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Biomedical subjects

David J Webb

Publications and source records attributed to David J Webb.

At least 37 records · Page 2Linked to original sources
PubMed2006

Are rare diseases still orphans or happily adopted? The challenges of developing and using orphan medicinal products.

Orphan medicinal products (OMPs) are targeted at the diagnosis, prevention or treatment of rare diseases and have a special status in European law. This status brings incentives for pharmaceutical companies to invest in OMP development. The goal of the legislation is to encourage the development of more treatments for life-threatening rare disorders, but increased availability of OMPs raises important issues surrounding the public funding of very expensive treatments by national health services. In this article we review OMPs and the incentives for their development and discuss the challenges presented by funding these treatments.

Drug Design↗
PubMed2006

Effects of short-term isocapnic hyperoxia and hypoxia on cardiovascular function.

Both hypoxia and hyperoxia have major effects on cardiovascular function. However, both states affect ventilation and many previous studies have not controlled CO(2) tension. We investigated whether hemodynamic effects previously attributed to modified O(2) tension were still apparent under isocapnic conditions. In eight healthy men, we studied blood pressure (BP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI) and arterial stiffness (augmentation index, AI) during 1 h of hyperoxia (mean end-tidal O(2) 79.6 +/- 2.0%) or hypoxia (pulse oximeter oxygen saturation 82.6 +/- 0.3%). Hyperoxia increased SVRI (18.9 +/- 1.9%; P < 0.001) and reduced HR (-10.3 +/- 1.0%; P < 0.001), CI (-10.3 +/- 1.7%; P < 0.001), and stroke index (SI) (-7.3 +/- 1.3%; P < 0.001) but had no effect on AI, whereas hypoxia reduced SVRI (-15.2 +/- 1.2%; P < 0.001) and AI (-10.7 +/- 1.1%; P < 0.001) and increased HR (18.2 +/- 1.2%; P < 0.001), CI (20.2 +/- 1.8%; P < 0.001), and pulse pressure (13.2 +/- 2.3%; P = 0.02). The effects of hyperoxia on CI and SVRI, but not the other hemodynamic effects, persisted for up to 1 h after restoration of air breathing. Although increased oxidative stress has been proposed as a cause of the cardiovascular response to altered oxygenation, we found no significant changes in venous antioxidant or 8-iso-prostaglandin F(2alpha) levels. We conclude that both hyperoxia and hypoxia, when present during isocapnia, cause similar changes in cardiovascular function to those described with poikilocapnic conditions.

Adaptation, Physiological↗
PubMed2006

Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma.

PURPOSE: Vasospasm, resulting from a generalized dysfunction in the vascular endothelium, is implicated in the development of normal-pressure glaucoma (NPG). Impaired endothelium-derived nitric oxide activity and abnormalities of the endothelin system suggest systemic endothelial cell dysfunction in patients with NPG. Endothelin (ET)-1 vasoreactivity was assessed in the peripheral circulation of patients with NPG. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in eight patients with untreated NPG and eight age- and sex-matched healthy volunteers during intra-arterial infusion of ET-1 (5 pmol/min) and, on a separate occasion, to BQ123, a selective endothelin-A receptor antagonist, (100 nmol/min). Blood pressure and heart rate were measured in the noninfused arm, and plasma ET-1 concentrations were measured using a radioimmunoassay. RESULTS: Forearm blood flow fell during infusion of ET-1 (P<0.001 for both) to a similar extent in both groups (P=0.7; patients versus control subjects). In contrast, BQ123 increased forearm blood flow in both groups (P<0.001 for both), although the vasodilatation was lower in patients than in control subjects (P<0.001; patients versus control subjects). There was no difference in basal plasma ET-1 concentrations between the two groups (P=0.81; patients versus control subjects). CONCLUSIONS: Despite normal responses to ET-1, patients with NPG have reduced vasodilatation in response to ETA-receptor antagonism. This could be due to attenuated ETA-receptor-mediated tone, increased ETB-receptor-mediated contraction or impaired ETB-receptor-mediated release of endothelial nitric oxide. These results are consistent with the authors' previous demonstration of systemic vascular dysfunction in patients with NPG.

