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2.  Use of statins 
BMJ : British Medical Journal  1998;317(7156):473.
PMCID: PMC1113724  PMID: 9703541
3.  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
4.  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
5.  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
6.  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
11.  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
12.  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
14.  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
16.  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
17.  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
18.  Side-effects of beta-adrenoceptor blocking drugs assessed by visual analogue scales. 
A series of visual analogue scales (VAS) was used to examine the prevalence of side-effects among hypertensive patients taking beta-adrenoceptor blocking drugs. When compared to untreated non-hypertensive control subjects, patients taking beta-adrenoceptor blockers had a greater prevalence of tired legs (P less than 0.001), cold digits (P less than 0.01), insomnia (P less than 0.01) and loss of overall wellbeing (P less than 0.01). Side-effects did not differ significantly between patients taking atenolol (n = 30), oxprenolol (n = 16), propranolol (n = 15) or metoprolol (n = 10). If there is an important difference in the prevalence of side-effects between different beta-adrenoceptor blockers, a much larger study will be needed to demonstrate it.
PMCID: PMC1463712  PMID: 2859044
19.  Quantification of side-effects of beta-adrenoceptor blockers using visual analogue scales. 
We have devised a series of visual analogue scales (VAS) to measure the side-effects prevalent amongst hypertensive patients taking beta-adrenoceptor blockers, and we present the results of a pilot study. These show that the method is suitable for studying side-effects and suggest that patients on beta-adrenoceptor blockers experience a greater incidence of tiredness of the legs, (P = 0.001), cold digits (P = 0.005) and vivid dreaming (P = 0.01) when compared to hypertensive patients not taking beta-adrenoceptor blockers.
PMCID: PMC1463646  PMID: 6148958
20.  The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol. 
The pharmacokinetics and pharmacodynamics of propranolol (80 mg by mouth) were studied in seven extensive and four poor metabolisers of debrisoquine. Evidence for impairment of the 4'-hydroxylation of propranolol was found in poor metabolisers. However, no significant difference was detected in the oral clearance of unchanged drug between the two groups of debrisoquine oxidation phenotypes. Poor metabolisers of debrisoquine did not experience more intense or more prolonged beta-adrenoceptor blockade than extensive metabolisers of debrisoquine.
PMCID: PMC1463425  PMID: 6743465
21.  Relative potency of spironolactone, triamterene and potassium chloride in thiazide-induced hypokalaemia. 
1 The influence of spironolactone 50 mg and 100 mg daily, triamterene 100 mg and 200 mg daily, potassium chloride 32 mmol and 64 mmol daily and placebo on plasma potassium and other variables was examined in a random crossover study of nine hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone and triamterene had significant and parallel dose-response curves for plasma potassium, with a relative potency for triamterene:spironolactone of 0.25:1, significantly lower than the accepted 0.5:1 ratio. These drugs also lowered serum sodium, bicarbonate and body weight, and increased serum urea and creatinine. 3 Potassium chloride increased plasma potassium above placebo values, but the dose-response was not significant and was not parallel with those of the potassium-sparing drugs. Seven of nine patients remained hypokalaemic despite treatment with 64 mmol potassium chloride daily. 4 The relative expense, convenience and toxicity of the potassium-sparing drugs should be assessed at equivalent doses, namely spironolactone 50 mg:triamterene 200 mg:amiloride 20 mg. Potassium chloride does not correct moderate diuretic-induced hypokalaemia even at doses of 64 mmol daily.
PMCID: PMC1427745  PMID: 7104176

Results 1-21 (21)