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Biomedical subjects

N C Barnes

Publications and source records attributed to N C Barnes.

At least 19 recordsLinked to original sources
PubMed1997

Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1.

In order to determine whether the airway inflammatory cells of chronic obstructive pulmonary disease (COPD) are different from those seen in asthma, we have studied a subepithelial zone, 100 microns deep to the epithelial reticular basement membrane in bronchial biopsies taken from five normal nonsmoking subjects without chronic bronchitis or asthma (FEV1 percentage of predicted [mean +/- SD] 105.7 +/- 25.3), 11 subjects with chronic bronchitis alone (FEV1 percentage of predicted 98.5 +/- 12.9), and 13 subjects with chronic bronchitis in whom there was also evidence of airflow limitation (i.e., COPD; FEV1 percentage of predicted 59.7 +/- 10.0). Using immunohistochemical markers, we counted distinct types of inflammatory cell and expressed them as [median and range] per mm basement membrane. When there was airflow limitation we found significantly increased numbers of CD3+ T lymphocytes (COPD 22.3 [2.6 to 68.2] versus normal 3.7 [1.5 to 16.3]; p < 0.05), an increased number of CD8+ cells (COPD 19.3 [1.8 to 45.5] versus normal 2.3 [0.9 to 4.2]; p < 0.01), and increased expression of HLA-DR (COPD versus normal; p = 0.01). There was also an increased number of CD68+ cells (i.e., macrophages) (COPD 7.4 [0.4 to 16.9] versus normal 0.7 [0 to 2.6]; p < 0.01; COPD versus chronic bronchitis alone 2.7 [0 to 12.8]; p < 0.05). There were no significant differences between the groups in the numbers of subepithelial neutrophils, mast cells, eosinophils or B lymphocytes. There were weak but significant negative associations between the CD8+ T-cell subset (r = -0.42), neutrophils (r = -0.46), and eosinophils (r = -0.53) and FEV1 percentage of predicted in all the chronic bronchitic smokers (p < 0.05). The data confirm the involvement of subepithelial T lymphocytes and macrophages in smoking-induced airflow limitation and provide novel data which support the view that COPD is distinct from asthma with respect to the predominance of the CD8+ T-cell subset in this smoking-related condition.

Adult↗
PubMed1997

Worldwide clinical experience with the first marketed leukotriene receptor antagonist.

Pranlukast (SB 205312, ONO-1078) is an orally active, potent, selective blocker of peptidyl-leukotriene receptors. Pranlukast has been studied in a worldwide clinical development program and recently was approved in Japan for the treatment of asthma. This worldwide experience includes a pivotal safety and efficacy study conducted in Japan, a leukotriene D4 (LTD4) challenge study conducted in Europe, and two safety, tolerability, and clinical activity studies conducted in Europe and North America. The pivotal study was a randomized, double-blind, 8-week comparison of pranlukast, 225 mg bid, and azelastine, 2 mg bid. Improvements in asthma symptom scores, morning and evening peak expiratory flow rate (PEFR), and a decreased need for bronchodilators and corticosteroids in the pranlukast-treated group were statistically significant when compared with those in the azelastine-treated group. The most common adverse experiences were GI. The European challenge study evaluated the ability of 5-day therapy with pranlukast, 450 mg bid, to block the bronchoconstrictor effect of inhaled LTD4. A single dose of pranlukast resulted in a 10.6-fold increase in the concentration of LTD4 required to produce a 35% decrease in specific airways conduction; following 5 days of therapy, this increased to 25.9-fold. The two safety, tolerability, and clinical activity studies were randomized, double-blind, placebo-controlled, 4-week evaluations of pranlukast, 225 to 450 mg bid. Improvements in FEV1, PEFR, and asthma symptoms were noted. Ongoing studies will define further the role of pranlukast as a treatment for asthma and allergic rhinitis.

Anti-Asthmatic Agents↗
PubMed1996

Pleural fluid accumulation due to intra-abdominal endometriosis: a case report and review of the literature.

