PubMed Health⌕ Search

Biomedical subjects

T Higenbottam

Publications and source records attributed to T Higenbottam.

At least 19 recordsLinked to original sources
PubMed2005

Relationship between respiratory symptoms and medical treatment in exacerbations of COPD.

Exacerbations of chronic obstructive pulmonary disease (COPD) can be defined symptomatically or by healthcare contacts, yet the relationship between these events is unknown. Data were collected during a 1-yr study of the budesonide/formoterol combination in COPD patients, where exacerbations, defined by increases in treatment, were compared with daily records of respiratory symptoms, rescue medication use and peak expiratory flow (PEF). The relationship between changes in these variables and the medical event was examined using different modelling approaches. Data from the first exacerbation treated with oral corticosteroids and/or antibiotics and/or hospitalisation (event based) were available in 468 patients. Patients exacerbating were significantly more breathless and more likely to report cough than healthy patients, but did not differ in baseline spirometry. Exacerbations defined by changes in individual symptoms were only weakly related to event-based exacerbations; however, defined with 63% of such events being predicted from symptom changes. Changes in rescue medication use or PEF were poor predictors of event-based exacerbations. The mean peak change in symptoms was closely related to the onset of therapy. In conclusion, event-based exacerbations are a valid way of identifying acute symptom change in a chronic obstructive pulmonary disease population. However, daily symptom monitoring is too variable using the current diary cards to make individual management decisions.

Acute Disease↗
PubMed2004

Understanding the mechanisms of drug-associated interstitial lung disease.

Drugs have been implicated in lung injury as a result of direct pharmacological action, persistence or metabolism in the tissue, or via the production of a reactive metabolite or metabolites. The result of this apparent drug-associated injury ranges from cellular dysfunction through to cell death (apoptosis) and alteration of repair mechanisms that are essential in replacing critical tissue elements and function. There is limited knowledge on how timing of drug administration or drug interactions may interfere with the repair mechanisms or modulate the expression of pulmonary toxicity. Chemotherapeutic drugs and novel agents, such as those targeting the epidermal growth factor receptor (EGFR), appear to affect both normal and neoplastic cells. However, unlike chemotherapy, where the actions are systemic and directly as a result of biotransformation or cell injury, it has been postulated that effects of EGFR-targeting agents are more likely to be focused on epithelia via a pharmacological effect. Furthermore, risk factors for the development of adverse pulmonary reactions, as well as biological markers indicating incipient toxicity, need to be prospectively identified. Proteomics, through the identification of >/=1000 proteins or peptides in blood samples, will hopefully identify candidates for this role.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Chronic cough and the cough reflex in common lung diseases.

Following the experience of asthma, characterised by the presence of bronchial hyper-responsiveness, the notion has been accepted that the chronic cough of disease occurs as a result of altered sensitivity of the afferent limb of the cough reflex. Methods for testing for the 'threshold' for eliciting the cough reflex have also been borrowed from asthma care. In the main aerosols are inhaled that contain the relevant stimulus.A number of factors influence the cough response to inhaled aerosols. The distribution of the inhaled aerosol is important as certain chemically sensitive receptors are distributed in different regions of the lungs. The larynx and central airways are important but so too are the peripheral airways. The degree of bronchodilatation is also important as airway narrowing can, itself, induce coughing in man.Asthma, oesophageal reflux and rhinitis patients experience increased coughing, that is associated with increased sensitivity to inhaled capsaicin. In syndromes of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) increased sensitivity to coughing with capsaicin is common. This appears a specific effect of the pathogenic process of the disease. Modification of the disease process can lessen coughing and the sensitivity to capsaicin.

Asthma↗
PubMed2001

Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis.

BACKGROUND: Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO-synthase inhibitor NGL-arginine methyl ester (L-NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen. METHODS: Nitric oxide levels in the nose were measured by the chemiluminescence method in nine non-atopic volunteers and in seven patients with seasonal rhinitis at rest and after an acute challenge with the allergen. NAR were measured by active anterior rhinomanometry. RESULTS: Basal nasal NO concentration in allergic rhinitis was 496.5 +/- 151.4 parts per billion (ppb). (n = 7) and it was not significantly different from levels found in the control group: 458.4 +/- 105.9 ppb (n = 9). The topical administration of L-NAME in allergic rhinitis reduced the NO concentration (338.6 +/- 99.3 ppb, P < 0.001; n = 7). In the rhinitic patients the challenge with the allergen did not modify the nasal NO levels (504.5 +/- 138.5 ppb). The application of the allergen after the pretreatment with placebo caused a significant increase in NAR (from 0.32 +/- 0.11 Pa s cm-3 to 1.01 +/- 0.12 Pa s cm-3, P < 0.001; n = 7). Pre-treatment with L-NAME did not prevent the increase in NAR induced by allergen challenge (from 0.36 +/- 0.15 Pa s cm-3 to 1.06 +/- 0.26 Pa s cm-3). CONCLUSIONS: The results indicate that nasal administration of a NOS inhibitor L-NAME, at doses capable of decreasing nasal NO levels, has no effect on NAR and it does not prevent the NAR increase induced by an acute challenge with allergen in subjects with seasonal rhinitis.

