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Papers by Mark Richards

Research paper thumbnail of Assay of endopeptidase-24.11 activity in plasma applied to in vivo studies of endopeptidase inhibitors

Clinical Chemistry

We developed a fluorometric assay for endopeptidase-24.11 (EC 3.4.24.11) in human plasma. Substra... more We developed a fluorometric assay for endopeptidase-24.11 (EC 3.4.24.11) in human plasma. Substrate [glutaryl-Ala-Ala-Phe-amidomethylcoumarin(AMC)] was incubated with plasma (20 microL, 30 min, pH 7.6) with (control) or without the endopeptidase-24.11 inhibitor phosphoramidon. Further incubation with aminopeptidase M released free AMC. Within-assay CVs were 4.5% and 8.6%, respectively, at 3.31 and 0.27 nmol of AMC released per milliliter per minute. The between-assay CV was 10.4% at 0.31 nmol/mL per minute and the detection limit was 0.05 nmol/mL per minute. A highly skewed distribution of endopeptidase-24.11 in 41 normal samples was found, ranging from 0.12 to 6.84 nmol/mL per minute (median = 0.44). Mean endopeptidase-24.11 concentrations were significantly higher in hypertensive subjects (0.68 nmol/mL per minute) than in normotensive subjects (0.34 nmol/mL per minute; P less than 0.05). Compared with placebo administration, the oral endopeptidase-24.11 inhibitor UK 79300 signific...

Research paper thumbnail of Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure

European heart journal, Jan 21, 2014

Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompe... more Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but ...

Research paper thumbnail of Substituted 2-phenyl-benzimidazole derivatives: novel compounds that suppress key markers of allergy

The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of ... more The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade, while neglecting targets that play an early role in their development. Reasoning that IgE is central to the expansion of atopic diseases, we identified and extended a novel family of 2-(substituted phenyl)-benzimidazole inhibitors of IgE response. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups composed of either bis cycloalkyl or combinations of aliphatic and halogen-substituted aromatic groups. These compounds also inhibit IL-4 and IL-5 responses in T cells and CD23 expression on B cells, with potencies that parallel their inhibition of IgE. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma.

Research paper thumbnail of Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial

Journal of the American College of Cardiology, Jan 30, 2011

The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-... more The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 9...

Research paper thumbnail of Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study

Circulation. Heart failure, 2010

Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart ... more Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure. Associations between hyponatremia and other prognostic variables in acutely decompensated heart failure, such as amino-terminal pro-B type natriuretic peptide remain unclear. Six hundred twenty-eight patients presenting to the emergency department with acutely decompensated heart failure were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at 1 year, alone and relative to other predictors of death. Hyponatremia (Na < or =135 mmol/L) was diagnosed in 24%(n=149) patients. Compared with those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease but were more likely to have severe symptoms, to be anemic, and to have higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (all P< or =0.05). When examined as a function of ...

Research paper thumbnail of Urocortin 2 inhibits furosemide-induced activation of renin and enhances renal function and diuretic responsiveness in experimental heart failure

Circulation. Heart failure, 2009

Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics ha... more Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Because any prospective new treatment is likely to be used in conjunction with standard diuretic therapy, it is necessary to investigate the combined effects of these agents. Ucn2 and furosemide were administered for 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2), and creatinine excretion (Ucn2>furosemide) and creatinine clearance (Ucn2>furosemide). Compared with furosemide treatment alone, Ucn2+furosemide produced a further diuresis (P<0.05), natriuresis (P<0.05), and a sustained increase in creatinine excretion (P<0.05) and clearance (P<0.05), withou...

Research paper thumbnail of Amino-Terminal Pro-C-Type Natriuretic Peptide in Heart Failure

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart fail... more The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive

Research paper thumbnail of Novel 2-(Substituted phenyl)benzimidazole Derivatives with Potent Activity against IgE, Cytokines, and CD23 for the Treatment of Allergy and Asthma

Journal of Medicinal Chemistry, 2004

The effectiveness of the injectable anti-IgE antibody omalizumab has validated IgE as an importan... more The effectiveness of the injectable anti-IgE antibody omalizumab has validated IgE as an important target for allergic diseases, thus spawning the development of small-molecule IgE inhibitors. Herein, a brief SAR is described for novel phenylbenzimidazole compounds that potently suppress IgE responses. In addition to IgE, these agents inhibit other targets critical for allergic response. The profile of orally active AVP-13358, the lead compound of this series currently in clinical trials, is described.

