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Biomedical subjects

R J MacFadyen

Publications and source records attributed to R J MacFadyen.

69 records · Page 4Linked to original sources
PubMed1992

Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men.

Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin-angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18-32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 +/- 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 +/- 6.1 ng/ml) with the slow infusion (mean time to peak 121 +/- 99 min). Both fast (135.2 +/- 26 ng/ml/h2) and slow (121.0 +/- 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0-24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0-10 for PRA was significantly less for slow (1.7 +/- 0.6 ngAI/ml/h2) than fast (4.9 +/- 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 +/- 65.9 pg/ml) and slow (195.2 +/- 110.5 pg/ml) infusions as compared with placebo (49.9 +/- 18.6 pg/ml). Similarly, AUC0-10 for AR was greater for slow (990.2 +/- 582.1 pg/ml/h) than fast (512.4 +/- 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers.

1. Intravenous ACE inhibitor therapy is of increasing importance in the treatment of patients with unstable heart failure after myocardial infarction. Available pharmacokinetic and concentration effect data with this route of administration are limited. 2. The pharmacokinetics and blood pressure responses to perindoprilat were studied during prolonged low dose (1 mg) infusions in eight normotensive salt replete male volunteers. 3. Subjects received randomised, single (subject) blinded therapy with saline placebo (30 ml) over 3 h or active treatment (1 mg in 30 ml) over 1 h, 3 h or 6 h by constant rate infusion. 4. Significant falls in blood pressure greater than placebo were noted with active infusions without changes in heart rate. Mean maximal plasma perindoprilat concentrations reflected the rate of infusion (1 h, 51.5 +/- 11.4 ng ml-1; 3 h, 30.4 +/- 8.4 ng ml-1; 6 h 19.0 +/- 4.0 ng ml-1) and mean maximal plasma ACE inhibition was less with slower infusions (1 h, 95.7 +/- 0.5%; 3 h 92.3 +/- 2.7%; 6 h 87.4 +/- 5.1%, P less than 0.013). 5. Concentration-time profiles showed a sigmoid drug accumulation profile with delay in the early accumulation of drug particularly during the 3 h and 6 h infusions. The pharmacokinetic data was assessed by statistical comparison of a hierarchy of standard compartmental models and non linear saturable binding models. A non linear model incorporating elements to describe both tissue and plasma binding of the drug provided the best fit to observed data. 6. Low dose constant rate infusions are a means of optimising intravenous ACE inhibitor therapy to allow individual dose titration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs.

1. There is a body of circumstantial and direct evidence supporting the existence and functional importance of a tissue based RAS at a variety of sites. 2. The relation between circulatory and tissue based systems is complex. The relative importance of the two in determining haemodynamic effects is unknown. 3. Despite the wide range of ACE inhibitors already available, it remains unclear whether there are genuine differences related to tissue specificity. 4. Pathological states such as chronic cardiac failure need to be explored with regard to the contribution of tissue based ACE activities in generating acute and chronic haemodynamic responses to ACE inhibitors. 5. The role of tissue vs plasma ACE activity may be clarified by study of the relation between drug concentration and haemodynamic effect, provided that the temporal dissociation is examined and linked to circulating and tissue based changes in ACE activity, angiotensin peptides and sympathetic hormones.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Transpulmonary pharmacokinetics of an ACE inhibitor (perindoprilat) in man.

1. The transpulmonary pharmacokinetics of the intravenous diacid ACE inhibitor perindoprilat were studied in 10 male patients undergoing diagnostic cardiac catheterisation for the management of ischaemic heart disease. 2. Following successful completion of diagnostic cardiac catheterisation and ventriculography, subjects received a low dose (1 mg) constant rate infusion of perindoprilat over 20 min with co-infusion of the intravenous marker dye indocyanine green (0.5 mg kg-1). Simultaneous transpulmonary blood sampling was conducted for 1 h and subsequent peripheral venous blood samples were collected for 20 h. 3. No acute changes in blood pressure or heart rate were noted despite rapid and marked inhibition of central circulation plasma ACE activity persisting in peripheral venous blood for 20 h. A delayed rise in plasma renin activity was noted. 4. Transpulmonary passage during early accumulation of the drug was seen to incorporate an early delay. Concurrent ICG measurements suggested that this was entirely due to circulatory delay and not to binding of the drug. Thus, despite the suggested high concentration of tissue ACE activity in the pulmonary circulation, transpulmonary passage of perindoprilat was not measurably influenced by binding at this site under the conditions studied.

Adult↗
PubMed1991

The response to the first dose of an angiotensin converting enzyme inhibitor in uncomplicated hypertension--a placebo controlled study utilising ambulatory blood pressure recording.