Administration, Intranasal↗
PubMed2001

The direct and indirect action of inhaled agents on the lung and its circulation: lessons for clinical science.

Inhalation of particles, gases, and vapors from environmental pollution results in a number of localized and general responses by the lungs. In this article we report investigations performed in humans that have enabled the identification of these specific processes in response to inhaled materials. We also offer insights that could help generalize environmental inhaled pollutants and potential means of studying them in humans. Three specific areas are covered: impact of denervation of the lungs and airway inflammation on the acute defense mechanism of the lungs to inhaled "irritants," differential uptake of inhaled particles into separate regions of the lungs, and the effect of inhaled nitric oxide on pulmonary vasculature and gas exchange. The inhalation of nitric oxide reflects the potential of inhaled pollutants to influence gas exchange, especially in patients with established lung disease, such as chronic obstructive pulmonary disease.

Air Pollutants↗
PubMed2000

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family.

BACKGROUND: Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS: We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS: We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH. CONCLUSION: The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.

Adolescent↗
PubMed1999

The acute effects of dexfenfluramine on human and porcine pulmonary vascular tone and resistance.

STUDY OBJECTIVES: Treatment with anorectics has become an important aspect of care for the severely obese. One such anorectic, the phenylethylamine dexfenfluramine (dFen), has been associated with the development of pulmonary hypertension. It works by reducing the neuronal uptake of 5-hydroxytryptamine (5-HT; serotonin) through inhibition of the 5-HT transporter. In this study we investigated whether dFen has a direct vasoconstrictor action on human and porcine pulmonary vasculature. DESIGN: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10(-5) mol/L), or nitric oxide synthase (NOS) blockade (N(G)-nitro-L-arginine, 10(-5) mol/L). RESULTS: In the human study, 5-HT and dFen caused only limited increases in tension of isolated rings of PA. The concentration of dFen, 10(-4) mol/L, that was needed to increase tension was higher than that found normally in treated patients where peak levels are 3. 3 x 10(-7) mol/L. Other vasoconstrictors such as prostaglandin F(2)alpha, 10(-5) mol/L, and the thromboxane analog U46619, 10(-6) mol/L, produced far greater increases in tension. Ketanserin, 10(-4) mol/L, attenuated the constrictor response to 5-HT but had no effect on the constrictor response to dFen. Removal of the endothelium did not influence the response to dFen. In the isolated ventilated and perfused lungs, dFen caused an increase in PVR again only at a comparatively high concentration, 10(-4) mol/L. In the porcine study, dFen, 10(-4) mol/L, did not increase any PVR during normoxia or following NOS blockade. Small insignificant increases in PVR occurred during hypoxia and after cyclo-oxygenase blockade. CONCLUSION: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.

Animals↗
PubMed1998

Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension.

OBJECTIVE: To investigate the relation between the severity of pulmonary hypertension and the outcome of medical treatment. METHODS: 98 patients with primary pulmonary hypertension--nine (6%) with systemic disease and pulmonary hypertension and 39 (27%) with thromboembolic pulmonary hypertension--received medical treatment and were followed between 1982 and 1995. They were given long term intravenous prostaglandin treatment (either epoprostenol (n = 61) or iloprost (n = 13)) or conventional treatment with oral anticoagulants (n = 24) with or without calcium channel blockers. Event-free survival was measured to death or transplant surgery, or pulmonary thromboendarterectomy. RESULTS: Prognosis (hazard ratio) was affected by: New York Heart Association grade, 1.52 (95% confidence interval 1.11 to 2.09); mixed venous oxygen saturation (SvO2%), 0.97 (0.95 to 0.98); cardiac index, 0.72 (0.49 to 1.06); mean right atrial pressure, 1.04 (1.01 to 1.07); and pulmonary vascular resistance, 1.02 (1.00 to 1.04). The median event-free survival time of patients with SvO2 < 60% was 239 days (0 to 502) on conventional treatment (n = 22) and 585 days (300 to 870) on prostaglandin treatment (n = 42). No difference was seen in patients with SvO2 > or = 60% between conventional treatment and prostaglandin treatment, survival being 1275 days (732 to 1818; (n = 48)) and 986 days (541 to 1431; n = 30)), respectively. Capacity for pulmonary vasodilatation did not predict outcome of treatment. CONCLUSIONS: Continuous intravenous prostaglandins were more effective than anticoagulants, with or without calcium channel blockers, in prolonging survival in patients with right heart failure. In these patients a capacity to vasodilate did not predict outcome from medical treatment.