A case is presented of massive ascites and right sided pleural effusion caused by endometriosis. The final diagnosis was not made for a considerable time. Massive ascites and a right sided pleural effusion caused by endometriosis is rare, with fewer than 10 reports in the literature worldwide. Physicians should be aware of this potentially tentially treatable cause, having excluded other possibilities such as malignancy and tuberculosis.

Adult↗
PubMed1996

Eicosanoid mediator expression in mononuclear and polymorphonuclear cells in normal subjects and patients with atopic asthma and cystic fibrosis.

BACKGROUND: Eicosanoids such as leukotrienes, prostaglandins, lipoxins, and 15-hydroperoxyeicosatetraenoic acid (15-HETE) cause bronchoconstriction, increased microvascular permeability, mucus secretion, and polymorph chemotaxis. These pro-inflammatory effects are important in diseases such as asthma and cystic fibrosis where the levels of mediators are increased both in the stable and acute state. A study was conducted to examine the expression of the mRNA for the enzymes of the eicosanoid pathways (5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), cyclo-oxygenases 1 and 2 (COX-1, COX-2), and 15-lipoxygenase (15-LO)) in normal subjects and in patients with stable atopic asthma and stable cystic fibrosis. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the expression of total RNA for 5-LO, FLAP, COX-1, COX-2, and 15-LO in peripheral blood polymorphonuclear cells and mononuclear cells from the three subjects groups. RESULTS: The expression of mRNA for 5-LO and FLAP was similar in normal subjects and in patients with asthma and cystic fibrosis. COX-1 was increased in both cell types in asthmatic patients. COX-2 and 15-LO were increased in polymorphs of patients with atopic asthma but not in mononuclear cells. COX-2 and 15-LO were undetectable in either cell type in patients with cystic fibrosis whereas COX-1 levels in polymorphs were similar to those in patients with asthma. CONCLUSIONS: The increased leukotriene production in asthma and cystic fibrosis is not explained by an increase in transcription of 5-LO and FLAP. Transcription of 15-LO and COX-2 is increased in atopic asthma. Transcription of COX-1 is increased in both atopic asthma and cystic fibrosis.

5-Lipoxygenase-Activating Proteins↗
PubMed1996

Comparison of characteristics of patients and treatment outcome for pulmonary non-tuberculous mycobacterial infection and pulmonary tuberculosis.

BACKGROUND: Patients with non-tuberculous mycobacteria are usually started on conventional antituberculous triple therapy once acid fast bacilli are detected, before the exact type of mycobacteria has been identified. The ability to identify the characteristics of patients with tuberculous and non-tuberculous mycobacteria may be helpful in identifying before treatment those patients more likely to have non-tuberculous infection. METHODS: A retrospective study was conducted of all patients in one unit in whom non-tuberculous mycobacteria were identified in sputum or bronchoalveolar washings in the period 1987-93. The pattern of drug resistance was determined from laboratory records, and all case notes and chest radiographs were reviewed to identify the underlying disease and treatment outcome. All cases were compared with a matched control group of patients with culture positive Mycobacterium tuberculosis diagnosed during the same period. RESULTS: In the period studied there were 70 non-tuberculous and 221 tuberculous isolates. The non-tuberculous bacteria were typed as follows: M xenopi 23 (33%), M kansasii 19 (27%), M fortuitum 14 (20%), others 14 (20%). Of those with non-tuberculous mycobacteria, 83% were white subjects compared with 47% for tuberculosis. Patients with non-tuberculous mycobacteria were older than those with tuberculosis. Pre-existing lung disease or AIDS was present in 81% of patients with non-tuberculous mycobacteria and in 17% of patients with tuberculosis. Sensitivity to rifampicin and ethambutol was seen in 95% of M xenopi and 96% of M kansasii isolates. Relapse occurred in 60% of cases infected with M xenopi, 20% infected with M kansasii, and in 7% of cases with tuberculosis. CONCLUSIONS: In the population studied non-tuberculous mycobacteria occurred most frequently in elderly white subjects with pre-existing lung disease. If mycobacteria are detected in this group, consideration should be given to the possibility of non-tuberculous infection before embarking on treatment. A combination containing rifampicin and ethambutol is effective. The relapse rate for infection with M xenopi is high and prospective studies of the effect of the above combination of antituberculosis drugs are needed.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma.

