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Biomedical subjects

K R Lees

Publications and source records attributed to K R Lees.

At least 127 records · Page 7Linked to original sources
PubMed1994

Differentiation between gaseous and formed embolic materials in vivo. Application in prosthetic heart valve patients.

BACKGROUND AND PURPOSE: Doppler emboli detection is an established technique, but the nature of the underlying embolic material remains unclear. The intensity and spectral distribution of emboli signals could help to distinguish between signals arising from formed and gaseous emboli. We undertook this study to develop and evaluate a differentiation algorithm based on the spectral characteristics of emboli signals. Subsequently the algorithm was applied to patients with mechanical prosthetic cardiac valves. METHODS: Emboli signals detected in patients with carotid disease, acute stroke, and atrial fibrillation were used as formed emboli data, and signals detected in patients undergoing cardiac catheterization studies were used as gaseous emboli data. For each embolus signal, the maximal amplitude, the sum of amplitudes, and the spectral intensity distribution were calculated. Two hundred emboli signals from each category were used to develop a differentiation algorithm, which was subsequently evaluated on 501 additional solid and 995 gaseous emboli signals. The same algorithm was used to analyze 5958 emboli signals detected in 60 patients with mechanical prosthetic valves. RESULTS: The best results were obtained with an algorithm based on both the maximal amplitude and the sum of amplitudes (sensitivity, 99%; specificity, 96.5%). On subsequent evaluation, the sensitivity and specificity of the algorithm were 99.6% and 89.8%, respectively. Of the 5958 emboli signals detected in prosthetic valve patients, 92.4% were classified as gaseous. CONCLUSIONS: Differentiation between gaseous and formed emboli signals, as detected by transcranial Doppler in vivo, is feasible by means of spectral analysis. Application of the differentiation algorithm in prosthetic valve patients suggests that the embolic material in these patients is gaseous. The possibility of distinguishing between different formed embolic materials with this technique remains to be evaluated.

Adult↗
PubMed1993

Blood pressure response to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

Aged↗
PubMed1993

Angiotensin-converting enzyme inhibitors in heart failure: blood pressure changes after the first dose.

Angiotensin-converting enzyme (ACE) inhibitors prevent the formation of angiotensin II in the circulation and a range of tissues. ACE inhibitors not only are effective, well-tolerated antihypertensive drugs but also improve symptoms and signs in patients with congestive cardiac failure. In addition, they improve long-term survival in these latter patients. Although ACE inhibitors are relatively free of side effects in patients with heart failure, hypotension after the first dose has been reported that may lead to symptomatic renal, cardiac, or cerebral hypoperfusion. Most reports have been uncontrolled and anecdotal. We report a double-blind placebo-controlled study in a parallel group of patients with cardiac failure (New York Heart Association classes II through IV). In total, 72 patients (6 groups of 12) were studied after either placebo, captopril, 6.25 mg, enalapril, 2.5, or perindopril, 2 mg orally, enalaprilat 1.5 mg, or perindoprilat, 1.0 mg intravenously. The blood pressure responses differed between the groups, with a short-lived early fall after captopril and a long-lasting fall after enalapril, whereas perindopril was no different from placebo. There was no significant difference between the two active intravenous regimens. Plasma ACE measurements suggested that the relative doses used were at least comparable. Further studies are in progress to investigate the mechanisms underlying the differential hemodynamic responses and also to explore the clinical relevance to safety and efficacy in the management of heart failure.

Acetylcholinesterase↗
PubMed1993

Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was approximately 10-20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses > 10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

Adult↗
PubMed1993

The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension.

1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.

Aged↗
PubMed1993

Double blind controlled study of low dose intravenous perindoprilat or enalaprilat infusion in elderly patients with heart failure.