1. The importance of total dose to the initial hypotensive response with an angiotensin converting enzyme inhibitor (quinapril) was assessed using a suggested 'maintenance' dose (20 mg) or matched placebo in a randomised double-blind study in patients with uncomplicated hypertension. 2. Thirty-two patients were recruited who were not on therapy or had not received diuretic therapy in their existing drug treatment in the preceding 4 weeks. Secondary causes of hypertension had previously been excluded and sustained clinic blood pressures of SBP greater than 160 mmHg and/or DBP greater than 90 mmHg were taken as indications for a trial of adjuvant or monotherapy with an ACE inhibitor. 3. After uneventful supervised therapy with quinapril in an open pilot study (n = 5) 27 patients entered a double-blind, randomised, crossover study of quinapril or placebo using ambulatory monitoring to assess BP response. 4. All patients remained asymptomatic and both therapy and monitoring were well tolerated. A smooth onset of antihypertensive effect was noted with an overall 24 h placebo corrected fall in systolic BP of 9.9 mmHg (7.2-12.6 95% CI) and diastolic BP of 6.4 mmHg (4.2-8.8) with no significant effect on heart rate. Individual placebo corrected maximal responses during the first 8 h following quinapril showed a wide range for both systolic (+1.56 to 44.0 mmHg) and diastolic (+2.3 to -35.6 mmHg) pressure. Larger falls tended to be associated with higher baseline pretreatment pressures but in no case did absolute systolic pressure fall below 100 mmHg during the first 8 h following administration of placebo or quinapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A study of the acute pharmacodynamic interaction of ramipril and felodipine in normotensive subjects.

1. The possibility of an acute pharmacokinetic or pharmacodynamic interaction between the ACE inhibitor ramipril and the calcium antagonist felodipine was examined in 12 normotensive male volunteers. 2. Ramipril (5 mg) and felodipine ER (10 mg) were administered orally in a double-blind, randomised, placebo-controlled, Latin square design to fasting subjects. 3. There was no evidence of a pharmacokinetic interaction between agents. The concentration-time profiles remained unaltered by coadministration of both agents. 4. Plasma ACE inhibition by ramiprilat was unaffected by concurrent felodipine. The trend towards increased fractional sodium excretion after felodipine was not influenced by ramipril. Plasma renin activity, aldosterone and catecholamines remained unaltered. 5. Combination therapy produced a statistically significant fall in blood pressure supine and erect which was not evident with monotherapy. The reflex tachycardia associated with felodipine monotherapy was significantly attenuated by the coadministration of ramipril. 6. This study presents further evidence for the effective combination of ACE inhibitors and calcium antagonists to lower blood pressure. The reflex tachycardia associated with calcium antagonist therapy can be significantly reduced by coadministration with sustained antihypertensive effect.

Adult↗
PubMed1991

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE: To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN: Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING: General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS: 48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION: Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES: Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS: The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS: This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.

Aged↗
PubMed1991

The contribution of ambulatory blood pressure measurement to the evaluation of new antihypertensive drugs.

Ambulatory blood pressure recording can provide information on blood pressure changes throughout the day and night and during normal daily activities. The former features are of particular use in evaluating the duration of action and dose-response relationships for new antihypertensive drugs, especially those developed for once daily dosing. Improved precision and multiple measurements through the dose interval may reduce the number of patients required in trials. We have recently used ambulatory blood pressure recording to assess the magnitude and duration of the first dose of an angiotensin converting enzyme (ACE) inhibitor, quinapril, compared to placebo. In addition, the effects on blood pressure of long-acting calcium antagonists, alone and in combination, have been measured. Ambulatory blood pressure recording can complement conventional approaches in determining the dose range, frequency of administration and concentration-effect relationships of new and existing antihypertensive drugs.

Antihypertensive Agents↗
PubMed1990

Tissue angiotensin converting enzyme inhibition. Relevant to clinical practice?

Accumulating data indicate that tissue and systemic renin-angiotensin systems may coexist. Evidence supporting the existence of local regulatory systems derives from several sources. Firstly, it has been clearly demonstrated that all components of the renin-angiotensin system are detectable in the tissues of organs such as the brain, heart, lung, kidney, testis, and blood vessels. Secondly, many diverse actions of angiotensin II have been defined in different tissues, all of which have a common mechanism: maintaining or increasing vascular tone, blood volume, or both. Evidence supporting the concept that the local and systemic renin-angiotensin systems are functionally independent includes the discrepancy in the time courses of hemodynamic changes and enzyme inhibition following administration of angiotensin-converting enzyme (ACE) inhibitors; and the observation that ACE inhibitor treatment results in decreases in blood pressure in anephric subjects, who have extremely low circulating concentrations of angiotensin II. These and other data suggest that inhibition of tissue ACE may be as, or more, important than its effects on the more easily measured circulating ACE. This raises the question of whether there are differences among ACE inhibitors in their selectivity for one or more organ systems. Some experimental data indicate that the binding affinity and time course of ACE inhibition can vary from one tissue to another, and among individual agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1986

NPY stimulates nett absorption across rat intestinal mucosa in vivo.

