Search tips
Search criteria

Results 1-25 (30)

Clipboard (0)
more »
Year of Publication
more »
1.  Book review 
PMCID: PMC2015015
2.  A new regimen for starting warfarin therapy in out-patients 
Oral anticoagulation is increasingly used in elderly patients with atrial fibrillation to prevent embolic phenomena. The use of anticoagulants in this population is prophylactic rather than therapeutic and so there is no urgency to establish anticoagulation within the desired therapeutic range. The aim of the study was to develop an out-patient regimen for initiation of oral anticoagulation with warfarin which requires only weekly monitoring of the International Normalized Ratio (INR).
The study was undertaken in two phases. In the first phase, factors which predict the final maintenance dosage of warfarin were defined and used to build a decision tree and dosage algorithm. In the second study the algorithm was tested. Patients were given 2 mg warfarin daily for 2 weeks and the INR at this time was used to predict the maintenance dose. Patients then attended for weekly measurements of the INR until steady state had been reached. Dosage adjustments were not made unless the INR was >4.0 or <1.5 for 2 consecutive weeks. The accuracy of the prediction was measured by calculating the mean INR of weeks 6–8 and the number of patients in the target range 2.0–3.0 was determined.
One hundred and seven consecutive out-patients (mean age 70 years range 64–86) completed the first study. The age, sex, height, weight, alcohol intake, number of cigarettes smoked, concomitant medication, clinical evidence of right heart failure, liver failure, abnormalities in liver enzyme estimations, baseline INR and INR after 2 weeks of 2 mg warfarin daily were used in a polytomous logistic regression analysis with stepwise inclusion of factors to determine which factors influenced the eventual maintenance dosage of warfarin. The INR after 2 weeks of 2 mg warfarin therapy predicted 70% of the variability of the maintenance dose. Of other factors only the sex of the patient had a large enough effect to be included in the prediction algorithm. One hundred and six patients (mean age 71 years range 50–85 years) completed the second study. Only one patient needed a dose adjustment in the first 2 weeks of warfarin 2 mg daily (INR 4.4). Overall, 60% patients were in the narrow target range (INR 2.0–3.0) at steady state. In five patients the INR was >4.0 at any visit after the second week and needed dosage adjustment. In four patients the INR was <1.5 at steady state.
We have developed a method of predicting the maintenance dose of warfarin in an elderly population based on the INR after 2 weeks of warfarin 2 mg daily, and the sex of the patient. This is a safe and convenient way of initiating warfarin therapy as an out-patient which requires only weekly INR checks.
PMCID: PMC1873664  PMID: 9723825
anticoagulation; atrial fibrillation; warfarin
4.  Use of statins 
BMJ : British Medical Journal  1998;317(7156):473.
PMCID: PMC1113724  PMID: 9703541
5.  Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. 
1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.
PMCID: PMC1365187  PMID: 8703645
6.  Effect of dose adjustment on enalapril-induced cough and the response to inhaled capsaicin. 
1. In nine hypertensive patients with enalapril-induced cough the effect of altering the dose of enalapril on subjective cough and the cough response to inhaled capsaicin was examined in a random single-blind balanced cross-over study. They received three doses of enalapril, each for 3 weeks; the dose at entry (mean 10 mg daily); double this dose (mean 20 mg daily); and half this dose (mean 5 mg daily). 2. The cough response to inhaled capsaicin was also measured in two control groups: hypertensive patients on long-term enalapril treatment with no cough (n = 18), and hypertensive patients taking nifedipine (n = 17). 3. In patients with enalapril-induced cough there were significant dose-responses for enalapril as regards severity of cough (P < 0.05) and night time waking by cough (P < 0.05), but not for frequency of cough. Although the cough was less severe (P < 0.02) and caused less night time waking (P < 0.03) on the lowest dose of enalapril (mean 5 mg daily) it did not disappear completely in any patient. 4. The sensitivity to inhaled capsaicin did not differ significantly on the three doses of enalapril. The relative potency of capsaicin on enalapril 20 mg compared with enalapril 5 mg was 1.0 (95% CI 0.4-2.2). The wide confidence limits indicate that an important dose-dependent shift in capsaicin sensitivity is not excluded. 5. The sensitivity to inhaled capsaicin differed significantly between patients with enalapril-induced cough and both control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1365003  PMID: 7619668
7.  Relation between changes in blood pressure and serum ACE activity after a single dose of enalapril and ACE genotype in healthy subjects. 
