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Biomedical subjects

I B Squire

Publications and source records attributed to I B Squire.

At least 19 recordsLinked to original sources
PubMed1999

An immunoluminometric assay for cardiotrophin-1: a newly identified cytokine is present in normal human plasma and is increased in heart failure.

Cardiotrophin-1, a member of the interleukin-6 related cytokine family which acts via the glycoprotein 130 signalling pathway, may be involved in the process of ventricular remodelling. Its presence in human plasma has never been reported. We have devised a non-radioactive immunoluminometric sensitive and specific assay for CT-1 based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyl-oxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulfonate was used to label a peptide representing a domain in the middle section of CT-1. Assay of this domain of CT-1 (amino acids 105-120) in patients with heart failure revealed elevated CT-1 values median 87 [range 74.3-182.8] fmol/ml) compared to normal controls (CT-1 median 29.55 [range 6.9-48.3] fmol/ml, P<0.0005). The molecular weight of human CT-1 was estimated to be 26.7 kD from sodium dodecyl sulphate polyacrylamide gel electrophoresis. This is the first quantitative assessment of CT-1 in humans. Furthermore, this is the first demonstration of significant elevation of plasma CT-1 in patients with heart failure.

Aged↗
PubMed1999

Humoral and cellular immune responses up to 7.5 years after administration of streptokinase for acute myocardial infarction.

AIMS: Administration of streptokinase results in an immunological response which may lead to increased risk of anaphylactic reaction or reduced thrombolytic efficacy on repeat administration. For these reasons current recommendations suggest that streptokinase should not be given up to 1 year after first administration. We sought to define the profile of both the circulating antibody and T-cell response to streptokinase in patients who had received streptokinase up to 7.5 years previously following acute myocardial infarction. METHODS: Neutralizing anti-streptokinase antibody and total anti-streptokinase IgG were measured in 219 patients who had suffered acute myocardial infarction between 12 and 90 months previously and had received streptokinase. T-cell response to streptokinase was assessed by in-vitro proliferation of peripheral blood mononuclear cells (n=234). Data on all parameters were available in 184 patients. Controls (n=22) had suffered acute myocardial infarction between 73 and 84 months previously but had not received thrombolytic therapy. RESULTS: Compared to controls, anti-streptokinase antibodies were elevated at all time periods from 12 to 90 months after streptokinase treatment. Total anti-streptokinase titres showed the expected correlation with neutralizing anti-streptokinase antibodies (P<0.0001). Peripheral blood mononuclear cells showed a vigorous in-vitro proliferative response to streptokinase 6 days after treatment (P=0.05 vs pre-treatment), but this was not detectable at 6 weeks or subsequently. CONCLUSION: There is as yet no evidence of a time limit beyond which administration of streptokinase on a second occasion can be regarded as safe and likely to be effective. Measurement of neutralizing anti-streptokinase or total anti-streptokinase IgG titre appear to provide equivalent information regarding the antibody status of a population. Further studies are required regarding the apparent lack of peripheral blood mononuclear cells responsiveness in patients previously exposed to streptokinase.

Adult↗
PubMed1999

Plasma N-terminal pro-brain natriuretic peptide and the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population.

