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Biomedical subjects

W W Yeo

Publications and source records attributed to W W Yeo.

At least 19 recordsLinked to original sources
PubMed2001

Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.

AIMS: To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil. METHODS: Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1-250 microM). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate. RESULTS: When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 microM for all major metabolites. The IC50 values ranged from 4.8 to 5.6 microM on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from 110-127 microM and from 21-27 microM, respectively. Verapamil and diltiazem inhibited testosterone 6beta-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 +/- 0.04 min-1 (mean +/- s.d.) and 2.9 +/- 0.6 microM, respectively, for verapamil and 0.07 +/- 0.01 min-1 and 3.3 +/- 1.5 microM, respectively, for diltiazem. CONCLUSIONS: The IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.

Calcium Channel Blockers↗
PubMed2000

Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population.

OBJECTIVE: To examine the accuracy of a new version of the Sheffield table designed to aid decisions on lipids screening and detect thresholds for risk of coronary heart disease needed to implement current guidelines for primary prevention of cardiovascular disease. DESIGN: Comparison of decisions made on the basis of the table with absolute risk of coronary heart disease or cardiovascular disease calculated by the Framingham risk function. The decisions related to statin treatment when coronary risk is >/=30% over 10 years; aspirin treatment when the risk is >/=15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is >/=20% over 10 years. SETTING: The table is designed for use in general practice. SUBJECTS: Random sample of 1000 people aged 35-64 years from the 1995 Scottish health survey. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of the table. RESULTS: 13% of people had a coronary risk of >/=15%, and 2. 2% a risk of >/=30%, over 10 years. 22% had mild hypertension (systolic blood pressure 140-159 mm Hg). The table indicated lipids screening for everyone with a coronary risk of >/=15% over 10 years, for 95% of people with a ratio of total cholesterol to high density lipoprotein cholesterol of >/=8.0, but for <50% with a coronary risk of <5% over 10 years. Sensitivity and specificity were 97% and 95% respectively for a coronary risk of >/=15% over 10 years; 82% and 99% for a coronary risk of >/=30% over 10 years; and 88% and 90% for a cardiovascular risk of >/=20% over 10 years in mild hypertension. CONCLUSION: The table identifies all high risk people for lipids screening, reduces screening of low risk people by more than half, and ensures that treatments are prescribed appropriately to those at high risk, while avoiding inappropriate treatment of people at low risk.

Adult↗
PubMed1999

Association of panic disorder and panic attacks with hypertension.

PURPOSE: Previous studies of the association between hypertension and panic disorder were uncontrolled or involved small numbers of patients. PATIENTS AND METHODS: We compared the prevalence of panic disorder and panic attacks in 351 patients with documented hypertension who were randomly selected from all hypertensive patients registered in one primary care practice with age- and gender-matched normotensive patients from the same practice and with hypertensive patients attending a hospital clinic. All three groups completed questionnaires for panic disorder based on standard criteria, as well as the Hospital Anxiety and Depression scale. RESULTS: The prevalence of current (previous 6 months) panic attacks was significantly greater in primary care patients with hypertension (17%, P <0.05) and hospital-based hypertensive patients (19%, P <0.01) than in normotensive patients (11%). Similar results were seen for lifetime panic attacks (35% versus 39% versus 22%; both P for comparisons with normotensive patients <0.001). The prevalence of panic disorder was significantly greater in primary care patients with hypertension (13%) than normotensive patients (8%, P <0.05). Anxiety scores were significantly higher in both hypertensive groups than in normotensive patients. Depression scores were significantly higher in hospital-based hypertensive patients than in the other two groups. The reported diagnosis of hypertension antedated the onset of panic attacks in a large majority of patients (P <0.01). CONCLUSIONS: Physicians caring for patients with hypertension should be aware of the significantly greater prevalence of panic attacks in these patients.

Aged↗
PubMed1999

Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients.

