Dispositional factors do not contribute to the enantiospecificity of the cardiovascular effects of phenylpropanolamine.

The pharmacokinetics and blood pressure response of the phenylpropanolamine enantiomers (i.e., d- and l-phenylpropanolamine) were determined after the separate oral administration of racemic dl-phenylpropanolamine (75 mg), l-phenylpropanolamine (37.5 mg), and d-phenylpropanolamine (37.5 mg) to six healthy volunteers. No significant differences were observed between any of the pharmacokinetic parameters of d- and l-phenylpropanolamine when the enantiomers were administered individually or as the racemate. There was also no difference in the ex vivo plasma protein binding of d- and l-phenylpropanolamine, determined individually or as the racemate. Significant increases from baseline in systolic and diastolic blood pressure (supine and standing) were observed for dl- and l-phenylpropanolamine, whereas d-phenylpropanolamine had no effect on blood pressure. The effects of dl- and l-phenylpropanolamine on blood pressure were not significantly different. The data from this study show that pharmacokinetic factors do not contribute to the stereospecificity of the cardiovascular effects of phenylpropanolamine or to the interindividual variability in the blood pressure response to phenylpropanolamine.

Effects of age and isolated systolic hypertension on cardiovascular reflexes.

OBJECTIVES: Given the reported relationship between systolic hypertension and orthostatic hypotension in the elderly, to test the hypothesis that systolic hypertension causes impairment of the cardiovascular reflex function additional to the effects of age alone. DESIGN: Responses were compared in normotensive healthy young (n = 12) and elderly (n = 15) participants and elderly participants with disproportionate supine systolic hypertension (n = 11) using a baroreceptor-mediated stress (head-up tilt) and two non-baroreceptor-mediated stimuli (cold pressor test and isometric exercise). METHODS: Blood pressure and heart rate were measured by oscillometry before and during the three stress tests. Forearm blood flow was measured by venous occlusion plethysmography and pulse wave velocity (PWV) by Doppler ultrasound. RESULTS: Percentage changes in systolic/diastolic (SBP/DBP) blood pressure with head-up tilt were 0/+11, -3/0 and -6/+1 mmHg in the young and elderly normotensives and elderly systolic hypertensives, respectively. Both elderly groups had reduced DBP responses to tilt compared with the young (P < 0.01). All three groups had similar percentage changes in blood pressure responses to non-baroreflex-mediated stresses (cold pressor test: +10/+23, +11/+11, +10/+15; sustained isometric exercise: +18/+33, +22/+24, +13/+17 in the young and elderly normotensives and elderly systolic hypertensives, respectively). Aorto-iliac PWV adjusted for blood pressure was significantly higher in both elderly groups compared with the young (P < 0.01) but there was no difference between elderly normotensives and hypertensives. Unadjusted PWV was higher in elderly hypertensives than in elderly normotensives (P < 0.05). CONCLUSIONS: Compared with healthy young participants, both elderly groups had similarly attenuated blood pressure responses to tilt and reduced arterial compliance. Systolic hypertension is not associated with additional impairment of cardiovascular reflex function over and above the effects of age. The reported association between supine systolic hypertension and orthostatic hypotension does not appear to be a causative one.

Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy.

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Lack of effect of fish oil supplementation on blood pressure in treated hypertensives.

Fish and fish oils have been reported to reduce blood pressure in normotensives and untreated hypertensives. The present study examined the effect of dietary supplementation with fish oil on blood pressure in 20 treated hypertensives with controlled blood pressures who continued their usual antihypertensive drug treatment throughout. A double-blind, randomized crossover design was used, with two phases, each of 8 weeks' duration. In one phase, subjects took fifteen 1 g fish oil capsules (Lipitac; Reckitt and Colman Pharmaceuticals, Sydney, Australia) daily, and in the other, 15 capsules of identical appearance containing 1 g olive oil daily. There was no difference between the treatment phases for any blood pressure parameter, heart rate or body weight, but blood pressure was lower in both phases compared with pretreatment values. The fasting plasma triglyceride concentration was 30% lower in the fish oil phase (P less than 0.001), but there was no difference between the phases for plasma concentrations of total or high-density lipoprotein (HDL) cholesterol. We conclude that, in treated hypertensives with controlled blood pressures, any additional fall in blood pressure produced by dietary supplementation with fish oil is so small that the requirement for antihypertensive drug therapy is unlikely to be reduced.