AIMS: To examine the value of N-terminal pro-brain natriuretic peptide, abnormal electrocardiogram and other baseline clinical and laboratory variables in identifying patients with left ventricular systolic dysfunction in a high risk population. METHODS AND RESULTS: We studied 243 patients (129 male, median age 73 years, range 20-94) referred for echocardiography. The relationship between left ventricular wall motion index and log N-terminal pro-brain natriuretic peptide, log creatinine, electrocardiogram, age, history of hypertension, history of ischaemic heart disease, gender, valvular disease and current drug therapy was examined using regression analysis. There was a strong correlation between N-terminal pro-brain natriuretic peptide and left ventricular wall motion index for the whole population (r=-0.624, P<0.001) and in those receiving diuretic +/- angiotensin converting enzyme inhibitor (r= -0.661, P<0.005) and in those receiving neither (r=-0.584, P<0. 005). On multiple regression analysis, log N-terminal pro-brain natriuretic peptide (P<0.001), age (P=0.015), current diuretic (P=0. 002) or angiotensin converting enzyme inhibitor use (P=0.001) and male gender (P=0.026) were independently associated with a low left ventricular wall motion index. Log N-terminal pro-brain natriuretic peptide alone (R(2)=39%) was a better predictor of left ventricular wall motion index than any other single or combination of factors. Plasma N-terminal pro-brain natriuretic peptide>275 pmol l(-1)predicted left ventricular wall motion index < or =1.2 with a sensitivity of 93.8%, a specificity of 55% and a negative predictive value of 93%. Left ventricular function was impaired in 18/36 patients with a normal electrocardiogram, in all of whom N-terminal pro-brain natriuretic peptide was >275 fmol ml(-1). CONCLUSION: Of the variables studies, N-terminal pro-brain natriuretic peptide had the strongest correlation with reduced left ventricular wall motion index. The electrocardiogram had a poor predictive value for left ventricular systolic dysfunction in this population. Plasma N-terminal pro-brain natriuretic peptide can usefully predict patients with a reduced left ventricular wall motion index in whom echocardiographic examination may be appropriate.

Adult↗
PubMed1999

C-reactive protein and outcome after ischemic stroke.

BACKGROUND AND PURPOSE: Elevated concentrations of the acute-phase reactant C-reactive protein (CRP) predict ischemic cardiac events in both hospital- and population-based studies and may signify a role for inflammation in the destabilization of cardiovascular disease. We examined the relationship between CRP and outcome after acute ischemic stroke. METHODS: This was a subgroup analysis from a prospective observational study based in a University Hospital Acute Stroke Unit serving a population of approximately 260 000. Survival time and cause of death for up to 4 years after the index stroke were determined and related to CRP concentration within 72 hours of stroke and known prognostic variables by a Cox proportional hazards regression model. RESULTS: Ischemic stroke was diagnosed in 228 of 283 consecutive admissions. Median follow-up was 959 days. Geometric mean CRP concentration was 10.1 mg/L. Survival in those with CRP >10.1 mg/L was significantly worse than in those with CRP </=10.1 mg/L (P=0.00009, log-rank test). Higher CRP concentration was an independent predictor of mortality (hazard ratio, 1.23 per additional natural log unit; 95% CI, 1.13 to 1.35; P=0.02), together with age and stroke severity on the National Institutes of Health Stroke Scale. Cardiovascular disease accounted for 76% of deaths in those with CRP >10.1 mg/L and 63% of deaths in those with CRP </=10. 1 mg/L. CONCLUSIONS: CRP concentration is an independent predictor of survival after ischemic stroke. These findings are consistent with a role for inflammation in acute ischemic stroke, as well as with the hypothesis that elevated CRP may predict future cardiovascular mortality.

Acute-Phase Reaction↗
PubMed1999

An immunoluminometric assay for N-terminal pro-brain natriuretic peptide: development of a test for left ventricular dysfunction.

Measurement of plasma levels of brain natriuretic peptide (BNP) has been used to assess left ventricular dysfunction and prognosis. Levels of the N-terminus of the precursor of BNP (NT-proBNP) have been reported to be elevated to a greater extent than BNP in left ventricular dysfunction. We have devised a non-radioactive sensitive and specific assay for NT-proBNP based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyloxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulphonate was used to label peptides representing domains in the middle and C-terminal sections of NT-proBNP. Assay of the C-terminal section of NT-proBNP (amino acids 65-76) in patients with proven left ventricular dysfunction [left ventricular wall motion index median 0.9 (range 0.3-1.4)] revealed elevated values [median 639 (386-911) fmol/ml] compared with normal controls [left ventricular wall motion index of 2 in all, NT-proBNP median 159 (120-245) fmol/ml, P<0.001]. Measurement of the middle section of NT-proBNP (amino acids 37-49) was not a discriminating test. It is thus possible to derivatize small peptides with a methyl acridinium label and preserve immunodetection with specific antibodies. Such methodology may allow non-radioactive immunoluminometric assays to be devised.

Adult↗
PubMed1999

Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction.

Plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are raised in patients with left ventricular dysfunction. Measurement of this peptide has a potential diagnostic role in the identification and assessment of patients with heart failure. The stability of this peptide over time periods and conditions pertaining to routine clinical practice has not been reported previously. Blood samples were obtained from 15 subjects. One aliquot was processed immediately, and the remaining portions of the blood samples were stored for 24 h or 48 h at room temperature or on ice prior to processing. Plasma concentrations of NT-proBNP were measured with a novel immunoluminometric assay developed within our laboratory. Mean plasma concentrations of NT-proBNP were not significantly different whether blood samples were centrifuged immediately and stored at -70 degrees C or kept at room temperature or on ice for 24 h or 48 h. The mean percentage differences from baseline (reference standard) were +5.2% (95% confidence interval +18.2 to -7.8%) and +0.8% (+15.2 to -13.7%) after storage for 24 h at room temperature or on ice respectively, and +8.9% (+24.2 to -6. 5%) and +3.2% (+15.1 to -0.9%) for storage for 48 h at room temperature or on ice respectively. Pearson correlation coefficients for baseline NT-proBNP concentrations compared with levels at 48 h at room temperature or on ice were r=0.89 and r=0.83 respectively (both P<0.0001). Thus NT-proBNP extracted from plasma samples treated with EDTA and aprotinin is stable under conditions relevant to clinical practice.

Adult↗
PubMed1998

Determinants of the blood pressure response to the first dose of ACE inhibitor in mild to moderate congestive heart failure.

AIMS: To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables. METHODS: We studied individual placebo-corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis. RESULTS: BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2 = 5.8%, P = 0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2 = 14.4%, P = 0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r = 23.6%, P < 0.01) but left the majority of the variability in response unexplained. CONCLUSIONS: The first-dose blood pressure response to ACE inhibition cannot be accurately predicted from baseline pathophysiological variables in patients with mild to moderate CHF. The choice of ACE inhibitor accounts for a small proportion of the variability in response but wide inter-individual variability exists in the response to each treatment.

Aged↗
PubMed1996

Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

We previously demonstrated differing blood pressure (BP) responses to the first dose of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF). We wished to confirm the disparate responses to the first dose of these agents, study the response to repeated dosing, and explore possible explanations (slow, tight binding, and steric hindrance) for the phenomenon. Forty-eight elderly patients (aged 51-85 years) with stable CHF were studied for 48 hours. Groups (n = 12) received one of the following: (a) perindopril 2 mg orally (p.o.) + placebo intravenously (i.v.) (day 1) and perindopril 2 mg p.o. (day 2); (b) enalapril 2.5 mg p.o. + placebo i.v. (day 1) and enalapril 2.5 mg p.o. (day 2); (c) placebo p.o. + perindopril at 0.167 mg i.v. (day 1) and perindopril 2 mg p.o. (day 2); or (d) placebo p.o. + placebo i.v. (day 1) and placebo p.o. (day 2). Supine BP was measured on day 1. On day 2, BP was recorded by ambulatory BP monitor. Blood samples were taken at baseline and at intervals during the 48-h study period for estimation of neurohumoral parameters. Inhibition of the renin-angiotensin system (RAS) was estimated by plasma ACE inhibition and also by the ratio of angiotensin II (Ang II)/Ang I + Ang II. On day I, enalapril 2.5 mg caused a greater decrease in BP than did placebo response between 6 and 9 h postdose. Perindopril 2 mg produced a profile of BP response similar to that of placebo. Ambulatory BP on day 2 was consistently lower with enalapril as compared with perindopril. Profiles of plasma ACE inhibition were similar with each active therapy. Enalapril therapy produced a greater increase in plasma renin activity (PRA) than did other treatments. There was no temporal dissociation between plasma ACE inhibition and profile of Ang peptides for any treatment. We have confirmed the disparate BP responses to perindopril and enalapril in CHF. We noted no evidence of slow, tight binding or steric hindrance to explain these differences.

Aged↗
PubMed1994

Anticardiolipin antibodies in an unselected stroke population.