Patients with severe asthma who require long-term oral corticosteroid therapy are at risk of unwanted effects. Several immunosuppressive drugs have been assessed as corticosteroid-sparing agents in chronic asthma. We previously showed that cyclosporin A (CsA) administered for 12 wk improved lung function in corticosteroid-dependent patients. We have now investigated the corticosteroid-sparing properties of CsA over a 36-wk period. Following a 4-wk run-in period, 39 corticosteroid-dependent asthmatic patients were randomized to receive CsA (19 patients, initial doses 5 mg/kg/d) or matched placebo (20 patients) for 36 wk. Attempts were then made by a physician ignorant of the trial therapy to reduce their prednisolone dosages at 14-d intervals, provided that a patient's asthma remained stable or improved. Three patients receiving CsA had to be withdrawn from the study before they completed 12 wk of therapy. The remaining 16 patients achieved a statistically significant reduction in median daily prednisolone dosage of 62% (10 to 3.5 mg), compared with a decrease of 25% (10 to 7.5 mg) in the patients taking placebo (p = 0.043). This reduction was most pronounced during the last 12 wk of active therapy. In addition, morning peak expiratory flow rate (PEFR) improved significantly (mean 9.4%, SEM 3.0%) in the active-treatment group but not in the placebo group (p = 0.026 between groups). Predictable changes in renal function and blood pressure, and an increased incidence of hypertrichosis and paresthesia, were observed in the patients treated with CsA, but these did not necessitate withdrawal from the study, and were reversed during a 4-wk run-out period. Thus, low-dose CsA therapy, as compared with placebo, allowed a significant reduction in oral corticosteroid dosages in patients with severe asthma, and also improved lung function.

Administration, Oral↗
PubMed1996

Can clinical response to cyclosporin in chronic severe asthma be predicted by an in vitro T-lymphocyte proliferation assay?

This study tests the hypothesis that the clinical response to cyclosporin therapy of patients with chronic severe asthma is related to the sensitivity of their T-lymphocytes to the antiproliferative effects of cyclosporin in vitro. In a previous study, we observed such a relationship with glucocorticoids and the same lectin-driven proliferation assay was used in the present study. Peripheral blood mononuclear cells were obtained from 33 patients participating in a cross-over trial of oral cyclosporin therapy during both cyclosporin and placebo treatment periods, and cultured in the presence of phytohaemagglutinin and serial dilutions of cyclosporin and dexamethasone. Proliferation was measured by tritiated thymidine uptake. Both cyclosporin and dexamethasone inhibited T-lymphocyte proliferation in a concentration-dependent manner in vitro at concentrations encompassing those achieved in peripheral blood during therapy in vivo. T-lymphocytes from the asthmatic patients showed a range of sensitivity to the antiproliferative effects of cyclosporin, but this could not be correlated with improvements in peak expiratory flow rate (PEFR) or forced expiratory volume in one second (FEV1) during cyclosporin therapy as compared with placebo. In contrast to previous observations with glucocorticoids, this in vitro T-lymphocyte proliferation assay is not predictive of clinical response to cyclosporin therapy in chronic severe asthmatics.

Asthma↗
PubMed1995

Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma.

Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.

Adult↗
PubMed1995

Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations.

