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Biomedical subjects

J F Costello

Publications and source records attributed to J F Costello.

At least 73 records · Page 4Linked to original sources
PubMed1988

The metabolism "in vitro" of leukotriene B4 in blood of normal subjects and asthmatic patients.

The metabolism of exogenous leukotriene B4 (LTB4) was investigated in venous blood obtained from normal and asthmatic subjects. Using specific radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography (RP-HPLC) techniques we have demonstrated that LTB4 is relatively stable during a 2 hr incubation period at 37 degrees C in our system in vitro. Nevertheless, chromatographic analysis revealed the presence of two products which had retention times identical to 20-hydroxy LTB4 (20-0H LTB4) and 20-carboxy LTB4 (20-C00H LTB4) in which the dicarboxylic derivative was the main metabolite present after 15 min incubation. The amount of LTB4 and its w-oxidation products observed after a 2 hr incubation period was 73% and 24% respectively. There was no basal release of LTB4 from blood. The appearance of these oxidative products was totally suppressed at 4 degrees C and with incubations performed with either venous plasma or Hartmann's control. No significant difference was observed in substrate metabolism between normal and asthmatic subjects. Our results demonstrate that LTB4 is slowly degraded in human whole blood through a cellular dependent process of w-oxidation which may be an important pathway for regulating the availability of this potent biologically active substance.

Asthma↗
PubMed1988

Relationship between bronchial airway responsiveness and clinical severity of asthma.

The minimum medication required to control symptoms was individually established in a systematic manner in 10 asthmatics. A scoring system for the severity of asthma was designed using the indices of initial airway calibre (a reflection of the degree of airway obstruction) and the minimum medication requirement; all the subjects were so scored. Bronchial airway responsiveness to histamine, methacholine and isocapnic hyperventilation of cold air was then measured in these subjects. The relationship between the level of bronchial responsiveness and the asthma severity score was examined. The mean airway responsiveness to histamine or methacholine for the subjects who required a combination of drugs was not significantly greater than that for those who required single medication intermittently or daily, while the airway responsiveness to cold air was significantly different between the subjects in the two treatment subgroups. Similarly, there was no correlation between the asthma severity score and airway responsiveness to methacholine and histamine (r = -0.38 and -0.48; P greater than 0.1) while a significant correlation was found with responsiveness to cold air (r = 0.72; P less than 0.02). The results suggest that there is a qualitative difference between the bronchoconstriction induced in asthmatic subjects by pharmacological constrictor substances and natural physical stimuli such as cold air.

Adult↗
PubMed1987

The detection of 5-lipoxygenase and cyclo-oxygenase products in sputum of patients with chronic bronchitis and bronchiectasis.

Leukotrienes (LTs) and prostanoids (Ps) were detected in sputum of patients with chronic bronchitis and/or bronchiectasis (CB/B) using selective superfusion bioassay and radioimmunoassay (RIA) techniques. Analysis of sputum extracts showed a 4-fold increase in the level of LTB4 compared to the cysteinyl-containing LTs (LTC4/LTD4). The measurement of cyclo-oxygenase products (COPs) indicated relatively greater amounts of the vasodilator prostaglandin E2 (PGE2) and prostacyclin (PGI2) compared to the vasoconstrictor prostaglandin F2 alpha (PGF2 alpha) and thromboxane A2 (TxA2) agents (70:30% of total COPs respectively). The presence of eicosanoids (LTs and Ps) in sputum of patients with CB/B suggest that these biologically active substances may act as mediators of bronchoconstriction and inflammation in these diseases.

Adult↗
PubMed1987

Detection of sputum eicosanoids in cystic fibrosis and in normal saliva by bioassay and radioimmunoassay.

We have measured arachidonic acid (AA) metabolites, leukotrienes (LTs) and prostanoids (Ps), in sputum of patients with cystic fibrosis (CF) and in normal saliva using bioassay and radioimmunoassay (RIA). Almost three times as much LTB4 is present in CF extracts compared with slow reacting substances (SRSs). Leukotrienes were not detected in normal saliva. In CF sputum there is a three-fold increase in the level of the vasodilator prostanoid prostaglandin E2 (PGE2) and the stable metabolite of prostacyclin, 6-oxo PGF1 alpha compared with the vasoconstrictor prostaglandin F2 alpha (PGF2 alpha) and thromboxane B2 (TxB2), a hydrolysis product of thromboxane A2. Experiments with BW755c (25 micrograms ml-1, n = 3) indicated that the majority of this activity was not produced during the extraction procedure. The detection of LTs and Ps in sputum of CF patients shows that these substances are present at biologically active concentrations and may contribute to the pathophysiology of this disease.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Lipid mediators in cystic fibrosis and chronic obstructive pulmonary disease.