Postural hypotension.

Postural hypotension is a common and important problem in elderly patients and necessitates a careful review of medication and lifestyle factors which may precipitate it. Drugs to be avoided if possible include diuretics, alpha-adrenoceptor blocking agents and nitrates. Drugs which may be useful in general practice include low-dose fludrocortisone, ephedrine and caffeine.

Orthostatic blood pressure control and ageing.

Reflex haemodynamic responses to orthostatic stress are attenuated with ageing, the extent of attenuation increasing with advancing age. In 15-20% of individuals aged > 65 years, the attenuation may be so marked that there is an excessive fall of blood pressure (BP) on assumption of the upright posture, sufficient on occasions to cause symptomatic cerebral hypoperfusion--this is known as 'ageing-related' orthostatic hypotension (AOH), a major risk factor for morbidity and mortality. Comparison of the cardiovascular responses to a variety of physiological and pharmacological stresses in healthy young and elderly subjects and in those with AOH suggests that the predominant site of the ageing-related change in cardiovascular reflex function is in the central connections of the arterial baroreflex, affecting particularly the BP buffering response. There is no evidence for ageing-related impairment of the efferent limb of the baroreflex, i.e. there is no significant ageing change in sympathetic vasomotor function or cardiac drive. Ageing-related impairment of baroreflex function also does not appear to result from either attenuation of arterial compliance or the presence of systolic hypertension, despite the epidemiological association between systolic hypertension and AOH. Better understanding of this important problem has the potential to improve the health of all elderly people.

Evaluating the impact of moving from discipline-based to integrated assessment.

BACKGROUND: The move from discipline-based to problem-based learning (PBL) at Adelaide University in 2000 offered exciting opportunities to integrate the teaching and learning of the basic and clinical sciences for medical undergraduates. However, several cohorts of students still needed to progress through the first 3 years of the more traditional curriculum. Paradoxically, their readiness to function in the integrated learning and assessment environment of the last 3 years was assessed in 7 separate discipline-based examinations at the end of third year. When considerable examination-related stress was noted in the 1997 cohort and students petitioned formally for a reduced examination load, it was considered to be time for assessment to lead the way in integrating the disciplines. AIM: After introducing third year integrated written assessments in 1998, we aimed to develop an integrated practical examination (IPE) linking theory to practice, and evaluate its impact on staff and students. METHODS: After extensive staff collaboration, a structured objective multistation IPE was developed and administered in 1999 and 2000. Its utility was evaluated using a model proposed earlier. RESULTS: Assessment validity was maximised by an extensive item review process. Reliability, as measured by Cronbach's alpha, was 0.79 and 0.80 in 1999 and 2000, respectively. An independent evaluation yielded qualitative data on the examination's educational impact, cost and acceptability. CONCLUSIONS: Investing time in changing from discipline-based to integrated assessment, integrating theory and practice, resulted in gains in assessment reliability, validity and educational impact on both staff and students.

Interactions of non-steroidal anti-inflammatory drugs.

As NSAIDs are commonly used in patients receiving concomitant drug therapy, there is a risk of clinically significant drug interactions. Important interactions with NSAIDs involve one or both of two major mechanisms: pharmacokinetic (e.g. lithium, phenytoin and barbiturates) and pharmacodynamic (e.g. antihypertensive agents, diuretics). Prescription of a NSAID should be preceded by a careful evaluation of any coexisting pathology (such as renal dysfunction or hypertension) or concurrent drug therapy (such as anticonvulsant or anticoagulant agents) which may predispose a patient to the development of an interaction with potentially severe effects.