NPY is a peptide recently isolated from porcine brain which has been seen to be widely distributed in the central and peripheral nervous system. The peptide is known to be present in substantial quantities in the extrinsic and intrinsic innervation of the gut but few studies have yet been done on the functional activity of the peptide in this site. In this study, intravenous infusion of porcine NPY was seen to cause nett absorption in the proximal duodenum. In addition, NPY was found to inhibit the nett secretory effect of simultaneously infused VIP in the proximal duodenum and jejunum. This evidence of functional activity of NPY in the gut further supports a role for this peptide in controlling or modulating intestinal function.

Animals↗
PubMedDate not supplied

Nonadherence with ACE inhibitors is common and can be detected in clinical practice by routine serum ACE activity.

Our objective was to assess whether serum angiotensin-converting enzyme (ACE) activity during routine clinical practice accurately reflects patient adherence to ACE inhibitor treatment in chronic heart failure (CHF). During 1994-95, ACE was measured in 73 CHF patients who were routinely attending the heart failure clinic at Ninewells Hospital. At the same time, the Medicines Monitoring Unit collected data on whether and when prescriptions for ACE inhibitors were redeemed at community pharmacies, which enabled each patient's adherence over a prolonged period to be assessed. We then correlated whether an elevation in serum ACE was associated with poor adherence with ACE inhibitor treatment. In total, 18% of CHF patients appeared to exhibit less than 70% adherence with their ACE inhibitor treatment, with 34% exhibiting less than 85%adherence and 58% exhibiting less than 100% adherence. A serum ACE activity of more than 12 U/L gave 91% positive predictive accuracy that the patient was less than 100% adherent with his or her ACE inhibitor treatment. At the other extreme, a serum ACE less than 6.5 U/L gave 81% positive predictive accuracy that the patient was more than 85% adherent with ACE inhibitor treatment. Nonadherence with ACE inhibitor treatment, therefore, was found to be common in patients with CHF. The simple, inexpensive test of serum ACE activity can be used in CHF patients to identify many, although not all, nonadherent patients so that adherence-enhancing strategies can be targeted toward them. Further work is clearly required to explore the precise clinical utility of this promising test. (c)2001 by CHF, Inc.

Journal Article↗
PubMedDate not supplied

Assessment of distal tip position of long-term central venous feeding catheters using transesophageal echocardiology.

BACKGROUND: Central vein catheter position is a vital element in promoting longevity and minimizing adverse events associated with long-term parenteral nutrition. Traditionally, position has been verified using a chest radiograph. However, this mode of assessment has limitations as the catheter is placed in a dynamic system subject to forces from changes in posture and diaphragmatic movement. METHODS: We compared the reported position using a chest x-ray compared with assessment using transesophageal echocardiology (TOE) in 9 patients receiving home parenteral nutrition. The x-ray was reported by a radiologist unaware of the study. RESULTS: There were discordant results in 7 of the 9 cases with catheter tip placed in the right atrium or impinging in the tricuspid valve which was not evident from the chest x-ray. TOE offered greater information of catheter tip position and relationship to adjacent anatomy. CONCLUSIONS: Further work is required but this observational study suggests guidelines suggesting the use of a chest radiograph to confirm catheter position may need to be re-assessed.

Catheterization, Central Venous↗
PubMedDate not supplied

Current issues in hypertension research and therapy.

Essential hypertension is one of the most common cardiovascular diseases and treatment is based on reducing overall cardiovascular risk. This article reviews current growth areas in hypertension research and practice.

Angiotensin II↗
PubMedDate not supplied

Clinical pharmacology and classification of antiarrhythmic drugs.

Despite major contemporary strides in the treatment of cardiac arrhythmia, the bedrock for many patients management is still rooted in chronic drug therapy. In the last 10 years considerable changes in patterns of drug use has affected every aspect of these agents down to the basic level of drug classification and assessment of their clinical pharmacology. This review looks at the systems of antiarrhythmic drug classification currently used and the rationale for adopting newer approaches.

Anti-Arrhythmia Agents↗