1. The effects of a single oral dose of enalapril 10 mg on serum ACE activity and blood pressure in relation to the ACE genotype were studied in 27 healthy men, n = 9 each of genotype DD, ID and II, in a parallel group study design. 2. Before treatment serum ACE activity differed significantly between the genotypes, with serum ACE activity 56% higher in DD than II subjects, and the genotype explaining 40% of between-subject variance in serum ACE activity. 3. After oral enalapril 10 mg the absolute fall in serum ACE activity was significantly larger in DD than II subjects at 2, 4, and 6 h (by 9.0 (95% CI 0.7-17.2), 10.7 (3.8-17.6), and 9.7 (2.8-16.6) nmol ml-1 min-1 respectively), but not at 24 h (fall in II > DD by 1.1 (-8.9 to 6.7) nmol ml-1 min-1). 4. Serum ACE activity remained significantly related to the ACE genotype at each time-point after enalapril, with the genotype explaining 22-46% of between-subject variance in serum ACE. 5. Falls in mean arterial pressure in response to enalapril were not significantly related to the ACE genotype, with the average fall over 6 h in DD > II genotype by 0.7 mm Hg (95% CI -5.5 to 4.1). 6. Blood pressure responses to enalapril did not correlate significantly with the initial serum ACE, or the absolute or percent reductions in serum ACE activity after enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1364949  PMID: 7742150
8.  Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4-hydroxy propranolol. 
1. The 4-hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which binds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its catalytic function. Therefore, the effect of propranolol treatment (80 mg twice daily) on debrisoquine phenotype was examined, to see if it resulted in phenocopying in vivo. The role of 4-hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes from yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2. Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urinary debrisoquine/4-hydroxydebrisoquine ratio (D/4HD) was small, such that no extensive metaboliser who received propranolol treatment was reclassified as a poor metaboliser. The in vitro studies indicated that 4OHP is a potent inhibitor of metoprolol metabolism (Ki approximately 1 microM). This inhibitory effect was enhanced when 4OHP was pre-incubated in the presence of a NADPH generating system and human liver microsomes. The effect was decreased significantly when reduced glutathione was added to the pre-incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH generating system and irrespective of CYP2D6 phenotype; yeast expressing CYP2D6 did not metabolise 4OHP. 3. We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalytic function of CYP2D6, the inhibition is insufficient to result in phenocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and other nucleophiles.
PMCID: PMC1364831  PMID: 7946944
13.  Dietary reduction of serum cholesterol concentration: time to think again. 
BMJ : British Medical Journal  1991;303(6808):953-957.
OBJECTIVE--To evaluate the long term efficacy of diets in lowering serum cholesterol concentration. DESIGN--Descriptive overview of 16 published controlled trials of six months' duration or longer. SETTING--Trials had been conducted in hospital clinics (6), industry (3), mental hospitals or institutions (3), and in general populations (4). PATIENTS--Trials had been conducted in high risk subjects (5), in unselected healthy subjects (6), or for secondary prevention in patients with coronary heart disease (5). Women were included in only four trials. INTERVENTIONS--Diets equivalent to the step 1 diet were employed in eight trials, with individual intervention by dietitians (3) or occupational physicians (2) or with population advice (3). Intensive diets which were more rigorous than the step 2 diet were employed in eight trials. MAIN OUTCOME MEASURES--Net change in serum total cholesterol concentration in subjects receiving treatment with diet compared with values in control subjects after six months to 10 years. RESULTS--In five trials with the step 1 diet as individual intervention the net reduction in serum cholesterol concentration ranged from 0% to 4.0% over six months to six years. In trials with population education reductions in cholesterol concentrations were 0.6-2.0% over five to 10 years. When population and individual dietary advice were combined changes in cholesterol concentration ranged from a fall of 2.1% to a rise of 1.0% over four to 10 years. Diets more intensive than the step 2 diet reduced serum cholesterol concentration by 13% over five years in selected high risk men in the population; by 6.5-15.1% over two to five years in hospital outpatients; and by 12.8-15.5% over one to four and a half years in patients in institutions. CONCLUSIONS--The response to a step 1 diet is too small to have any value in the clinical management of adults with serum cholesterol concentrations above 6.5 mmol/l. Current guidelines recommend screening of serum cholesterol concentration in healthy subjects, followed by treatment with a step 1 diet. The guidelines should be reviewed to provide a more realistic estimate of the effect of a step 1 diet and of the likely need for lipid lowering drugs.