Research paper thumbnail of Validating aminoterminal BNP assays: a word of caution

The Lancet, 1999

... Titre du document / Document title. Validating aminoterminal BNP assays : a word of caution. ... more ... Titre du document / Document title. Validating aminoterminal BNP assays : a word of caution. Auteur(s) / Author(s). YANDLE T. (1) ; FISHER S. (1) ; ESPINER E. (1) ; RICHARDS M. (1) ; NICHOLLS G. (1) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s). ...

Research paper thumbnail of Urocortins: Putative Role in Cardiovascular Disease

Current Medicinal Chemistry-Cardiovascular & Hematological Agents, 2004

Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2beta) in peripheral tissues, ... more Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2beta) in peripheral tissues, including the heart and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, Ucn gene expression and/or immunoreactivity are increased in the ventricles of patients with failing hearts. Hemodynamic effects of Ucn include vasodilation and increases in cardiac contractility, coronary blood flow and conductance, cardiac output and heart rate. Due to the likely benefit of such actions in states of cardiac compromise, our laboratory has recently reported the first study examining the effects of Ucn in ovine experimental heart failure. We observed profound and sustained cardiovascular (reduced cardiac preload and afterload and increased cardiac output), hormonal (inhibition of vasopressin, endothelin and renin-angiotensin-aldosterone axis) and renal effects (natriuresis, diuresis and augmented creatinine clearance). Such effects incorporate many of the therapeutic goals of heart failure management. Recently, two further members of the CRF peptide family have been identified. In contrast to Ucn, Ucn II and III are reported to be highly selective for the CRF-R2beta, displaying negligible affinity for CRF-R1. As such, one could speculate that these new peptides might produce the salutary effects in heart failure as seen with Ucn, without concomitant activation of the stress-related hormone ACTH (mediated via CRF-R1). Clearly, further study is essential to confirm whether manipulation of this new family of peptides (especially Ucn II and Ucn III) offers benefit to the syndrome of heart failure with potential clinical applications in humans.

Research paper thumbnail of Substituted 2-Phenyl-benzimidazole Derivatives: Novel Compounds that Suppress Key Markers of Allergy

ChemInform, 2007

The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of ... more The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade, while neglecting targets that play an early role in their development. Reasoning that IgE is central to the expansion of atopic diseases, we identified and extended a novel family of 2-(substituted phenyl)-benzimidazole inhibitors of IgE response. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups composed of either bis cycloalkyl or combinations of aliphatic and halogen-substituted aromatic groups. These compounds also inhibit IL-4 and IL-5 responses in T cells and CD23 expression on B cells, with potencies that parallel their inhibition of IgE. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma.

Research paper thumbnail of Health Gains by Using Natriuretic Peptides in Diagnosis, Prognosis and Treatment

Scandinavian Journal of Clinical & Laboratory Investigation, 2005

The cardiac natriuretic peptides, and in particular plasma levels of the B-type natriuretic pepti... more The cardiac natriuretic peptides, and in particular plasma levels of the B-type natriuretic peptides, are acknowledged biomarkers of cardiac function and prognosis in cardiovascular disease. A growing body of evidence confirms plasma BNP and/or NT-proBNP are independent predictors of mortality and/or heart failure events in acute heart failure, established chronic heart failure, acute coronary syndromes and even in asymptomatic but at risk populations. Alongside this large body of associative observational data, there is a growing evidence base from controlled trials which indicates that knowledge of plasma B-type natriuretic peptide levels can be translated into improved clinical outcomes. Measurements of NT-proBNP improve diagnostic accuracy in patients presenting with heart failure in the community. Provision of plasma BNP data improves speed of diagnosis and reduces rates of hospital admission in patients with heart failure presenting with breathlessness (all whilst reducing overall costs). A randomised pilot study demonstrates serial measurements of NT-proBNP can assist in more effective optimisation of heart failure pharmacotherapy with a concomitant improvement in outcome. This finding has been corroborated by a recently reported multicentre study. Screening for left ventricular systolic dysfunction in the general population or in asymptomatic subjects at high risk of cardiovascular events appears to be cost-effective. This developing evidence base from controlled trials encourages further implementation of plasma BNP and/or NT-proBNP in diagnosis, risk stratification and management, not only of acute and chronic heart failure but also in those with coronary disease and asymptomatic subjects with cardiovascular risk factors.

