disease: the Caerphilly and Speedwell studies.

The Caerphilly and Speedwell studies have previously reported the predictive power of heat-precipitation, nephelometric, fibrinogen for 10-year incidence of ischaemic heart disease. A Clauss, clotting time, fibrinogen was also measured at baseline, but has not previously been reported. The predictive power of the two assays is compared. Both methods were employed on fasting blood samples from a total of 4391 men aged 45-63 years. Over the following 10 years 533 (12%) developed major ischaemic heart disease. Nephelometric fibrinogen was higher by 0.33 g/l among the men who developed disease; clottable fibrinogen was higher by 0.20 g/l. This difference is statistically significant (P=0.01). Relative odds of developing heart disease increased steadily to 3.53 (P<0.0001) in the 20% of men with the highest nephelometric fibrinogen; for clottable fibrinogen the corresponding relative odds increased to 2.24 (P<0.0001). When both measures of fibrinogen were included in logistic regression models together with age and smoking habit, the trend for incidence to increase with increasing nephelometric fibrinogen remained highly significant (P<0.0001), whereas for the Clauss fibrinogen the trend almost entirely disappeared (P = 0.37). We conclude that functional assays of clottable fibrinogen may not reflect all of the mechanisms which mediate the association between fibrinogen and cardiovascular disease and that assays of both 'heat precipitable' and 'clottable' fibrinogen should be included in all future prospective studies.

Aged↗
PubMed1998

Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants.

Thrombotic risk factors may be important in determining cardiovascular outcome in patients with symptomatic peripheral arterial disease. A cohort study with a 6-year follow-up period was established to determine the relationships between haemostatic and rheological factors and incident ischaemic heart disease (IHD) and stroke events in patients with peripheral arterial disease. A consecutive series of 607 patients with intermittent claudication was examined between 1989 and 1990 at the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. Main outcome measures were combined fatal and non-fatal stroke, non-fatal myocardial infarction (MI), coronary death and total coronary events. A total of 210 patients died during follow-up. 203 patients did not experience a vascular event or deterioration of limb ischaemia. Median levels of fibrinogen, von Willebrand factor (VWF), tissue plasminogen activator (t-PA) antigen, fibrin D-dimer and whole blood viscosity were significantly higher in those who experienced an event compared with those who did not. After adjusting for age and sex, fibrin D-dimer was significantly associated with risk of non-fatal myocardial infarction (RR 1.50, 95% CI 1.09-2.06, P < or = 0.01). Both fibrinogen and fibrin D-dimer were associated with risk of total coronary events (P < or = 0.05). The risk of stroke was related to baseline levels of t-PA antigen (RR 1.87, 95% CI 1.04-3.34, P < or = 0.05) and whole blood viscosity (RR 1.33, 95% CI 1.07-1.65, P < or = 0.01). All the relationships became weaker and statistically non-significant after further adjustment for cigarette smoking, systolic blood pressure, glucose and baseline IHD. The associations of these factors to IHD and stroke may therefore be partly related to cardiovascular risk factors, but are likely to be important in the pathogenesis of future atherothrombotic events in subjects with peripheral arterial disease.

Aged↗
PubMed1998

The effect of monoclonal or ion-exchange purified factor VIII concentrate on HIV disease progression: a prospective cohort comparison.

The CD4 count has been reported to decline less rapidly in HIV-infected haemophiliacs treated with monoclonally purified factor VIII concentrates than in those using intermediate-purity concentrates. No survival advantage has been demonstrated for this effect, and it is unclear whether this effect occurs with all high-purity concentrates. Two cohorts of patients with severe haemophilia A and HIV treated with either ion-exchange-purified or monoclonally-purified concentrates were compared. The CD4 count, survival, AIDS-defining illnesses, CDC category and anti-retroviral therapy were recorded at 6-monthly intervals for 3 years following the change from intermediate to high-purity factor VIII. 116 patients were recruited, 37 of whom were treated with an ion-exchange purified factor VIII concentrate at three centres, mean (SD) age 31.1 (12.2) years, and 79 were treated with monoclonally purified factor VIII concentrate at two centres, mean (SD) age 29.8 (11.2) years. At the start of the study the median CD4 count was (monoclonal v ion-exchange) 0.30 v 0.16 x 10(9)/l. The CD4 count declined in both arms to a median of (monoclonal v ion-exchange) 0.16 v 0.08 x 10(9)/l at the final visit. Analysis of the (CD4 count)(1/2) over time, using a random coefficients model, found that the mean (SE) rates of decline were not statistically significantly different in the two treatment groups (monoclonal v ion exchange: -0.050 (0.008) v -0.034 (0.011) (CD4 count)(1/2) per year, P = 0.24). No statistically significant difference in survival (log-rank test: P = 0.33) was found. There was no difference in the proportion of individuals experiencing one or more AIDS-defining illnesses (P = 0.32) or in the proportion progressing to CDC category IV (P = 0.28) during the study. The CD4 count declined during the study at a rate similar to that previously reported in patients treated with intermediate-purity factor VIII concentrate, and there was no evidence of any difference between the two treatment groups.

Blood Component Transfusion↗
PubMed1998

Influence of graft material on blood rheology and plasma biochemistry following insertion of an infrainguinal bypass graft.