AIMS: To investigate whether an interaction between diltiazem and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance the cholesterol-lowering response to simvastatin in diltiazem-treated patients. METHODS: One hundred and thirty-five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996-May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem. RESULTS: The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1-12.2%, P<0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16-4.11), and 3.42 at 20 mg daily (P<0.01, 95% CI 1.26-7.18). Concurrent diltiazem therapy (P<0.04), age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be significant independent predictors of percentage cholesterol response. CONCLUSIONS: Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events.

Anticholesteremic Agents↗
PubMed1999

Implication of recent trials with b-hydroxy-b-methylglutaryl coenzyme A reductase inhibitors for hypertension management.

BACKGROUND: There is broad agreement that statin treatment should be targeted at absolute coronary heart disease (CHD) risk but no consensus on the level of risk to target. We have examined the implications of adopting three different treatment policies for the management of hypertensive patients in the UK using data from treated hypertensives aged 35-69 years included in the Health Survey for England (1993). METHODS: We calculated the proportion of hypertensive patients with existing atherosclerotic cardiovascular disease requiring statin treatment for secondary prevention of CHD. For those without atherosclerotic cardiovascular disease (primary prevention), we estimated CHD risk from the Framingham equation and examined the proportion with CHD risk exceeding thresholds of 4.5, 3 and 1.5% per year. RESULTS: Twenty-one percent of treated hypertensives would require statin treatment for secondary prevention of CHD. When the CHD event threshold for statin treatment was set at > or =4.5% per year [equivalent to a number needed to treat (NNT) in 5 years of 13] a further 0.6% of hypertensive patients were identified for treatment; at a threshold of 3.0% per year (NNT = 20) 5.5% of patients were identified for primary prevention; and at a threshold of 1.5% per year (NNT = 40) 28.5% of patients were identified for primary prevention. CONCLUSIONS: Those needing secondary prevention are first priority for statins and 21% of hypertensive patients will require treatment Formulation of guidelines for primary prevention should take into account the NNT; the proportion of patients targeted for treatment; the cost-effectiveness and the total cost of treatment. Current British guidance will entail treating an additional 5.5% of hypertensive patients for primary prevention and therefore 27% of hypertensive patients.

Aged↗
PubMed1999

Is the Framingham risk function valid for northern European populations? A comparison of methods for estimating absolute coronary risk in high risk men.

OBJECTIVE: To examine the validity of estimates of coronary heart disease (CHD) risk by the Framingham risk function, for European populations. DESIGN: Comparison of CHD risk estimates for individuals derived from the Framingham, prospective cardiovascular Münster (PROCAM), Dundee, and British regional heart (BRHS) risk functions. SETTING: Sheffield Hypertension Clinic. Patients-206 consecutive hypertensive men aged 35-75 years without preexisting vascular disease. RESULTS: There was close agreement among the Framingham, PROCAM, and Dundee risk functions for average CHD risk. For individuals the best correlation was between Framingham and PROCAM, both of which use high density lipoprotein (HDL) cholesterol. When Framingham was used to target a CHD event rate > 3% per year, it identified men with mean CHD risk by PROCAM of 4.6% per year and all had CHD event risks > 1.5% per year. Men at lower risk by Framingham had a mean CHD risk by PROCAM of 1.5% per year, with 16% having a CHD event risk > 3.0% per year. BRHS risk function estimates of CHD risk were fourfold lower than those for the other three risk functions, but with moderate correlations, suggesting an important systematic error. CONCLUSION: There is close agreement between the Framingham, PROCAM, and Dundee risk functions as regards average CHD risk, and moderate agreement for estimates within individuals. Taking PROCAM as the external standard, the Framingham function separates high and low CHD risk groups and is acceptably accurate for northern European populations, at least in men.

Adult↗
PubMed1999

Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment.

OBJECTIVES: To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment. DESIGN: Cohort life table method using data from outcome trials. MAIN OUTCOME MEASURES: The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from pound 100 to pound 800 per year. RESULTS: The costs per life year gained according to annual CHD event risk were: for 4.5%, pound 5100; 3.0%, pound 8200; 2.0%, pound 10 700; and 1.5%, pound 12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks. CONCLUSIONS: At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.

Coronary Disease↗
PubMed1998

Protein binding of aspirin and salicylate measured by in vivo ultrafiltration.