PMCID: PMC1671346  PMID: 1954418
14.  Influence of debrisoquine oxidation phenotype on exercise tolerance and subjective fatigue after metoprolol and atenolol in healthy subjects. 
1. The effects of single doses of metoprolol 50 mg, metoprolol 100 mg and atenolol 100 mg on exercise tolerance were compared with placebo in a double-blind random cross-over study in 12 healthy subjects. Nine subjects were extensive metabolisers of debrisoquine, and three were poor metabolisers. 2. Three hours after dosing beta-adrenoceptor blocker treatments significantly reduced exercise heart rate, prolonged time to complete exercise, and increased subjective fatigue measured by visual analogue scale. 3. Scores for subjective fatigue did not correlate with reduction in exercise heart rate or prolongation of exercise time. Exercise time prolongation was weakly but not significantly correlated with exercise heart rate reduction. 4. When compared with placebo, prolongation of exercise time and increased fatigue with metoprolol were not significantly related to debrisoquine oxidation phenotype or to the debrisoquine/4-hydroxydebrisoquine (D/4OH-D) ratio. 5. When metoprolol responses were compared with those for atenolol, changes in exercise time and fatigue scores were significantly related to oxidation phenotype. For metoprolol 100 mg, poor metabolisers required 20.8 s longer to complete exercise (P less than 0.05) and had higher fatigue scores by 78% (P less than 0.05) as compared with extensive metabolisers.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1368323  PMID: 2049246
16.  Backtracking booze with Bayes--the retrospective interpretation of blood alcohol data. 
1. A Bayesian method is described which allows the explicit estimation of errors produced in estimating drug concentrations at times for which samples are not available for analysis. 2. This method was applied to the problem of 'backtracking' alcohol concentrations for medico-legal purposes. 3. Computer simulation allowed the effect of continuing alcohol absorption on the position and range of estimates of alcohol concentrations to be studied.
PMCID: PMC1368412  PMID: 2015171
17.  Unimodal distribution of the metabolic ratio for debrisoquine in Cuna Amerindians of Panama. 
1. The metabolic oxidation of debrisoquine (DB) was studied in 89 non-related Cuna Amerindian subjects. 2. Means and standard deviations for urinary recoveries of the intact drug and its 4-hydroxy metabolite (4-HD) were: %DB: 6.8 +/- 4.5; %4-HD: 16.0 +/- 9.1; %sum: 22.8 +/- 12.0. The log10 metabolic ratios for DB (LMRDB) were distributed within a single mode of insignificant skewness (-0.01, P greater than 0.10), which was unimodal (log kernel density and maximum likelihood methods) and normal (chi 2 = 22.5; d.f. = 15; P greater than 0.09; power of the test greater than 80%). 3. Therefore, no poor metabolizers (95% C.I.: 0.1%, 5.2%) were detected in the population sample studied.
PMCID: PMC1368229  PMID: 2206790
18.  Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism--histograms and probit plots. 
1. The shape of histograms used to illustrate density distributions of indices of polymorphic drug metabolism was shown to be sensitive to the position of the cell divisions. 2. Non-linearity of the probit plot was shown not to indicate bimodality of the original density distribution. Computer simulation was used to generate examples of unimodal density distributions with curvilinear probit plots. 3. Using the same technique probit plots for bimodal density distributions were constructed. Some were shown to differ less from the probit plots of certain unimodal distributions than did the original density distributions. 4. The position of the antimode was shown not to coincide with inflections seen in the probit plots. 5. A new method for determining the linearity of probit plots is suggested.
PMCID: PMC1380035  PMID: 2611087
19.  Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism--hypothesis testing. 
1. The theory of methods of hypothesis testing in relation to the detection of bimodality in density distributions is discussed. 2. Practical problems arising from these methods are outlined. 3. The power of three methods of hypothesis testing was compared using simulated data from bimodal distributions with varying separation between components. None of the methods could determine bimodality until the separation between components was 2 standard deviation units and could only do so reliably (greater than 90%) when the separation was as great as 4-6 standard deviation units. 4. The robustness of a parametric and a non-parametric method of hypothesis testing was compared using simulated unimodal distributions known to deviate markedly from normality. Both methods had a high frequency of falsely indicating bimodality with distributions where the components had markedly differing variances. 5. A further test of robustness using power transformation of data from a normal distribution showed that the algorithms could accurately determine unimodality only when the skew of the distribution was in the range 0-1.45.