Blood Flow Velocity↗
PubMed2006

Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers.

Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes (P < 0.001) and in smokers (P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes (P < 0.01) and in regular smokers (P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk.

Acetylcholine↗
PubMed2006

Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug.

Since its initial characterization in 1988, over 18,236 papers, including 2,485 reviews, have been published in the endothelin (ET) field. Over this period, several generations of selective and mixed (dual) ET receptor antagonists (ERAs), from peptidic backbones to orally active potent (subnanomolar) small molecular compounds, have been developed. These agents have been studied in many experimental animal models of various pathological conditions (cardiovascular, respiratory, and neuro-immunological). Continued basic research has led to a better understanding of the complex interactions between the ET axis and other biologic systems in human pathophysiology. The first clinical trial involved patients with idiopathic pulmonary arterial hypertension and led to approval of bosentan (Tracleer) for use in the United States and Europe in 2002. Since then, bosentan, the only currently approved dual (mixed) ERA, has been used in numerous other clinical trials. In addition, more selective ET(A) receptor antagonists (ambrisentan, atrasentan, avosentan, clazosentan, darusentan, and sitaxsentan) are undergoing clinical trials. Here we outline the ERAs undergoing development and summarize the standing of completed and ongoing trials at the time of the Ninth International Conference on Endothelin and even thereafter. This review is intended to provide a useful reference for those interested in the current state of clinical trials involving ERAs, and to identify lessons that might apply to the design of future trials.

Clinical Trials as Topic↗
PubMed2006

Clinical trials of endothelin antagonists in heart failure: a question of dose?

Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.

Clinical Trials as Topic↗
PubMed2006

Impact on hypertension control of a patient-held guideline: a randomised controlled trial.

BACKGROUND: Hypertension is generally poorly controlled in primary care. One possible intervention for improving control is the harnessing of patient expertise through education and encouragement to challenge their care. AIM: To determine whether encouraging patients to manage their hypertension in an 'expert' manner, by providing them with information in a clear clinical guideline, coupled with an explicit exhortation to become involved in and to challenge their own care if appropriate, would improve their care. DESIGN OF STUDY: Single blind randomised controlled trial of detailed guideline versus standard information. SETTING: Single urban general practice over 1 year. METHOD: Patient-held guideline with written explicit exhortation to challenge care when appropriate. Two hundred and ninety-four of 536 eligible patients on the practice hypertension register were recruited, all of whom were randomised into one of two groups. Two hundred and thirty-six patients completed the study. RESULTS PRIMARY OUTCOME: average systolic blood pressure. SECONDARY OUTCOMES: proportion of patients with blood pressure < 150 mmHg systolic and < 90 mmHg diastolic, average cholesterol, proportion of patients prescribed statins and aspirin according to guideline, hospital anxiety and depression score. No clinically, or statistically significant differences were found between intervention and control with respect to all parameters or in anxiety and depression levels. Statin and aspirin use improved throughout the course of the study in both groups. Statin use showed a trend (P = 0.02) in favour of control. CONCLUSION: In this study there was no clinically significant perceived benefit to patients as a result of providing them with a hypertension guideline. Patient guidelines are currently planned for many chronic illnesses. It is important to determine the utility of such interventions before scarce resources are applied to them.

Aged↗
PubMed2005

Continuous wave ultraviolet light-induced fiber Bragg gratings in few- and single-mode microstructured polymer optical fibers.

We report observations and measurements of the inscription of fiber Bragg gratings (FBGs) in two different types of microstructured polymer optical fiber: few-mode and an endlessly single mode. Contrary to the FBG inscription in silica microstructured fiber, where high-energy laser pulses are a prerequisite, we have successfully used a low-power cw laser source operating at 325 nm to produce 1 cm long gratings with a reflection peak at 1570 nm. Peak reflectivities of more than 10% have been observed.

Journal Article↗
PubMed2005

Impaired effect of endothelin-1 on coronary artery stiffness in type 2 diabetes.