OBJECTIVE: Methods for measuring protein binding of drugs generally require direct measurement of the concentration of unbound drug and thus may require a highly sensitive assay. In vivo ultrafiltration has been used to determine protein binding of endogenous substances. We have examined its value for measuring protein binding of drugs because it requires measurement of only the concentration of total drug, not unbound drug, in plasma. METHODS: The protein binding of aspirin and its metabolite salicylate was measured in 29 healthy subjects 20 minutes after a single oral dose of 600 mg soluble aspirin, by the new method, in vivo ultrafiltration, as well as by a standard method, in vitro ultracentrifugation. RESULTS: The data for salicylate were examined systematically to determine the optimal method of determining estimates of protein binding by in vivo ultrafiltration. Estimates of protein binding of salicylate were 81.7% +/- 10.1% (mean +/- SD) by the in vivo method and 81.6% +/- 11.3% by in vitro ultracentrifugation. Bland-Altman analysis of agreement showed that within-individual differences in percentage of protein binding determined by the two methods did not differ significantly from zero (mean difference, 0.07%; 95% confidence interval, -2.33 to +2.46). There was a highly significant correlation between estimates of protein binding by the two methods (r = 0.82; p = 0.001). Protein binding of aspirin was estimated of protein binding by the two methods (r = 0.82; p = 0.001). Protein binding of aspirin was estimated at 58.3% +/- 9.6% by in vivo ultrafiltration and could not be estimated by in vitro ultracentrifugation because the concentration of unbound aspirin in plasma was below the limit of detection for the assay. CONCLUSION: In vivo ultrafiltration can be used to measure protein binding of drugs and has potential advantages over conventional methods. A sensitive assay may not be required because the unbound drug need not be measured, measurement in vivo may maintain more physiologic conditions, and it may be useful in measuring protein binding of drugs that are degraded rapidly in vitro.

Adult↗
PubMed1998

The rationale for differing national recommendations for the treatment of hypertension.

This article examines the rationale for the differences in the guidelines for hypertension management of four national or international bodies: the Joint National Committee (JNC-V), The World Health Organization/International Society of Hypertension (WHO-ISH), the British Hypertension Society (BHS), and the New Zealand guidelines. These guidelines agree on many aspects of management, but differ on two very important points-the drugs of first choice for hypertension, and the indications for drug treatment of uncomplicated mild hypertension. JNC-V recommends treatment routinely of all people with a sustained blood pressure of 140/90 mm Hg, whereas the BHS guidelines advise treatment routinely at 160/100 mm Hg. Such differences in the threshold for treatment have a major impact on the proportion of the adult population to be treated, and on the benefit from treatment. JNC-V was heavily influenced by the Hypertension Detection and Follow-up Program (HDFP), which appeared to show a large benefit from the treatment of uncomplicated mild hypertension, whereas the BHS guidelines were influenced by the Medical Research Council (MRC) Trial, which showed a very small benefit. However, the apparent differences in absolute benefit between these, and other, randomized controlled trials is related entirely to differences in the absolute cardiovascular risk of the populations studied. In populations and in individual patients the benefit from antihypertensive treatment is determined by the absolute cardiovascular risk. Blood pressure by itself is a very weak predictor of risk or benefit from treatment. In uncomplicated mild hypertension the need for drug therapy should be based on the absolute risk of cardiovascular complications, estimated by considering age, sex, serum cholesterol level, diabetes mellitus status, and smoking habits, in addition to blood pressure. Doctors cannot estimate absolute risk accurately informally or intuitively, and the next generation of guidelines should incorporate a simple but accurate method for estimating cardiovascular risk, similar to that in the New Zealand guidelines. The decision to treat, or not treat, uncomplicated mild hypertension should be based on a formal estimate of absolute cardiovascular risk and not on an arbitrary blood pressure threshold. As regards drugs of first choice, the available evidence supports strongly the stance of JNC-V and JNC VI that diuretics and beta-blockers should be preferred unless they are contraindicated, or unless there are positive indications for other drug classes.

Adult↗