A pathogenetic role in thrombotic disease, particularly in young people, has been postulated for anticardiolipin antibody (ACA). We have carried out a prospective controlled study of 262 unselected patients with acute stroke and 226 controls to assess the prevalence and relation to age and vascular risk factors of ACA. Titres of IgG, IgA, or IgM ACA were above the upper normal limit in 38% of patients. The proportions of patients and controls with raised titres did not differ significantly (13 vs 8% IgG, 22 vs 29% IgA, 11 vs 7% IgM). IgG titres were higher among patients than among controls (mean 3.88 vs 2.86 u/mL [95% CI for difference 0.62-0.87], p = 0.0004), whereas IgA and IgM titres were lower in patients than in controls (IgA 4.82 vs 5.98 u/mL [1.12-1.60], p = 0.01; IgM 3.00 vs 3.64 u/mL [1.01-1.45], p = 0.04). However, within age tertiles the only significant difference between patients and controls for IgG ACA was in the oldest tertile. Analysis by number of risk factors for stroke showed a significant difference between the groups only for subjects with one risk factor. IgA and IgM ACA titres were higher among controls only in those with no vascular risk factors. We found no evidence to support the hypothesis that ACA is an independent risk factor for stroke in young people. The increase in IgG titre with age and number of vascular risk factors in stroke patients suggests that ACA may be a non-specific accompaniment of vascular disease. Routine testing for ACA in stroke patients is not justified.

Acute Disease↗
PubMed1994

Haemodynamic response and pharmacokinetics after the first dose of quinapril in patients with congestive heart failure.

1. Twenty-four elderly patients with stable, chronic congestive heart failure, NYHA II-IV, requiring addition of an ACE inhibitor to their existing therapy were randomised to receive double-blind a single dose of quinapril 2.5 mg p.o. or matching placebo after 24-48 h supervised diuretic withdrawal. 2. The effect of treatment on resting supine blood pressure, heart rate, plasma angiotensin converting enzyme (ACE) and circulating plasma renin activity was compared between groups over the first 24 h after dosing. The pharmacokinetic profiles of quinapril and the active metabolite quinaprilat were determined. 3. Compared with placebo, quinapril caused a statistically significant but modest fall in blood pressure from 3 to 10 h post dose. The maximum fall of 12 mm Hg (95% C.I. 5.4-18.5) was seen at approximately 5 h. Circulating ACE activity was 40% inhibited within 1 h. Maximum ACE inhibition (83.6%, 95% C.I. 76.7-90.5) was observed at 3 h. ACE remained 60% inhibited at 24 h post dose. tmax for quinapril was seen at 2.6 +/- 1.2 h. while tmax for quinaprilat was at 3.6, +/- 0.8 h. 4. Treatment with quinapril was associated with a significant rise in plasma renin activity (PRA) of 8.83 ng AI ml-1 h-1 (95% C.I. 0.30-17.96) compared with placebo. 5. Compared with placebo, quinapril 2.5 mg inhibits plasma ACE by over 60% for 24 h and reduces blood pressure for at least 10 h in patients with stable, chronic congestive heart failure. The blood pressure fall, although moderate and well tolerated, is more sustained than previously described for quinapril in heart failure.

Aged↗
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

Analysis of biogenic amines in plasma of hypertensive patients and a control group.

Procedures were developed for the determination of 17 circulating amines using gas chromatography-negative ion chemical ionisation mass spectrometry. The amines were quantified against their appropriate deuterated isotopomers. The mean concentrations and ranges of catecholamines and trace amines were high compared with previous studies. In comparison with nonhypertensives, plasma from hypertensives had higher concentrations of the following amines: noradrenaline (t = 4.0%); normetanephrine (t = 6.1%) and metanephrine (t = 1.9%). There were no significant differences between 5HT levels in plasma from hypertensives and controls. The following trace amines could be detected in variable amounts in plasma: p-tyramine, m-tyramine, p-octopamine, m-octopamine, p-synephrine, m-synephrine, and salsolinol. The trace amines melatonin, N-acetyl 5HT, tryptamine, 6-hydroxymelatonin and 5-methoxytryptamine could not be detected in plasma with limits of detection lying in the range 20-100 pg ml-1.

Biogenic Amines↗