Programmed stimulation after anterior myocardial infarction complicated by bundle branch block--late ventricular tachyarrhythmias and outcome.

One hundred and thirty consecutive patients with anterior myocardial infarction complicated by bundle branch block were retrospectively analyzed. Sixty died within 1 week of infarction. Of the remaining 70 patients, 36 had electrophysiology study with programmed stimulation 8-90 (mean 20) days after infarction. Of these, nine patients (35%) who clinically had not manifested either ventricular tachycardia or ventricular fibrillation more than 72 hours after infarction, had inducible ventricular tachycardia which was sustained more than 30 seconds in eight patients. By contrast, assessment of atrioventricular conduction added little to clinical management, long-term follow-up, extending up to 127 months, was available both in those patients whose therapy was directed by electrophysiology study, and was assessed among the other 34 patients who survived at least 7 days after myocardial infarction, but who did not undergo electrophysiology study. While the overall mortality was 55%, the majority of deaths (22/35) occurred within 4 months of infarction and many long-term survivors enjoy a gratifying quality of life. Although programmed stimulation in survivors of anterior myocardial infarction complicated by bundle branch block may identify a high risk subgroup, a prospective randomized trial is required to define the utility of more aggressive stimulation protocols following NASPE recommendations, to identify subgroups of patients in whom newer therapeutic interventions, including antiarrhythmic agents, electrical devices and surgery may be indicated.

Interethnic differences in drug glucuronidation: a comparison of paracetamol metabolism in Caucasians and Chinese.

Paracetamol disposition following a single oral 1 g dose of the drug was compared in groups (n = 12) of healthy young adult male Caucasians and Chinese. There was no difference between the groups in terms of paracetamol oral clearance, elimination half-life, or partial metabolic (glucuronidation, sulphation, oxidation) and renal clearances. The results demonstrate that drug glucuronidation is not universally impaired in Chinese and, together with previously published data, that paracetamol glucuronidation is minimally affected by race.

Reproducibility of conventional and power spectral measurements of cardiovascular sympathetic activation in normal subjects.

1. Normal subjects (n = 5; age 20-42 years; mean resting blood pressure (+/- 1 s.d.) 116 +/- 21/61 +/- 11 mmHg) underwent cardiovascular reflex testing five times each. On every occasion systolic blood pressure (SBP) responses to sustained handgrip (GRIP) and cold pressor (COLD) tests were measured and continuous non-invasive SBP and heart period (RRINT) data were analysed in the frequency domain using fast Fourier transforms. Power spectral (PS) density estimates of high frequency/total power (HF%; a measured of vagal activity), low frequency/HF ratio (LF/HF; a measure mainly of cardiovascular sympathetic activity for heart period) and low frequency/total power (LF%; a proposed measure of sympathetic activity for SBP) at rest, during and 2 min after the end of stimuli were calculated. 2. The data from the rest and recovery periods did not differ and showed that cardiovascular recovery to baseline measures following sympathetic stimulation occurred within 2 min. 3. There was a significant rise in SBP with GRIP and COLD. The LF/HF(RRINT) rose significantly with GRIP, but not with COLD. The LF%(SBP) did not change significantly with GRIP or COLD. 4. The SBP and PS analyses showed low intra-individual reproducibility of responses to reflex tests, with coefficients of variation for PS measures at rest of 25-41% and on sympathetic stimulation of up to 80%. 5. The high variability of these observations indicates that PS methods may not be suitable for the analysis of transient cardiovascular reflexes.

Cross-over comparison of nifedipine Oros and felodipine extended release with blind 24 h ambulatory blood pressure assessments.