Research paper thumbnail of Adrenomedullin and heart failure

Regulatory Peptides, 2003

Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. ... more Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. Circulating concentrations of AM are elevated in cardiovascular disease in proportion to the severity of cardiac and hemodynamic impairment. Raised plasma AM levels following acute cardiac injury and in heart failure provide prognostic information on adverse outcomes. In heart failure, elevated circulating AM also identifies patients likely to receive long-term benefit from inclusion of additional anti-failure therapy (carvedilol). Administration of AM in experimental and human heart failure induces reductions in arterial pressure and cardiac filling pressures, and improves cardiac output, in association with inhibition of plasma aldosterone (despite increased renin release) and sustained (or augmented) renal glomerular filtration and sodium excretion. Furthermore, AM in combination with other therapies (angiotensin-converting enzyme inhibition and augmentation of the natriuretic peptides) results in hemodynamic and renal benefits greater than those achieved by the agents separately. Manipulation of the AM system holds promise as a therapeutic strategy in cardiac disease.

Research paper thumbnail of Adrenomedullin and the renin–angiotensin–aldosterone system

Regulatory Peptides, 2003

Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenome... more Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenomedullin (AM) is hypotensive as a result of dramatic reductions in peripheral resistance. Furthermore, it does not appear to increase aldosterone secretion in spite of often vigorous activation of circulating renin. Hence, we postulate that AM may act as a functional antagonist to angiotensin II both in the vasculature and the adrenal glomerulosa. In the series of studies performed in sheep and human (normal and circulatory disorders) reviewed here, we report significant hemodynamic and hormonal actions of AM. These actions include consistent reduction of arterial pressure associated with rises in cardiac output and hence a dramatic reduction in calculated total peripheral resistance (CTPR). AM also consistently attenuates the pressor effects of angiotensin II (but not norepinephrine). Furthermore, AM consistently increases plasma renin activity (PRA) and induces either a reduction in plasma aldosterone, dissociation between aldosterone/PRA ratio, or attenuation of angiotensin II-induced aldosterone secretion. Thus, these results clearly point to a role for AM in pressure and volume homeostasis acting, at least in part, by interaction with the renin-angiotensin-aldosterone system (RAAS).

Research paper thumbnail of Bivariate assay for cleaved atrial natriuretic factor (ANF(101–105/106–126)) in sheep plasma

Regulatory Peptides, 1992

A bivariate assay has been developed to measure both ANF, and cleaved ANF (ANF(101-105/106-126)) ... more A bivariate assay has been developed to measure both ANF, and cleaved ANF (ANF(101-105/106-126)) the primary product of endopeptidase-24.11 action on rat ANF(101-126). The assay employed two different antisera directed to the carboxy-terminal and ring regions of ANF to enable discrimination and measurement of intact endogenous ANF(99-126) and infused cleaved ANF (rat ANF(101-105/106-126)) in sheep plasma extracts. The assay which was validated by HPLC analysis of plasma extracts, had sufficient accuracy and precision to measure the metabolic clearance rate and half-life of cleaved ANF when infused in normal sheep.

Research paper thumbnail of Single-sector thermophysiological human simulator

Physiological Measurement, 2008

Thermal sweating manikins are used to analyse the heat and mass transfer phenomena in the skin-cl... more Thermal sweating manikins are used to analyse the heat and mass transfer phenomena in the skin-clothing-environment system. However, the limiting factor of present thermal manikins is their inability to simulate adequately the human thermal behaviour, which has a significant effect on the clothing microenvironment. A mathematical model of the human physiology was, therefore, incorporated into the system control to simulate human thermoregulatory responses and the perception of thermal comfort over a wide range of environmental and personal conditions. Thereby, the computer model provides the physiological intelligence, while the hardware is used to measure the required calorimetric states relevant to the human heat exchange with the environment. This paper describes the development of a single-sector thermophysiological human simulator, which consists of a sweating heated cylinder &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Torso&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; coupled with the iesd-Fiala multi-node model of human physiology and thermal comfort. Validation tests conducted for steady-state and, to some extent, transient conditions ranging from cold to hot revealed good agreement with the corresponding experimental results obtained for semi-nude subjects. The new coupled system enables overall physiological and comfort responses, health risk and survival conditions to be predicted for adult humans for various scenarios.