Adult↗
PubMed1997

The role of nitric oxide in respiratory disease.

Nitric oxide (NO) is found in both the upper and lower airways of man. In the lower airways it is found at concentrations less than 3 ppb, and in the upper airways at about 400 ppb. The NO found in the upper airways is thought to play a role in maintaining the sterility of the paranasal sinuses. NO is also produced by the endothelium of the pulmonary vasculature. Endothelium-derived NO is a potent vasodilator involved in maintaining low pulmonary tone. Impaired endothelial NO production is thought to be involved in some types of pulmonary hypertension. When inhaled, NO acts as a selective pulmonary vasodilator which is used to treat respiratory diseases. One area in which NO has proven to be particularly effective is in the treatment of persistent pulmonary hypertension of the newborn. Inhaled NO therapy can be used in the treatment of adult respiratory distress syndrome, primary pulmonary hypertension and chronic obstructive pulmonary disease.

Adult↗
PubMed1997

UK guidelines for the use of inhaled nitric oxide therapy in adult ICUs. American-European Consensus Conference on ALI/ARDS.

OBJECTIVE: Although unlicensed, inhaled nitric oxide (NO) therapy is now widely used in the United Kingdom. Our aim was to produce guidelines for the clinical application of inhaled NO in adult intensive care practice, based upon the current level of published information. METHODS: The published data regarding the use of inhaled NO in the acute respiratory distress syndrome and right-sided cardiac failure was presented, analysed and discussed. Recommendations based on these data as well as on current experience in the United Kingdom were formulated. DESIGN: An expert group comprising intensive care specialists from within the United Kingdom, representatives from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine and individuals from the Departments of Health and Industry related to the field was assembled. RESULTS: United Kingdom guidelines for the indications, contraindications, dose, delivery, monitoring and scavenging of inhaled NO therapy were produced. CONCLUSIONS: The need for additional quality research to establish evidence of efficacy and safety was emphasized. The guidelines are designed to act within the context of current practice and knowledge and should be revised as further data emerge.

Acute Disease↗
PubMed1997

Lack of effect of nitric oxide inhibition on bronchial tone and methacholine-induced bronchoconstriction in man.

The role of nitric oxide (NO) as a bronchodilator has been studied in humans with controversial results. The aim of the present study was to investigate the role of endogenous NO on bronchial tone by studying whether nitric oxide synthase (NOS) inhibition with NGnitro-L-arginine-methyl-ester (L-NAME) influences basal bronchial tone, or potentiates methacholine-induced bronchoconstriction. In a preliminary experiment in five subjects, a significant reduction in exhaled NO was found after delivering L-NAME (15 mg in saline) (from 3.9 +/- 1.2 to 2.4 +/- 1.1 nmol min-1, P < 0.05). In nine healthy non-smokers, specific airway conductance (SGAW), as a measure of airway calibre, was recorded after delivering, in a double-blind, controlled vs. placebo fashion, both nebulized L-NAME and saline, at baseline and after methacholine-induced bronchoconstriction. There was no significant difference between the baseline SGAW values before and after delivering L-NAME (0.264 +/- 0.04 and 0.267 +/- 0.05 cm H2O-1 s-1, respectively). After pre-treatment with L-NAME, SGAW values during methacholine-induced bronchoconstriction were not different in comparison to values obtained after saline inhalation. It is concluded that decreased endogenous NO does not influence bronchial tone in healthy people, nor does it modify methacholine-induced bronchoconstriction.

Adult↗
PubMed1997

Pulmonary hypertension, family and environment.

The focus of interest on pulmonary hypertension (PH) has come through recent therapeutic advances which prolong and improve quality of life. From this interest, recent observations form family studies indicate that a gene located on chromosome 2 is associated with PH. Environmental factors, the use of an anorectic agent, dexfenfluramine, has been associated with a risk of developing primary PH. A link with hypoxic induced PH has emerged in that a strain of rat, the fawn-hooded rat (FHR) which has a susceptibility to developing PH with mild hypoxia has an inherited storage defect to serotonin. Dexfenfluramine, by inhibiting the serotonin transporter, produces a similar pattern of disturbance of biogenic amine metabolism. This observation provides some insight into potential mechanisms for this complex disorder.

Animals↗