OBJECTIVE: Comparison of the first dose responses to low dose constant rate infusions of diacid angiotensin converting enzyme (ACE) inhibitors. DESIGN: Double blind, randomised, placebo controlled, parallel group prospective study. SETTING: General hospital inpatient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of ACE inhibitor treatment. PATIENTS: 36 unselected elderly (aged 60-87 years) patients with symptomatic but stable chronic cardiac failure (New York Heart Association grades II-IV). ACE inhibitor started under double blind conditions with blood pressure monitoring. INTERVENTION: Patients were randomly allocated to receive intravenous placebo (saline), enalaprilat (1.5 mg over six hours) or perindoprilat (1 mg over six hours) by constant rate intravenous infusion (5 ml/hour). The protocol allowed for discontinuation of infusion if mean arterial blood pressure fell by 30% from the value before treatment. MAIN OUTCOME MEASURES: Blood pressure and heart rate responses, drug concentration, plasma renin, and ACE activities. RESULTS: The three groups had similar age, severity of heart failure, diuretic dose before treatment, plasma renin activity, and serum electrolyte state. All patients remained symptom free throughout the study. Infusions were only ended early with active treatment: 5/12 perindoprilat cases, (mean (SD) dose 0.88 (0.18) mg, and 5/12 enalaprilat cases (mean (SD) dose 1.2 (0.4) mg. Both active treatments lowered mean arterial pressure until discontinuation of infusion. Heart rate was not altered. Two patients (one perindoprilat, one enalaprilat) showed transient and symptom free renal impairment. CONCLUSIONS: Slow intravenous infusion of diacid ACE inhibitors may allow safe initiation of treatment in patients with heart failure and with activated renin angiotensin systems. The similar effects of intravenous perindoprilat and enalaprilat on blood pressure contrast with previously reported differences when perindopril and enalapril were given orally.

Aged↗
PubMed1993

The experiences of an acute stroke unit--implications for multicentre acute stroke trials.

The suitability of 200 consecutive patients admitted to a newly established acute stroke unit was assessed for participation in two multicentre trials currently in their pilot phase: the International Stroke Trial of aspirin and heparin, and the Multicentre Acute Stroke Trial of streptokinase versus placebo. Of the 200 patients (74 men, 126 women, mean age 71 years), 96% had cerebral CT, and 94% had a final diagnosis of cerebrovascular disease. Overall, 50% of patients presented within 6 hours and 70% within 12 hours of the onset of ictus. A total of 113 patients (56.5%) were potentially eligible for trial treatment with aspirin/heparin. Only 9 patients (4.5%) were eligible for streptokinase treatment: 50% were excluded because they presented after 6 hours; 23% had a previous stroke with clinical sequelae and 23% had severe systemic illness. Forty eight per cent of patients had more than one exclusion criterion. The potentially high enrollment rates in trials of antithrombotic agents contrast with the restricted recruitment for trials of streptokinase, emphasising the need for multiple centres to achieve useful study enrollment.

Adult↗
PubMed1993

Transhemispheric passage of microemboli in patients with unilateral internal carotid artery occlusion.

BACKGROUND AND PURPOSE: Ischemic episodes distal to an internal carotid artery occlusion are common. We undertook this study to look for evidence of transhemispheric passage of embolic material in this patient category as a mechanism for embolic events. METHODS: Seven symptomatic patients with unilateral internal carotid artery occlusion and contralateral stenosis were examined by transcranial Doppler ultrasonography with 2-MHz probe (average monitoring time, 2.5 hours per patient). Both middle cerebral arteries and (if present) the reverse-flow anterior cerebral artery ipsilateral to the occluded internal carotid were monitored. Three patients were reexamined 1 month after carotid endarterectomy. RESULTS: Embolic signals were detected in the middle cerebral artery ipsilateral to the stenosed internal carotid artery in all seven patients and in the opposite middle cerebral artery in four patients. In these four patients, a reverse-flow anterior cerebral artery was observed in which embolic signals were detected. No embolic signals were detected after surgery in any of the three patients who underwent carotid endarterectomy. CONCLUSIONS: Transhemispheric passage of embolic material occurs in patients with unilateral internal carotid artery occlusion and contralateral stenosis. Endarterectomy of the stenosed internal carotid artery may eliminate the detected embolic signals in both hemispheres. Transcranial Doppler ultrasonography could be used as a diagnostic tool to identify the embolic source in patients with unilateral carotid occlusion.

Aged↗
PubMed1993

Quantification of ultrasound emboli signals in patients with cardiac and carotid disease.