Research paper thumbnail of Central and peripheral forms of C-type natriuretic peptide (CNP): Evidence for differential regulation in plasma and cerebrospinal fluid

Peptides, 2011

Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in ... more Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 ± 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 ± 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 ± 55) was much higher than in plasma (31 ± 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = -0.29, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders.

Research paper thumbnail of Skeletal contributions to plasma CNP forms: Evidence from regional sampling in growing lambs

Peptides, 2009

Unlike the cardiac circulating hormones, atrial natriuretic peptide (ANP) and B-type natriuretic ... more Unlike the cardiac circulating hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) appears to be largely tissue-based and circulates at concentrations considered insufficient to affect organ function. Consistent with CNP&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s crucial role in regulating skeletal growth, serial studies in juveniles show that both plasma CNP and aminoterminal proCNP (NTproCNP) are highly correlated with growth velocity raising the possibility that skeletal tissues contribute to circulating concentrations of CNP forms during the growing period. Hypothesizing that venous blood draining from bone dense regions is relatively enriched in CNP, we have performed trans-organ regional blood sampling for measurement of CNP forms in 4-week-old lambs and compared the findings to simultaneous levels of ANP and BNP. Because bone growth and CNP synthesis are inhibited by glucocorticoids, identical studies were also undertaken in lambs pretreated with dexamethasone. Highly significant positive arterio-venous gradients of CNP were found across the head, heart, leg and foot. Dexamethasone significantly reduced the CNP arterio-venous gradient across the head and leg but not heart, liver or kidney. In contrast, there was no evidence of tissue secretion of ANP or BNP except across the heart, and no effect on these gradients from dexamethasone. These findings of CNP enrichment in samples from bone dense regions in growing lambs, and their selective reduction by dexamethasone, provide in vivo evidence linking plasma and skeletal tissue concentrations of CNP and further support the use of plasma CNP forms as markers of bone growth.

Research paper thumbnail of Urotensin II: Evidence for cardiac, hepatic and renal production

Peptides, 2005

Although urotensin II (UII) has been reported to circulate in human plasma and be raised in cardi... more Although urotensin II (UII) has been reported to circulate in human plasma and be raised in cardiovascular disorders, little, if any, information is available regarding the source of plasma UII. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of UII concentration in anesthetized sheep. Plasma UII levels were measured in the low picomolar range in normal sheep and arterial plasma levels rose steadily with increasing time of anesthesia. Significant arteriovenous gradients were observed across the heart (36%), liver (40%) and kidney (44%). This is the first report to identify the heart, liver and kidney as sources of UII in the circulation.

Research paper thumbnail of Regional sampling and the effects of experimental heart failure in sheep: Differential responses in A, B and C-type natriuretic peptides

Peptides, 2006

While regional plasma concentrations of the endocrine hormones atrial and brain natriuretic pepti... more While regional plasma concentrations of the endocrine hormones atrial and brain natriuretic peptide (ANP and BNP) have been studied, there are few reports of regional changes in the largely paracrine C-type natriuretic peptide (CNP) and its amino terminal fragment NT-CNP. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of plasma ANP, BNP, CNP and NT-CNP in anesthetized sheep before and after induction of experimental heart failure. ANP and BNP plasma concentrations are sourced from a single organ (the heart) and are subject to substantial extraction across most tissue beds. In contrast, our data demonstrate that multiple tissues including liver, heart, hind limb and kidney contribute to circulating CNP. Given that arteriovenous gradients for NT-CNP were similar, this is likely to represent de novo secretion. Circulating levels of CNP and NT-CNP were raised in heart failure but to a much lesser degree than ANP and BNP. There was no evidence of net extraction of CNP or NT-CNP across any tissue bed.