BACKGROUND: Occlusive arterial disease causes alterations in blood rheology and levels of potential thrombotic and fibrinolytic mediators. The aim of this study was to investigate the effect of graft materials on these parameters in patients undergoing successful infrainguinal revascularization. METHODS: Some 186 consecutive infrainguinal grafts were observed for 12 months. Venous blood was sampled before operation and at 3, 6, and 12 months after surgery. Samples were assayed for thrombotic and rheological parameters. An area under the curve analysis was used to compare the effects of vein and synthetic grafting on these parameters in 99 patients whose grafts remained patent and free from stenosis. RESULTS: Plasma levels of fibrin degradation products were significantly higher in patients with synthetic grafts (n = 46) than in those with autogenous vein grafts (n = 53) (median 274 versus 150 ng/ml; P < 0.001). There were no significant differences in plasma fibrinogen or any other parameters between the two groups. CONCLUSION: Patients with a synthetic infrainguinal graft have a higher fibrin turnover than those with a vein graft. Further studies are required to determine whether this increase in fibrin turnover is an essential requirement to maintain patency of a synthetic infrainguinal graft.

Aged↗
PubMed1998

Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women. The Scottish Heart Health Study.

AIMS: Fibrinogen was measured in 5095 men and 4860 men aged 40-59 in a random population sample from 25 districts of Scotland recruited during 1984-87: the Scottish Heart Health Study. Fibrinogen was then related to the chance of fatal and non-fatal coronary events and death from any cause during a subsequent follow-up period of around 8 years. METHODS AND RESULTS: Fibrinogen was measured by the Clauss assay. The effect of fibrinogen on coronary heart disease and death was assessed through age-adjusted means and Cox proportional hazards regression models, accounting for age, cotinine (a measure of tobacco smoke inhalation) and 11 other major coronary risk factors. Fibrinogen was found to be an important risk factor for coronary heart disease in men and women, with and without pre-existing coronary heart disease. There appears to be a threshold effect, with those in the highest fifth of the distribution having a much increased risk. Estimated age-adjusted hazard ratios by sex and pre-existing coronary heart disease group for the highest to lowest fifth of fibrinogen range between 1.93 and 4.86. Fibrinogen is also important as a risk factor for coronary death and all-causes mortality, with a similar threshold effect. Comparing the two extreme fifths, the hazard ratios for coronary death are 3.01 and 3.42, and for all-cause mortality are 2.59 and 2.20, for men and women respectively. Adjustment for cotinine reduces the hazard ratios, but further adjustment for the other 11 risk factors has little effect for coronary heart disease events. After full adjustment there is a remaining significant (P < 0.05) hazard ratio for coronary death and death from any cause and for a coronary heart disease event for those free of coronary heart disease at baseline, amongst men, comparing the highest to the lowest fifth. CONCLUSION: Fibrinogen is a strong predictor of coronary heart disease, fatal or non-fatal, new or recurrent, and of death from an unspecified cause, for both men and women. Its effect is only partially attributable to other coronary risk factors, the most important of which is smoking.

Adult↗
PubMed1998

Etiopathogenesis of cardiovascular disease: hemostasis, thrombosis, and vascular medicine.

The role of hemostatic variables (which promote hemostatic plugs and thrombi) and rheological variables (which affect blood flow) in the pathogenesis of vascular diseases (ischemic heart disease, stroke, and peripheral arterial disease) is reviewed, with emphasis on epidemiological studies. Rheological variables are consistently associated with both prevalent and incident cardiovascular disease. These associations are only partly explained by conventional risk factors. The predictive value of plasma viscosity for cardiovascular events is partly explained by fibrinogen, and partly by lipoproteins. The associations of whole blood viscosity with cardiovascular disease are partly explained by plasma viscosity and partly by hematocrit. White cell count, but not platelet count, predicts ischemic heart disease events. Cigarette smokers have higher levels of rheological variables than non-smokers, these increases are partly or wholly reversible in ex-smokers. Lipoprotein reduction by pravastatin lowers plasma and whole-blood viscosity, which may be one mechanism through which lipid lowering produces an early reduction in cardiovascular events. Data from the Edinburgh Artery Study suggest that viscosity is related both to the extent of atherosclerosis, and to ischemia in the presence of a given degree of atherosclerotic stenoses. Among hemostatic variables, fibrinogen, factor VIII: vWF complex, tpA antigen, and fibrin D-dimer are associated with both prevalent and incident cardiovascular disease. Again, these associations are only partly explained by conventional risk factors They suggest that endothelial disturbance and increased fibrin turnover may play roles in cardiovascular disease. Hemostatic and rheological variables are therefore associated with both prevalent and incident cardiovascular disease, and may be mechanisms through which risk factors such as smoking, hyperlipidemia and infections (including oral infections) promote vascular events.

Biomarkers↗
PubMed1998

Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study.

Plasma levels of fibrin D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI) have been associated with ischaemic heart disease (IHD). However their associations with incident IHD in samples of the general population are not established. D-dimer antigen, tPA antigen and PAI activity were measured in stored, fasting plasma samples from 1,998 men aged 45-65 examined between 1984 and 1988, during the first re-examination of the Caerphilly Study cohort. These variables were related to major IHD events (myocardial infarction or IHD death) which occurred in 129 men during a follow-up period which averaged 61 months. Mean fibrin D-dimer was higher in men who developed IHD events (90 vs. 71 ng/ml; age-adjusted logarithmic mean difference 0.21; 95% CI 0.11, 0.30; p <0.0001). This association remained after adjusting for baseline IHD and for other risk factors including fibrinogen: the adjusted relative odds of IHD in the highest fifth of D-dimer were 3.5 (95% CI 1.8, 6.9; p = 0.0003). Mean tPA antigen was also higher in men who developed IHD (12.6 vs. 11.6 ng/ml; mean difference 0.9; 95% CI 0.2, 1.7; p = 0.02); however this difference largely disappeared after adjusting for other risk factors. PAI activity was not associated with risk of IHD.

Aged↗