In order to investigate the possible role of arachidonic acid metabolites as lipid mediators in cystic fibrosis and chronic obstructive pulmonary disease (COPD), sputum from patients with cystic fibrosis, chronic bronchitis, or bronchiectasis was analyzed for various eicosanoids using a combination of radioimmunoassay and bioassay. Leukotriene (LT) B4, cysteinyl-containing LTs, and prostaglandins (PGs) E2, F2 alpha, 6-oxo-PGF1 alpha, and thromboxane B2 were found in all sputum samples. Saliva, which can contaminate sputum, contained low concentrations of prostanoids but not LTs. Inflammatory cells, including polymorphonuclear leukocytes (PMNs) are present in sputum. Because LTB4 generated by these cells is chemotactic for PMNs, it is suggested that this dihydroxy acid contributes to the inflammation of cystic fibrosis and other diseases characterized by airway obstruction. The source of the cysteinyl-containing LTs is less clear; these LTs may constrict respiratory smooth muscle and/or stimulate mucus formation.

Adult↗
PubMed1985

Characteristics of prostaglandin induced cough in man.

Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non-prostanoid tussive agents. In addition a comparison was sought between the present observations and those in the cat, the only laboratory animal which consistently coughs to prostanoids. Five healthy volunteers were repeatedly challenged at 90 min intervals with aerosols of PGE2 (100-500 micrograms ml-1) and tussive activity was monitored. In a second separate study again monitoring tussive activity 10 healthy volunteers inhaled aerosols of either PGF2 alpha (0.1-100 micrograms ml-1), PGE2 (0.1-100 micrograms ml-1), acetylcholine (0.1-50 mg ml-1) or citric acid (5-20% w/v) in a randomised procedure. Objective measurement of tussive activity was achieved using a throat microphone linked via a discriminator to a pen recorder. All four compounds produced two distinct phases of tussive activity, an early phase during challenge and a late phase 1-15 min post-challenge. Repeated challenges with PGE2, produced significant (P less than 0.01) tachyphylaxis to the late phase responses only. Both PGF2 alpha and PGE2 were approximately 1000 and 10,000 times more potent than acetylcholine and citric acid respectively for both phases of tussive activity. Tussive activity was accompanied with retrosternal soreness and tightness of the chest for PGE2, increased sputum for PGF2 alpha, and sore throats with citric acid. Although a correlation exists for man and cat with regards to the tussive potency and the early and late phases of PGF2 alpha activity no such correlation seems to exist for PGE2. The high tussive potency of the prostaglandins in man suggest that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying coughs/irritancy.

Acetylcholine↗
PubMed1985

Effects of ketotifen on in vitro bronchoconstriction.

We have studied the effects of Ketotifen [Ke] (10(-4)M and 10(-6)M) on two in vitro models of bronchoconstriction: actively sensitized guinea-pig trachea (GPT), and passively sensitized human bronchial muscle (HBM). Experiments were performed on matched pairs of tissues. Cumulative dose response curves [CDRC] for histamine and acetyl choline were constructed, and repeated after pre-incubation with Ke or saline control. The effect of Ke on maximal antigen induced contractions was also studied. Contraction of GPT by histamine and acetyl choline was inhibited by Ke 10(-4)M, though this effect was not apparent at high doses of acetyl choline. Ke 10(-6)M had a weaker inhibitory effect on histamine and acetyl choline induced responses. Contraction of GPT by antigen was unaffected by Ketotifen. In the HBM model, Ke 10(-4)M inhibited acetyl choline and antigen induced responses. Ketotifen, 10(-6)M had an inhibitory effect on acetyl choline induced contractions, though this was small, and not seen at higher agonist doses. Contraction of HBM by antigen was unaffected by Ke 10(-6)M. We were unable to obtain reproducible CD RC's to histamine with HBM. The weaker or absent effects of Ke 10(-6)M, a level close to that obtained in clinical practice, may explain some of the poor results of clinical trials, and suggest that efficacy may be improved by the use of higher doses.

Acetylcholine↗
PubMed1984

Diminished bronchial reactivity to cold air in diabetic patients with autonomic neuropathy.

To investigate the role of neural pathways in the nonasthmatic response to eucapnic hyperventilation with below freezing air five diabetic patients with severe symptomatic autonomic neuropathy were studied. Their responses were compared with those shown by five diabetic patients without autonomic neuropathy and five non-diabetic controls. After bronchial provocation testing with cold air the diabetic patients with autonomic neuropathy did not show a significant fall in specific airways conductance (mean (SE) maximum percentage fall 2.0 (3)%), whereas conductance fell in the diabetic patients without neuropathy by 30.8 (2.0)% (p less than 0.001) and in the non-diabetic controls by 22.7 (4.6)% (p less than 0.02). In subjects who do not have asthma the bronchial response to cold air is mediated largely via neural mechanisms.

Adult↗
PubMed1984

Delivery of sodium cromoglycate by pressurized aerosol.