Research paper thumbnail of Assay of endopeptidase-24.11 activity in plasma applied to in vivo studies of endopeptidase inhibitors

Clinical Chemistry

We developed a fluorometric assay for endopeptidase-24.11 (EC 3.4.24.11) in human plasma. Substra... more We developed a fluorometric assay for endopeptidase-24.11 (EC 3.4.24.11) in human plasma. Substrate [glutaryl-Ala-Ala-Phe-amidomethylcoumarin(AMC)] was incubated with plasma (20 microL, 30 min, pH 7.6) with (control) or without the endopeptidase-24.11 inhibitor phosphoramidon. Further incubation with aminopeptidase M released free AMC. Within-assay CVs were 4.5% and 8.6%, respectively, at 3.31 and 0.27 nmol of AMC released per milliliter per minute. The between-assay CV was 10.4% at 0.31 nmol/mL per minute and the detection limit was 0.05 nmol/mL per minute. A highly skewed distribution of endopeptidase-24.11 in 41 normal samples was found, ranging from 0.12 to 6.84 nmol/mL per minute (median = 0.44). Mean endopeptidase-24.11 concentrations were significantly higher in hypertensive subjects (0.68 nmol/mL per minute) than in normotensive subjects (0.34 nmol/mL per minute; P less than 0.05). Compared with placebo administration, the oral endopeptidase-24.11 inhibitor UK 79300 signific...

Research paper thumbnail of Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure

European heart journal, Jan 21, 2014

Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompe... more Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but ...

Research paper thumbnail of Substituted 2-phenyl-benzimidazole derivatives: novel compounds that suppress key markers of allergy

The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of ... more The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade, while neglecting targets that play an early role in their development. Reasoning that IgE is central to the expansion of atopic diseases, we identified and extended a novel family of 2-(substituted phenyl)-benzimidazole inhibitors of IgE response. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups composed of either bis cycloalkyl or combinations of aliphatic and halogen-substituted aromatic groups. These compounds also inhibit IL-4 and IL-5 responses in T cells and CD23 expression on B cells, with potencies that parallel their inhibition of IgE. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma.

Research paper thumbnail of Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial

Journal of the American College of Cardiology, Jan 30, 2011

The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-... more The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 9...

Research paper thumbnail of Hyponatremia, natriuretic peptides, and outcomes in acutely decompensated heart failure: results from the International Collaborative of NT-proBNP Study

Circulation. Heart failure, 2010

Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart ... more Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure. Associations between hyponatremia and other prognostic variables in acutely decompensated heart failure, such as amino-terminal pro-B type natriuretic peptide remain unclear. Six hundred twenty-eight patients presenting to the emergency department with acutely decompensated heart failure were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at 1 year, alone and relative to other predictors of death. Hyponatremia (Na < or =135 mmol/L) was diagnosed in 24%(n=149) patients. Compared with those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease but were more likely to have severe symptoms, to be anemic, and to have higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (all P< or =0.05). When examined as a function of ...

Research paper thumbnail of Urocortin 2 inhibits furosemide-induced activation of renin and enhances renal function and diuretic responsiveness in experimental heart failure

Circulation. Heart failure, 2009

Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics ha... more Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Because any prospective new treatment is likely to be used in conjunction with standard diuretic therapy, it is necessary to investigate the combined effects of these agents. Ucn2 and furosemide were administered for 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2), and creatinine excretion (Ucn2>furosemide) and creatinine clearance (Ucn2>furosemide). Compared with furosemide treatment alone, Ucn2+furosemide produced a further diuresis (P<0.05), natriuresis (P<0.05), and a sustained increase in creatinine excretion (P<0.05) and clearance (P<0.05), withou...

Research paper thumbnail of Amino-Terminal Pro-C-Type Natriuretic Peptide in Heart Failure

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart fail... more The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive

Research paper thumbnail of Novel 2-(Substituted phenyl)benzimidazole Derivatives with Potent Activity against IgE, Cytokines, and CD23 for the Treatment of Allergy and Asthma

Journal of Medicinal Chemistry, 2004

The effectiveness of the injectable anti-IgE antibody omalizumab has validated IgE as an importan... more The effectiveness of the injectable anti-IgE antibody omalizumab has validated IgE as an important target for allergic diseases, thus spawning the development of small-molecule IgE inhibitors. Herein, a brief SAR is described for novel phenylbenzimidazole compounds that potently suppress IgE responses. In addition to IgE, these agents inhibit other targets critical for allergic response. The profile of orally active AVP-13358, the lead compound of this series currently in clinical trials, is described.