PMCID: PMC1380036  PMID: 2611088
20.  Timolol metabolism and debrisoquine oxidation polymorphism: a population study. 
1. The metabolism of orally administered timolol (T) to its ring cleavage ethanolamine (TE) and glycine (TG) products was studied in 108 unrelated hypertensive patients. 2. Statistically significant correlations between the 0-8 h urinary debrisoquine/4-hydroxy-debrisoquine ratio and the T/TE (rs = 0.74, P less than 0.001), T/TG (rs = 0.42, P less than 0.001) and T/TE + TG (rs = 0.49, P less than 0.001) ratios were found. 3. The log10 T/TE, T/TG and T/TE + TG ratios from poor metabolisers of debrisoquine (PMs) were grouped at the upper end of a unimodal distribution. 4. These results indicate that timolol metabolism is partly under monogenic control of the debrisoquine-type. 5. The mean +/- s.d. plasma timolol concentration in PMs (82 +/- 43 ng ml-1) was double that in extensive metabolisers (45 +/- 19 ng ml-1) (P = 0.011). The clinical significance of this observation remains to be established.
PMCID: PMC1379721  PMID: 2719899
21.  Mental health of unemployed men in different parts of England and Wales. 
In a study of mental health among unemployed men two contrasting hypotheses about the importance of the local unemployment rate were examined--namely, that very high local unemployment might be associated with either impoverishment or resilience of the community, which would affect health in opposite ways. The mental health of 954 unemployed men registered at 41 unemployment benefit offices in England and Wales was assessed by the general health questionnaire, men in areas of particularly high unemployment being compared with men in areas of moderate and relatively low unemployment. Scores for ill health were significantly lower in areas of particularly high unemployment, even when personal factors known to affect mental health during unemployment were controlled for. These results support the hypothesis that communities with high rates of unemployment develop resilience that is beneficial for the mental health of the unemployed.
PMCID: PMC1247430  PMID: 3117205
22.  Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices. 
The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined. Pharmacokinetic determinants in addition to partial metabolic clearance down the polymorphic route were identified in each index. The ability of the various indices to discriminate bimodality in population data was assessed using a computer simulation. With the exception of the AUC data, bimodality was apparent to varying extents in all of the frequency distributions and, in general, logarithmic transformation allowed clearer visualisation of the two phenotypic groups. Simulated distributions were compared with those observed experimentally for metoprolol and its alpha-hydroxy metabolite. Detailed pharmacokinetic data from controlled studies in small numbers of volunteers can form the basis of the input to the simulation programme. Inspection of the output may help in the design of further studies in larger numbers of subjects in whom only limited data collection is possible.
PMCID: PMC1401184  PMID: 3790400
24.  Measuring side-effects of beta-adrenoceptor antagonists: a comparison of two methods. 
The prevalence of side-effects of beta-adrenoceptor antagonists among hypertensive patients was assessed by two methods. Using visual analogue scales, scores for tired legs, cold digits and vivid dreaming were significantly higher in patients taking beta-adrenoceptor blockers than in patients not taking beta-adrenoceptor blockers. When measured by numerical scales, from 1 to 10, these symptoms showed no relation to beta-adrenoceptor blocker treatment. The visual analogue scales were more sensitive than the numerical scales because the scores were distributed more evenly over the analogue scales.
PMCID: PMC1463863  PMID: 2862895
25.  Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. 
The pharmacokinetics and pharmacodynamics of atenolol and timolol were studied in six extensive and four poor metabolisers of debrisoquine. There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and the area under the plasma concentration time curve (AUC) for timolol (rs = 0.75, P less than 0.02). The mean of the AUC values for timolol was significantly greater in the poor metabolisers than in the extensive metabolisers (P less than 0.05). There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and beta-adrenoceptor blockade 24 h after dosing with timolol (rs = 0.66, P less than 0.05). The mean degree of beta-adrenoceptor blockade was significantly greater in the poor metabolisers than in the extensive metabolisers 24 h after dosing with timolol (P less than 0.01). There was no relation between the debrisoquine to 4-hydroxydebrisoquine ratio and the pharmacokinetics or pharmacodynamics of atenolol.
PMCID: PMC1463731  PMID: 2859048

Results 1-25 (30)