AIM: We examined whether there is a differential effect of endothelin-A antagonism on coronary artery compliance in type 2 diabetes mellitus compared to non-diabetic patients. PATIENT AND METHODS: We examined 32 patients, 11 type 2 diabetes mellitus and 21 non-diabetic patients, with atherosclerotic epicardial arteries free of significant luminal stenoses. Intracoronary BQ-123 (6 micromol), an endothelin-A receptor antagonist, was infused over 20 min. The artery lumen area in the proximal arterial segment was measured at end diastole and end systole before and after BQ-123 administration using an intravascular ultrasound catheter. Calculations were made of normalized arterial compliance index, in mm Hg(-1) x 10(3) and of arterial stiffness index beta. RESULTS: Pulse pressure and heart rate did not change after BQ-123. In type 2 diabetes mellitus, normalized compliance index decreased from 1.79+/-1.36 at baseline to 1.29+/-0.82 after BQ-123 administration, whereas in non-diabetic patients it increased from 2.10+/-1.36 to 3.00+/-2.07 (p<0.05 versus baseline) (F=6.39, p=0.02). In type 2 diabetes mellitus, beta index increased from 1.97+/-0.53 to 2.46+/-0.95, whereas in non-diabetic patients it decreased from 1.83+/-0.95 to 1.63+/-0.84 (F=7.80, p=0.009). Big endothelin-1 at baseline was correlated with the baseline beta index (p<0.0001, r=0.68). CONCLUSIONS: Big endothelin-1 is correlated with the coronary artery stiffness. The effect of endogenous endothelin-1 on coronary artery stiffness is impaired in type 2 diabetes mellitus. This may have important therapeutic implications with respect to the introduction of endothelin receptor antagonists as cardiovascular therapeutic agents.

Aged↗
PubMed2005

Strain and temperature sensitivity of a single-mode polymer optical fiber.

We have measured the optical phase sensitivity of fiber based on poly(methyl methacrylate) under near-single-mode conditions at 632.8 nm wavelength. The elongation sensitivity is 131 +/- 3 x 10(5) rad m(-1) and the temperature sensitivity is -212 +/- 26 rad m(-1) K(-1). These values are somewhat larger than those for silica fiber and are consistent with the values expected on the basis of the bulk polymer properties.

Journal Article↗
PubMed2005

Stimulated tissue plasminogen activator release as a marker of endothelial function in humans.

The initiation, modulation, and resolution of thrombus associated with eroded or unstable coronary plaques are critically dependent on the efficacy of endogenous fibrinolysis. This is dependent on the cellular function of the surrounding endothelium and vascular wall. In particular, the acute release of tissue plasminogen activator from the endothelium makes an important contribution to the defense against intravascular thrombosis. Here, we describe the rationale and methodology for, and clinical relevance of, assessing acute endothelial tissue plasminogen activator release in humans. The investigation of endothelial fibrinolytic function has the potential to provide major new insights into the pathophysiology of cardiovascular disease, and to shape future therapeutic interventions.

Atherosclerosis↗
PubMed2005

Influence of scanning frequency and ultrasonic contrast agent on reproducibility of left ventricular measurements in the mouse.

BACKGROUND: Mice are now widely used as models of cardiovascular disease. Their small size and fast heart rates are technically challenging to echocardiography. This study examined the influence of different scanning frequencies and ultrasonic contrast agent (UCA) on the accuracy and reproducibility of measurements of left ventricular (LV) structure and function. METHODS: Normal mouse hearts (C57BL6) were imaged at 3 different scanning frequencies before and after intravenous injection of the UCA, Optison. Coronary artery ligation mice and sham-operated controls were scanned at 10-22 MHz with and without UCA. RESULTS: Scanning frequency had no significant effect on intraobserver or interobserver variation of LV measurements in normal mice under baseline conditions. Use of UCA significantly reduced estimated ejection fraction at 10-22 MHz compared with baseline (baseline 50.8 +/- 7.6% vs UCA 39.7 +/- 7.6%; P = .03) and significantly increased values for LV cavity dimensions (eg, LV area diastole 20.74 +/- 1.20 vs 23.23 +/- 0.98 mm 2 ; P = .002). UCA significantly reduced intraobserver and interobserver variation in LV ejection fraction. CONCLUSIONS: Scanning frequency had no significant effect on reproducibility of LV measurements in the mouse but UCA significantly reduced interobserver variation. Use of UCA could reduce the number of mice required in any given experiment to observe a statistically significant change in LV function.