Research paper thumbnail of Validating aminoterminal BNP assays: a word of caution

The Lancet, 1999

... Titre du document / Document title. Validating aminoterminal BNP assays : a word of caution. ... more ... Titre du document / Document title. Validating aminoterminal BNP assays : a word of caution. Auteur(s) / Author(s). YANDLE T. (1) ; FISHER S. (1) ; ESPINER E. (1) ; RICHARDS M. (1) ; NICHOLLS G. (1) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s). ...

Research paper thumbnail of Urocortins: Putative Role in Cardiovascular Disease

Current Medicinal Chemistry-Cardiovascular & Hematological Agents, 2004

Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2beta) in peripheral tissues, ... more Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2beta) in peripheral tissues, including the heart and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, Ucn gene expression and/or immunoreactivity are increased in the ventricles of patients with failing hearts. Hemodynamic effects of Ucn include vasodilation and increases in cardiac contractility, coronary blood flow and conductance, cardiac output and heart rate. Due to the likely benefit of such actions in states of cardiac compromise, our laboratory has recently reported the first study examining the effects of Ucn in ovine experimental heart failure. We observed profound and sustained cardiovascular (reduced cardiac preload and afterload and increased cardiac output), hormonal (inhibition of vasopressin, endothelin and renin-angiotensin-aldosterone axis) and renal effects (natriuresis, diuresis and augmented creatinine clearance). Such effects incorporate many of the therapeutic goals of heart failure management. Recently, two further members of the CRF peptide family have been identified. In contrast to Ucn, Ucn II and III are reported to be highly selective for the CRF-R2beta, displaying negligible affinity for CRF-R1. As such, one could speculate that these new peptides might produce the salutary effects in heart failure as seen with Ucn, without concomitant activation of the stress-related hormone ACTH (mediated via CRF-R1). Clearly, further study is essential to confirm whether manipulation of this new family of peptides (especially Ucn II and Ucn III) offers benefit to the syndrome of heart failure with potential clinical applications in humans.

Research paper thumbnail of Substituted 2-Phenyl-benzimidazole Derivatives: Novel Compounds that Suppress Key Markers of Allergy

ChemInform, 2007

The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of ... more The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade, while neglecting targets that play an early role in their development. Reasoning that IgE is central to the expansion of atopic diseases, we identified and extended a novel family of 2-(substituted phenyl)-benzimidazole inhibitors of IgE response. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups composed of either bis cycloalkyl or combinations of aliphatic and halogen-substituted aromatic groups. These compounds also inhibit IL-4 and IL-5 responses in T cells and CD23 expression on B cells, with potencies that parallel their inhibition of IgE. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma.

Research paper thumbnail of Health Gains by Using Natriuretic Peptides in Diagnosis, Prognosis and Treatment

Scandinavian Journal of Clinical & Laboratory Investigation, 2005

The cardiac natriuretic peptides, and in particular plasma levels of the B-type natriuretic pepti... more The cardiac natriuretic peptides, and in particular plasma levels of the B-type natriuretic peptides, are acknowledged biomarkers of cardiac function and prognosis in cardiovascular disease. A growing body of evidence confirms plasma BNP and/or NT-proBNP are independent predictors of mortality and/or heart failure events in acute heart failure, established chronic heart failure, acute coronary syndromes and even in asymptomatic but at risk populations. Alongside this large body of associative observational data, there is a growing evidence base from controlled trials which indicates that knowledge of plasma B-type natriuretic peptide levels can be translated into improved clinical outcomes. Measurements of NT-proBNP improve diagnostic accuracy in patients presenting with heart failure in the community. Provision of plasma BNP data improves speed of diagnosis and reduces rates of hospital admission in patients with heart failure presenting with breathlessness (all whilst reducing overall costs). A randomised pilot study demonstrates serial measurements of NT-proBNP can assist in more effective optimisation of heart failure pharmacotherapy with a concomitant improvement in outcome. This finding has been corroborated by a recently reported multicentre study. Screening for left ventricular systolic dysfunction in the general population or in asymptomatic subjects at high risk of cardiovascular events appears to be cost-effective. This developing evidence base from controlled trials encourages further implementation of plasma BNP and/or NT-proBNP in diagnosis, risk stratification and management, not only of acute and chronic heart failure but also in those with coronary disease and asymptomatic subjects with cardiovascular risk factors.