Activated T-lymphocytes play an important role in asthma pathogenesis and release soluble interleukin-2 receptor (sIL-2R), which can be detected in the serum. In a recent randomized, cross-over trial we showed that cyclosporin, an inhibitor of T-lymphocyte activation, improved lung function in patients with chronic severe asthma. To investigate whether changes in serum sIL-2R concentration could be related to clinical response we prospectively compared serum sIL-2R concentrations in patients during cyclosporin and placebo treatment. Peripheral venous blood was obtained from 22 patients during the last 4 weeks of both the cyclosporin and placebo treatment periods and serum stored at -80 degrees C pending measurement of sIL-2R concentration by enzyme immunoassay. Soluble IL-2R was detected in all samples at a concentration range of 191-2,297 U.ml-1. Mean serum concentrations of sIL-2R were significantly lower on cyclosporin therapy (560 U.ml-1) as compared with placebo (676 U.ml-1). The decreases in serum sIL-2R concentrations associated with cyclosporin therapy in these patients correlated with the percentage increases in their morning peak expiratory flow rate (PEFR) measurements on cyclosporin as compared with placebo. These data demonstrate that in patients with chronic severe asthma, cyclosporin therapy which results in clinical improvement is associated with a decrease in serum concentrations of sIL-2R. This is compatible with the hypothesis that cyclosporin ameliorates asthma, at least partly, by inhibition of T-lymphocyte activation.

Asthma↗
PubMed1994

Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma.

BACKGROUND: Interleukin (IL)-5 is thought to play a part in asthmatic bronchial mucosal inflammation and is a potential therapeutic target. Detectable serum IL-5 concentrations have been found previously in a proportion of patients with acute severe asthma, but not in the same patients following oral glucocorticoid therapy or in normal controls. A study was undertaken to investigate whether or not IL-5 is detectable in the serum of patients with glucocorticoid-dependent chronic severe asthma. METHODS: Serum concentrations of IL-5 were measured in 29 patients with stable oral glucocorticoid-dependent chronic severe asthma (mean PEFR 59.7% predicted) and seven normal controls using a specific enzyme-linked immunoassay calibrated with recombinant human IL-5 standards (lower limit of sensitivity 40 pg/ml). RESULTS: Interleukin 5 was detectable in the serum of 15 of the 29 patients at a median concentration of 150 pg/ml (range 40-690), but was undetectable in the serum of all the control subjects. The patients with detectable serum IL-5 concentrations did not differ from those with undetectable concentrations in terms of atopic status, disease severity (percentage predicted PEFR or FEV1), prednisolone dosage, serum IgE concentrations, or peripheral eosinophil count. CONCLUSIONS: Interleukin 5 is detectable in the serum of a proportion of both atopic and non-atopic patients with chronic severe asthma, and concentrations in these patients were higher than in normal controls. These observations are compatible with the hypothesis that IL-5 release occurs in these patients during a period of stable asthma despite systemic glucocorticoid therapy.

Adult↗
PubMed1994

Intrapleural streptokinase in the management of empyema.

BACKGROUND: Significant morbidity and mortality result from the ineffective evacuation of empyema. Failure of conventional first line treatment with closed intercostal tube drainage and antibiotic therapy may result in fibrin deposition and loculated empyema. Enzymatic debridement using intrapleural instillation of streptokinase is a non-invasive therapeutic option which may obviate the need for surgical intervention. METHODS: Eleven adults with multiloculated post-pneumonic empyemas who had failed to respond satisfactorily to intercostal tube drainage and antibiotic therapy were treated with intrapleural streptokinase between November 1992 and January 1994. A small catheter was inserted under ultrasound guidance into a loculation within the pleural space. Aliquots of 250,000 units of streptokinase in 100 ml normal saline were instilled into the pleural cavity and the tube clamped for four hours. Response was assessed by clinical outcome, measurement of drain output after unclamping, and subsequent pleural ultrasound, chest radiography, or both. RESULTS: Streptokinase enhanced drainage in all patients. Complete resolution of the empyema with re-expansion of the underlying lung was effected in eight patients, all of whom remain well. Further resolution of minimal pleural thickening was shown on subsequent chest radiographs. Two patients with considerably thickened visceral pleura following empyema drainage underwent successful decortication. The other, with myocarditis and a pyopneumothorax, underwent surgery for non-resolution of the pneumothorax but died perioperatively from cardiac failure. The number of streptokinase instillations per patient ranged from two to six (median three), and the volume of empyema fluid drained per patient ranged from 100 ml to 4870 ml (median 900 ml). Streptokinase was well tolerated in all patients. CONCLUSIONS: Intrapleural streptokinase is an effective adjunct in the management of complicated empyema and may reduce the need for surgery.

Adult↗