Albumins↗
PubMed2005

Endothelial dysfunction in patients with recent myocardial infarction and hyperhomocysteinaemia: effects of vitamin supplementation.

Hyperhomocysteinaemia is a prothrombotic condition that may cause oxidative endothelial injury and impair endogenous fibrinolysis. Vitamin supplementation enhances endothelial function in hyperhomocysteinaemic patients, but responses in patients with co-existing coronary artery disease have been variable. It is also unknown whether hyperhomocysteinaemia is associated with reduced fibrinolytic responses in patients with coronary artery disease. The study aims were to test the hypothesis that patients with recent myocardial infarction and hyperhomocysteinaemia have impaired endothelium-dependent vasomotion and fibrinolysis that is rectified by vitamin supplementation. From a cohort of 120 patients admitted with acute myocardial infarction, 18 patients were recruited from the upper (n=9) and lower (n=9) plasma homocysteine quartiles into a randomized double-blind placebo-controlled crossover trial. Following a 4-week course of placebo or folate/cyanocobalamin/pyridoxine supplements, FBF (forearm blood flow) was measured using venous occlusion plethysmography during intra-arterial substance P (4-16 pmol/min), acetylcholine (5-20 microg/min) and sodium nitroprusside (2-8 microg/min) infusions. All vasodilators caused dose-dependent increases in infused FBF (P<0.05). Patients in the upper homocysteine quartile (16.8+/-2.9 compared with 7.9+/-0.7 micromol/l; P=0.003) had reduced vasodilatation to acetylcholine (P=0.01) and substance P (P<0.05), but not sodium nitroprusside. There were no differences in substance P-induced tissue plasminogen activator release. Vitamin supplementation increased serum folate and vitamin B12 concentrations (P<0.05), but did not significantly lower homocysteine, or affect FBF or fibrinolytic responses. In patients with recent myocardial infarction, hyperhomocysteinaemia is associated with impaired endothelium-dependent vasodilatation, but no alteration in the acute fibrinolytic capacity. This endothelial vasomotor dysfunction is unaltered by vitamin supplementation.

Acetylcholine↗
PubMed2005

Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

Endothelium, Vascular↗
PubMed2005

Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Cardiovascular Diseases↗
PubMed2005

Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database.

PURPOSE: To compare the incidence of various fractures in a cohort of patients with epilepsy with a reference cohort of patients not having epilepsy. METHODS: Patients were included in the epilepsy cohort if they had at least one diagnosis of epilepsy in their medical history and had sufficient evidence of "active" epilepsy (use of antiepileptic drugs, diagnoses) after the practice was included in the General Practice Research Database (GPRD). Two reference patients were sampled for each patient with epilepsy from the same practice. Primary outcome was the occurrence of any fracture during follow-up. Poisson regression analysis was used to estimate incidence density ratios (IDRs). RESULTS: The study population comprised 40,485 and 80,970 patients in the epilepsy and reference cohorts, respectively. The median duration of follow-up was approximately 3 years. The overall incidence rate in the epilepsy cohort was 241.9 per 10,000 person-years. This rate was about twice as high as that in reference cohort: age- and sex-adjusted IDR, 1.89 (95% CI, 1.81-1.98). When comparing IDRs among the different groups of fractures, the highest relative-risk estimate was found for hip and femur fractures (adjusted IDR, 2.79; 95% CI, 2.41-3.24). IDRs were consistently elevated across age and sex groups and across fracture subtypes. CONCLUSIONS: The overall risk of fractures was nearly twice as high among patients with epilepsy compared with the general population. The relative fracture risk was highest for hip and femur. Further study is necessary to elucidate whether this elevated risk is due to the disease, the use of antiepileptic drugs, or both.

Adult↗