Research paper thumbnail of Adrenomedullin and heart failure

Regulatory Peptides, 2003

Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. ... more Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. Circulating concentrations of AM are elevated in cardiovascular disease in proportion to the severity of cardiac and hemodynamic impairment. Raised plasma AM levels following acute cardiac injury and in heart failure provide prognostic information on adverse outcomes. In heart failure, elevated circulating AM also identifies patients likely to receive long-term benefit from inclusion of additional anti-failure therapy (carvedilol). Administration of AM in experimental and human heart failure induces reductions in arterial pressure and cardiac filling pressures, and improves cardiac output, in association with inhibition of plasma aldosterone (despite increased renin release) and sustained (or augmented) renal glomerular filtration and sodium excretion. Furthermore, AM in combination with other therapies (angiotensin-converting enzyme inhibition and augmentation of the natriuretic peptides) results in hemodynamic and renal benefits greater than those achieved by the agents separately. Manipulation of the AM system holds promise as a therapeutic strategy in cardiac disease.

Research paper thumbnail of Adrenomedullin and the renin–angiotensin–aldosterone system

Regulatory Peptides, 2003

Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenome... more Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenomedullin (AM) is hypotensive as a result of dramatic reductions in peripheral resistance. Furthermore, it does not appear to increase aldosterone secretion in spite of often vigorous activation of circulating renin. Hence, we postulate that AM may act as a functional antagonist to angiotensin II both in the vasculature and the adrenal glomerulosa. In the series of studies performed in sheep and human (normal and circulatory disorders) reviewed here, we report significant hemodynamic and hormonal actions of AM. These actions include consistent reduction of arterial pressure associated with rises in cardiac output and hence a dramatic reduction in calculated total peripheral resistance (CTPR). AM also consistently attenuates the pressor effects of angiotensin II (but not norepinephrine). Furthermore, AM consistently increases plasma renin activity (PRA) and induces either a reduction in plasma aldosterone, dissociation between aldosterone/PRA ratio, or attenuation of angiotensin II-induced aldosterone secretion. Thus, these results clearly point to a role for AM in pressure and volume homeostasis acting, at least in part, by interaction with the renin-angiotensin-aldosterone system (RAAS).

Research paper thumbnail of Bivariate assay for cleaved atrial natriuretic factor (ANF(101–105/106–126)) in sheep plasma

Regulatory Peptides, 1992

A bivariate assay has been developed to measure both ANF, and cleaved ANF (ANF(101-105/106-126)) ... more A bivariate assay has been developed to measure both ANF, and cleaved ANF (ANF(101-105/106-126)) the primary product of endopeptidase-24.11 action on rat ANF(101-126). The assay employed two different antisera directed to the carboxy-terminal and ring regions of ANF to enable discrimination and measurement of intact endogenous ANF(99-126) and infused cleaved ANF (rat ANF(101-105/106-126)) in sheep plasma extracts. The assay which was validated by HPLC analysis of plasma extracts, had sufficient accuracy and precision to measure the metabolic clearance rate and half-life of cleaved ANF when infused in normal sheep.

Research paper thumbnail of Single-sector thermophysiological human simulator

Physiological Measurement, 2008

Thermal sweating manikins are used to analyse the heat and mass transfer phenomena in the skin-cl... more Thermal sweating manikins are used to analyse the heat and mass transfer phenomena in the skin-clothing-environment system. However, the limiting factor of present thermal manikins is their inability to simulate adequately the human thermal behaviour, which has a significant effect on the clothing microenvironment. A mathematical model of the human physiology was, therefore, incorporated into the system control to simulate human thermoregulatory responses and the perception of thermal comfort over a wide range of environmental and personal conditions. Thereby, the computer model provides the physiological intelligence, while the hardware is used to measure the required calorimetric states relevant to the human heat exchange with the environment. This paper describes the development of a single-sector thermophysiological human simulator, which consists of a sweating heated cylinder &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Torso&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; coupled with the iesd-Fiala multi-node model of human physiology and thermal comfort. Validation tests conducted for steady-state and, to some extent, transient conditions ranging from cold to hot revealed good agreement with the corresponding experimental results obtained for semi-nude subjects. The new coupled system enables overall physiological and comfort responses, health risk and survival conditions to be predicted for adult humans for various scenarios.