BACKGROUND AND PURPOSE: The use of Doppler ultrasound to detect arterial emboli has major implications for the classification and treatment of stroke. Experimental studies indicate that embolic materials produce different ultrasound signals, depending on their acoustic properties. To examine the possibility of characterizing emboli of different sources in the clinical setting, we compared the emboli signals of patients with cardiac embolic sources with those of patients with signals of carotid embolic sources. METHODS: Transcranial Doppler monitoring (30 minutes per patient) of the middle cerebral arteries was performed in 80 patients with prosthetic cardiac valves and 20 patients with internal carotid artery stenosis. The signal power of emboli was calculated in relation to the background Doppler signal. RESULTS: In patients who were embolizing from prosthetic heart valves, the frequency of embolus signals was greater than in patients with carotid stenosis who were embolizing (mean +/- SEM: 58.2 +/- 11 versus 8.2 +/- 3 signals per hour; P < .0001, two-sample t test), and total signal power and duration also were higher (power, 2231 +/- 63 versus 455 +/- 109 power units; duration, 55.9 +/- 0.8 versus 29.9 +/- 1.4 milliseconds; both P < .001). The majority of emboli signals were seen during cardiac systole, especially in patients with carotid stenosis (89% in the first half of the cardiac cycle versus 72% in prosthetic valve patients). In 19 patients with prosthetic valves, embolus signals were also recorded from the anterior cerebral artery; the signal count was not significantly different from the middle cerebral artery (43.2 +/- 12.5 versus 64.3 +/- 16 per hour), but anterior cerebral artery signals were of higher power (3306 +/- 148 versus 2441 +/- 109 power units, P < .001). CONCLUSIONS: There is promise of being able to distinguish emboli on the basis of power measurements. Emboli of different sources (eg, carotid and cardiac) appear to have different ultrasonic characteristics, which are likely to be based on composition and size.

Aged↗
PubMed1993

Role of angiotensin in the extravascular system.

Angiotensin receptors are present in many tissue types, including adrenal cortex, renal glomeruli, heart, hypothalamus, liver, pancreas, pituitary, platelets, renal tubules, uterus and vascular smooth muscle. Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors. Angiotensin II may be produced locally in tissues outside the humoral system. For example, it is found in the brain, kidney and heart. Within the brain, the heptapeptide angiotensin(1-7) mimics some effects of angiotensin II, but may be formed directly from angiotensin I. Evidence for non-ACE-mediated angiotensin II production has been reported in the heart. Intravascular angiotensin II receptors are implicated in the central release of vasopressin and other hypophyseal hormones, in increasing sympathetic outflow, in the thirst response and, possibly, in cognitive function; in the inotropic and chronotropic effects of angiotensin II on the heart as well as in growth/hypertrophy; in the control of aldosterone release and in the balance between cortisol and aldosterone secretion; and in modulating sodium, chloride and bicarbonate transport within the kidney. Effects on the reproductive system, liver and pancreas have not been established. The pharmacological effects of angiotensin II antagonists will depend on their distribution characteristics as well as affinity for specific receptor subtypes. At present, however, the physiological role of AT2 receptors has not been defined.

Angiotensin II↗
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↗
PubMed1992

Therapeutic interventions in acute stroke.

1. Potential therapies for ischaemic stroke include agents to reduce oedema, to improve cerebral perfusion, to reduce excitotoxic damage, to minimise free-radical induced injury and to reduce complications such as deep venous thrombosis. 2. Of the anti-oedema drugs, steroids are ineffective and possibly dangerous; intravenous glycerol is unproven. 3. Haemodilution to reduce whole blood viscosity and improve perfusion is ineffective. Thrombolytic drugs have not been adequately tested but several randomised multicentre trials are now commencing. Early treatment and CT scanning are essential. 4. Anticoagulants and antiplatelet drugs may have wide applicability but have not been tested in the acute phase of stroke. A multi-centre trial will address this issue. 5. Neuronal cytoprotection offers exciting prospects for acute stroke treatment. Antagonists of glutamate at the NMDA receptor, calcium and sodium channel blocking agents and free radical scavenging drugs have potent effects experimentally. Several agents are now reaching clinical trials. The calcium antagonist nimodipine has been disappointing in large scale trials but some studies were flawed by late treatment. 6. Successful treatment of acute stroke is likely to combine several approaches. 7. Therapeutic trials in stroke must include CT scanning, early treatment and a multicentre approach to achieve large numbers of patients.

Acute Disease↗