1. The aim of the present study was to compare the efficacy of nifedipine Oros and felodipine extended release (ER) in controlling 24 h ambulatory blood pressures (ABP) in hypertensive patients. 2. The study was a randomized cross-over design with a 2 week open placebo run-in phase and two observer-blind treatment periods. 3. Subjects were males and females, aged between 18 and 65 years, suffering from mild to moderate essential hypertension with a sitting mean diastolic blood pressure (DBP) within the range of 95-114 mmHg. Twenty-three subjects were randomized to treatment; 15 patients completed the study. 4. Treatment intervention was 2 weeks of placebo followed by either 30 mg nifedipine OROS once daily or 5 mg felodipine ER once daily for 6 weeks, which was titrated up to 60 mg nifedipine OROS daily or 10 mg felodipine ER daily after 2 weeks of treatment on the lower doses if the DBP was > 90 mmHg. The main outcome measure was 24 h ABP after 6 weeks of active treatment, evaluated by an independent observer blinded as to treatment allocation. 5. Compared with placebo, mean (+/- SD) 24 h DBP was reduced by 6.2 +/- 6.8 and 5.2 +/- 5.1 mmHg after nifedipine and felodipine, respectively. The 24 h mean systolic blood pressure (SBP) fell by 11.8 +/- 10.9 and 10.1 +/- 8.2 mmHg for nifedipine and felodipine, respectively, compared with placebo. There were no significant differences between the two active treatments in the reduction of DBP or SBP during the 24 h period, daytime or night-time. 6. Similar antihypertensive effects are achieved with nifedipine Oros and felodipine ER when doses are individually titrated, with no significant differences between the two treatments.

Afferent baroreflex dysfunction and age-related orthostatic hypotension.

1. To test the hypothesis that in apparently healthy elderly subjects with orthostatic hypotension there is afferent baroreflex dysfunction, cardiovascular and neurohumoral responses were measured after separate stimuli which activated baroreceptor (head-up tilt) and non-baroreceptor (cold stress, isometric exercise) afferent pathways. 2. In 15 healthy elderly control subjects blood pressure did not change with 60 degrees head-up tilting and there was a moderate increase in heart rate, whereas in 13 subjects with age-related orthostatic hypotension head-up tilting was associated with a marked fall in blood pressure but a similar heart rate response to that in the elderly control group. In contrast, both groups of subjects had similar blood pressure and heart rate responses to cold stress and sustained isometric exercise. 3. Nine subjects with autonomic neuropathy also showed a marked hypotensive response to head-up tilt, but produced no pressor response to cold stress or isometric exercise. 4. The plasma concentrations of noradrenaline, adrenaline and neuropeptide-Y-like immunoreactivity rose and that of atrial natriuretic peptide fell after head-up tilt in the study population as a whole. There were no significant differences between groups despite the much greater blood pressure drops in the subjects with autonomic neuropathy and in those with age-associated orthostatic hypotension. 5. The aorto-iliac pulse wave velocity index was significantly higher in subjects with age-associated orthostatic hypotension compared with that in control subjects. 6. The pattern of responses to the separate stresses observed in the group with age-associated orthostatic hypotension is characteristic and different from that in the elderly control subjects and the subjects with autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen in humans.

The effects of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen were studied in groups of healthy adult males, females and oral contraceptive steroid (OCS) using females. The values of AUC, CLpo, t1/2 and Vss, app did not differ significantly between the groups. Similarly, the percentage unbound of (R)-ibuprofen in pooled plasma from the three groups was not statistically different. Since chiral inversion is the major determinant of (R)-ibuprofen clearance in humans, it may be inferred from these data that gender and OCS have little or no effect on conversion of (R)-ibuprofen to the pharmacologically active S-enantiomer. Moreover, it is unlikely that hormonal factors influence the activity of the human hepatic long-chain fatty-acid:CoA ligase, the enzyme mediating the rate limiting step of (R)-ibuprofen inversion.