Sodium cromoglycate (SCG) has recently been formulated as a pressurized aerosol. Twenty-five asthmatic outpatients taking SCG via the Spinhaler were studied in a double-dummy, double-blind cross-over trial in which subjects took Spincaps containing 20 mg of SCG for 2 months, and for the alternate 2 months were treated with SCG aerosol delivering 1 mg/actuation. There was no evidence of clinical deterioration occurring during the period on aerosol SCG. During this period however cough frequency was significantly lower and when data for the 8-13 and 14-46 year age groups were analysed separately, this decrease was seen to be confined to the younger group. Furthermore, this group but not the adults, showed a significant improvement in morning peak expiratory flow rate. We conclude that the aerosol preparation of SCG is a useful alternative to delivery by Spinhaler for patients who are able to coordinate, and that it may have special advantages for children.

Adolescent↗
PubMed1984

Cold air as a bronchial provocation technique. Reproducibility and comparison with histamine and methacholine inhalation.

Bronchial provocation testing with cold air was carried out on 36 asthmatic and 13 normal subjects in order to assess the reproducibility and clinical relevance of the technique as a test of airways reactivity. Sixteen subjects underwent repeat testing after an interval of two to three weeks. Using a least squares linear regression analysis, the technique was highly reproducible, with a correlation of r = 0.93 (p less than 0.001). The 21 asthmatic subjects who had exercise-provoked symptoms required a significantly lower level of ventilation of cold air to produce a 35 percent drop in specific airways conductance (PD35) than did those who had no exercise-induced asthma (33.9 L min-1 vs 45.8 L min-1; p less than 0.02). Subjects requiring no regular treatment for their asthma had a geometric mean PD35 of 62.6 L min-1, significantly higher than those requiring inhaled therapy (44.9 L min-1; p less than 0.005). Subjects requiring oral in addition to inhaled treatment had the lowest PD35 (23.6 L min-1; p less than 0.02). Atopic status did not appear to influence the response. There was a strong correlation between the PD35 to cold air and to histamine (r = 0.92; p less than 0.001) and between the PD35 to cold air and to methacholine (r = 0.86; p less than 0.001). The three techniques of assessing bronchial reactivity were equally successful in separating the normal and asthmatic groups. The results indicate that cold air provocation may be reliably and reproducibly used to assess bronchial reactivity. The use of a naturally-occurring stimulus of asthma in all subjects has great potential as an investigational technique.

Adolescent↗
PubMed1984

The influence of pretreatment with prostaglandin F2 alpha on bronchial sensitivity to inhaled histamine and methacholine in normal subjects.

The effect of pretreatment with prostaglandin F2 alpha (PGF2 alpha) on the bronchial sensitivity to histamine and methacholine has been studied in three groups of six normal subjects, and compared with the effect of citric acid aerosol as a non-specific stimulant of bronchial irritant receptors. Aerosols were generated by Wright's nebulizer and dose-response curves to histamine and methacholine constructed following preadministration of saline, prostaglandin F2 alpha or citric acid. Following prostaglandin F2 alpha pretreatment, the PC20 histamine fell from 12.9 mg/ml to 3.4 mg/ml (P less than 0.01), but the PC20 methacholine was unchanged. Citric acid was without effect. The results indicate that prostaglandin F2 alpha can increase bronchial sensitivity to inhaled histamine, possibly via a direct effect on the airway smooth muscle.

Adult↗
PubMed1983

The bronchial response to cold air challenge: evidence for different mechanisms in normal and asthmatic subjects.

We have investigated possible mechanisms of response to airway cooling by studying the effects of sodium cromoglycate and ipratropium bromide on the changes in airways resistance that followed eucapnic hyperventilation with subfreezing air in a group of 12 patients with mild asthma and 10 normal subjects. We have also studied the period of refractoriness to repeated challenge. Maximum bronchoconstriction was not reduced after the second challenge, but in the asthmatics the one-second forced expiratory volume recovered more rapidly after the second challenge. The response in normal subjects was completely abolished by ipratropium bromide (p less than 0.0005) whereas sodium cromoglycate was without effect. In the asthmatics both ipratropium and cromoglycate were effective in attenuating the response (p less than 0.005). These results suggest that in normal subjects the response to airway cooling is produced predominantly via neural mechanisms, whereas in asthmatics there is an additional mechanism which can be abolished by sodium cromoglycate.

Adolescent↗
PubMed1983

Effect of nifedipine on bronchoconstriction induced by inhalation of cold air.

The effect of nifedipine (20 mg sublingually) on the bronchial response to cold air was studied in eight asthmatic patients and eight normal subjects. Eucapnic hyperventilation with dry subfreezing air was performed for three minutes by each subject, with a minute volume of 30 X FEV1 for normal subjects and half that for the asthmatics. In the normal subjects there was no difference in the falls in the one-second forced expiratory volume (FEV1) and specific airways conductance (sGaw) produced by cold air inhalation on the days when they were pretreated with placebo and with nifedipine. In asthmatic patients, however, significant protection with nifedipine was demonstrated. The maximum recorded fall in FEV1 was reduced from 13% +/- 2% (SE) to 4% +/- 2% (p less than 0.005) and the maximum fall in sGaw from 35% +/- 5% to 17% +/- 4% (p less than 0.002). The possible causes of this difference are discussed. It is suggested that these results present further evidence for a different mechanism of response to cold air in asthmatic and normal subjects.

Adult↗