Research paper thumbnail of Central and peripheral forms of C-type natriuretic peptide (CNP): Evidence for differential regulation in plasma and cerebrospinal fluid

Peptides, 2011

Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in ... more Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 ± 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 ± 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 ± 55) was much higher than in plasma (31 ± 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = -0.29, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders.

Research paper thumbnail of Skeletal contributions to plasma CNP forms: Evidence from regional sampling in growing lambs

Peptides, 2009

Unlike the cardiac circulating hormones, atrial natriuretic peptide (ANP) and B-type natriuretic ... more Unlike the cardiac circulating hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) appears to be largely tissue-based and circulates at concentrations considered insufficient to affect organ function. Consistent with CNP&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s crucial role in regulating skeletal growth, serial studies in juveniles show that both plasma CNP and aminoterminal proCNP (NTproCNP) are highly correlated with growth velocity raising the possibility that skeletal tissues contribute to circulating concentrations of CNP forms during the growing period. Hypothesizing that venous blood draining from bone dense regions is relatively enriched in CNP, we have performed trans-organ regional blood sampling for measurement of CNP forms in 4-week-old lambs and compared the findings to simultaneous levels of ANP and BNP. Because bone growth and CNP synthesis are inhibited by glucocorticoids, identical studies were also undertaken in lambs pretreated with dexamethasone. Highly significant positive arterio-venous gradients of CNP were found across the head, heart, leg and foot. Dexamethasone significantly reduced the CNP arterio-venous gradient across the head and leg but not heart, liver or kidney. In contrast, there was no evidence of tissue secretion of ANP or BNP except across the heart, and no effect on these gradients from dexamethasone. These findings of CNP enrichment in samples from bone dense regions in growing lambs, and their selective reduction by dexamethasone, provide in vivo evidence linking plasma and skeletal tissue concentrations of CNP and further support the use of plasma CNP forms as markers of bone growth.

Research paper thumbnail of Urotensin II: Evidence for cardiac, hepatic and renal production

Peptides, 2005

Although urotensin II (UII) has been reported to circulate in human plasma and be raised in cardi... more Although urotensin II (UII) has been reported to circulate in human plasma and be raised in cardiovascular disorders, little, if any, information is available regarding the source of plasma UII. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of UII concentration in anesthetized sheep. Plasma UII levels were measured in the low picomolar range in normal sheep and arterial plasma levels rose steadily with increasing time of anesthesia. Significant arteriovenous gradients were observed across the heart (36%), liver (40%) and kidney (44%). This is the first report to identify the heart, liver and kidney as sources of UII in the circulation.

Research paper thumbnail of Regional sampling and the effects of experimental heart failure in sheep: Differential responses in A, B and C-type natriuretic peptides

Peptides, 2006

While regional plasma concentrations of the endocrine hormones atrial and brain natriuretic pepti... more While regional plasma concentrations of the endocrine hormones atrial and brain natriuretic peptide (ANP and BNP) have been studied, there are few reports of regional changes in the largely paracrine C-type natriuretic peptide (CNP) and its amino terminal fragment NT-CNP. Accordingly, we have performed trans-organ arteriovenous sampling for measurement of plasma ANP, BNP, CNP and NT-CNP in anesthetized sheep before and after induction of experimental heart failure. ANP and BNP plasma concentrations are sourced from a single organ (the heart) and are subject to substantial extraction across most tissue beds. In contrast, our data demonstrate that multiple tissues including liver, heart, hind limb and kidney contribute to circulating CNP. Given that arteriovenous gradients for NT-CNP were similar, this is likely to represent de novo secretion. Circulating levels of CNP and NT-CNP were raised in heart failure but to a much lesser degree than ANP and BNP. There was no evidence of net extraction of CNP or NT-CNP across any tissue bed.