PIP: In Australia, clinical researchers studied the effects of gender and oral contraceptive (OC) steroids on the pharmacokinetics of (R)-ibuprofen in 8 healthy adult males (mean age = 21 years), adult females (24 years), and OC users (22 years). There were no statistically significant differences between males, females, and OC users for any pharmacokinetic parameter for (R)-ibuprofen. These parameters included areas under the plasma total concentration-time curve (AUC), maximal plasma concentration, time to maximal plasma concentration, half-life, CLpo, and apparent steady-state volumes of distribution. The AUC to the last data point observed for (S)-ibuprofen (derived from (R)-ibuprofen) was similar, suggesting that hormonal factors do not affect plasma clearance of (S)-ibuprofen. The average percentages unbound of (R)- and (S)-ibuprofen across the concentration was not statistically different between the groups: 1.82% and 2.84% for males, 1.83% and 3.01% for females, and 2.1% and 2.97% for OC users, respectively. The mean fraction unbound of (S)-ibuprofen was 53.6% greater than that of (R)-ibuprofen. Since chiral inversion may explain 62-92% of (R)-ibuprofen clearance in humans, these data may suggest that gender and OCs do not effect or have only a limited effect on the conversion of (R)-ibuprofen to the pharmacologically active S-enantiomer. These findings indicate that hormonal factors probably do not affect the activity of the human hepatic long-chain fatty-acid:CoA ligase, the enzyme mediating the rate limiting step of (R)-ibuprofen inversion.

Cardiovascular responses to orthostatic and other stressors in men and women are independent of sex.

1. Cardiovascular responses to the stress of orthostasis, forearm (FA) ischaemia (reactive hyperaemia) and FA exercise (postexercise hyperaemia) are well described. Although sex differences in responses to orthostatic stress have been reported, few studies have examined the impact of sex on reactive hyperaemia and none has commented with regard to postexercise hyperaemia. 2. We investigated 11 men (mean (+/-SEM) age 18.5 +/- 0.3 years) and 10 women (18.8 +/- 0.8 years), all of whom were sedentary, with women being studied in the mid-follicular phase of their menstrual cycle. We measured blood pressure (BP), heart rate (HR) and forearm blood flow (FBF) in response to a fixed sequence of orthostatic, ischaemic and exercise stressors. 3. Orthostatic stress (10 min at -50 mmHg lower body negative pressure; LBNP) induced presyncopal signs in one man and three women. In all other subjects, BP was well maintained, with FBF decreasing and HR increasing similarly in both sexes. The tachycardia was earlier in onset in men and reached significantly higher absolute levels in women during the final 5 min of LBNP, but the percentage changes and integrated responses of both HR and FBF were not different between sexes. 4. The increases in FBF following either 10 min FA ischaemia or 10 min FA exercise were similar in men and women in terms of peak blood flow, percentage change, rate of recovery and total blood flow response. 5. In conclusion, although women were less tolerant of orthostatic stress than men, the cardiovascular responses to this and the other stressors appeared essentially independent of sex.

How accurate are hypertension treatment decisions? Absolute risk assessment and prescribing for moderate hypertension--a study of Cambridge general practitioners.

OBJECTIVE: To determine the factors influencing general practitioners' prescribing for patients with moderate hypertension, and to investigate their ability to assess patients' absolute risk of cardiovascular disease. DESIGN: Decision-making was assessed by a postal questionnaire involving five standardised example patients, send to all general practitioners in the CB-postcode area (Cambridge, UK). Patients varied in age, gender, diabetic and smoking status, blood pressure and total cholesterol, giving 5-year absolute risks ranging from less than 5% to greater than 20%. GP treatment decisions and risk factor influence, age bias, absolute risk calculations and cost-awareness were analysed with SPSS. Absolute risk was calculated using the New Zealand Core Services Committee (NZCSC) Guidelines, 1995. RESULTS: GP response rate was 66%. Sample demographics (mean age 42 years, 39% female) did not differ statistically from local health authority data. High blood pressure alone was the most common reason for instituting therapy (67%), independent of other risk factors. Drug choices did not differ statistically from Prescription Pricing Authority data. This supports the validity of the questionnaire. GP estimations of absolute risk were inconsistent, and there was a significant association between underestimation of elderly patient risk and overestimation of younger patient risk (p = 0.05). CONCLUSIONS: The Cambridge GPs more frequently based treatment decisions on patients' blood pressure level alone, rather than considering absolute risk as recommended by NZCSC and WHO guidelines. The relationship between patient age and risk estimations may indicate a "young age premium" influencing treatment. The data support the need for risk-based guidelines and education in treatment of hypertension.

Phaeochromocytoma: intraoperative changes in blood pressure and plasma catecholamines.

The aim of this study was to assess the relationship between changes in plasma catecholamine concentrations and intra-arterial blood pressure (BP) measured simultaneously during resection of phaeochromocytoma (n = 14). Arterial plasma concentrations of noradrenaline (NA), adrenaline (A) and dopamine (DA) were measured by a radio-enzymatic method. Arterial NA concentrations (pmol/ml; median and Wilcoxon 95% CI) were 71.8 (46,162) before induction of anaesthesia, 113.0 (79,231) after intubation, 375.0 (285,931) during tumour handling and 32.5 (18,88) following tumour removal. Simultaneous mean BP values (mmHg; Mean +/- SEM) were 119 +/- 8, 114 +/- 7, 159 +/- 7 (p = 0.0001) and 72 +/- 6 (p < 0.0001) respectively. At the time of tumour handling there was a weak correlation between plasma NA and A combined and mean BP (r = 0.583, p = 0.029) and a stronger correlation between log plasma NA and A combined and pulse pressure (r = 0.749, p = 0.008). The very large rises in plasma catecholamine concentrations and in BP are likely to have been causally related. Individual patients maintained a constant ratio of NA to A in plasma from pre-induction to tumour handling (r = 0.916, p < 0.0001). The maintenance of a constant NA:A ratio suggests that the pattern of catecholamine synthesis and release may be a characteristic of the individual tumour.

Perturbation of paracetamol urinary metabolic ratios by urine flow rate.

The effects of high and low urine flow rates on the urinary metabolic ratios for paracetamol glucuronidation, sulphation and oxidation were determined at steady-state in seven healthy young adult volunteers. Metabolic partial clearances were unaffected by urine flow rate, but individual paracetamol metabolic ratios varied 2.5- to 3.2-fold over a 7.4-fold range of urine flow rates (0.81-6.00 ml min-1). The change in metabolic ratios was due entirely to a 2.5-fold change in renal clearance of unchanged paracetamol. These data emphasise the limitations of the metabolic ratio as a measure of intrinsic clearance for compounds which undergo some degree of tubular reabsorption.

The preoperative management of phaeochromocytoma.

Although the preoperative use of alpha-receptor antagonist drugs is generally accepted for patients with phaeochromocytoma, evidence on the most appropriate treatment and its timing is scarce. In this retrospective study, the effectiveness of the preoperative preparation of fourteen patients who required surgical excision of a phaeochromocytoma was examined in the light of their operative stability. A simple score was developed of blood pressure stability by scoring the need for additional antihypertensive agents intraoperatively before, and blood pressure support after, tumour removal. A higher score indicated greater instability. Twelve patients received phenoxybenzamine and their stability was superior to the two patients treated with labetalol and with prazosin. There was no correlation between the duration of treatment with phenoxybenzamine and the operative stability (r = 0.18 P = 0.55 Spearman). The five patients who were treated with phenoxybenzamine for longer than 10 days did not have better perioperative blood pressure stability than the five patients who had treatment for less than a week. Predictive factors for intra-operative blood pressure stability were also sought. The degree of postural hypotension after treatment with phenoxybenzamine did not predict operative stability (r = -0.31, P = 0.33 Spearman). However, the peak total catecholamine level found during surgery correlated quite well with more operative instability (r = 0.65, P = 0.031, Spearman), suggesting that patients with phaeochromocytomas with high production of catecholamines are more likely to show cardiovascular instability.