The diagnosis and management of chronic cough.
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Adult↗
Biomedical subjects
F O'Connell
Publications and source records attributed to F O'Connell.
Summary: clinical needs for cough therapy.
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Adult↗
A single amino acid substitution beyond the C2H2-zinc finger in Ros derepresses virulence and T-DNA genes in Agrobacterium tumefaciens.
Ros is a chromosomally-encoded repressor containing a novel C2H2 zinc finger in Agrobacterium tumefaciens. Ros regulates the expression of six virulence genes and an oncogene on the Ti plasmid. Constitutive expression of these genes occurs in the spontaneous mutant 4011R derived from the octopine strain Ach-5, resulting in T-DNA processing in the absence of induction, and in the biosynthesis of cytokinin. Interestingly, the mutation in 4011R is an Arg to Cys conversion at amino acid residue 125 near the C-terminus well outside the zinc finger of Ros. Yet, Ros bearing this mutation is unable to bind to the Ros-box and is unable to complement other ros mutants.
Agrobacterium tumefaciens↗
Treatment of persistent dry cough: if possible, treat the cause; if not, treat the cough.
Persistent dry cough is a common presenting symptom which may be associated with considerable morbidity. In the majority of patients, systematic investigation reveals an underlying cause, usually asthma, postnasal drip, gastrooesophageal reflux or various combinations of these conditions. Intensive treatment of the underlying cause usually leads to improvement or resolution of the cough. However, in a minority of patients, no underlying cause is identified despite appropriate investigation. In these patients with idiopathic persistent dry cough, cough sensitivity to inhaled tussigens is enhanced, suggesting that increased sensitivity of airway sensory nerves is important in pathogenesis. An ideal antitussive would reduce this increased sensitivity to normal levels without significant adverse effects but currently available antitussives fall short of this expectation. This review discusses the currently available antitussive therapy and explores potential avenues for the development of future novel antitussive therapies.
Animals↗
Management of persistent dry cough.
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Chronic Disease↗
Capsaicin cough sensitivity increases during upper respiratory infection.
The mechanism of cough associated with upper respiratory infection (URI) is poorly understood. This paper reports a study of the role of altered sensitivity of capsaicin-sensitive airway nerves. In a prospective study, baseline (B) capsaicin-induced cough and methacholine-induced airway responsiveness were measured in 103 healthy volunteers. During the following year, 31 subjects reattended for challenge testing during URI (I) and after recovery (R). The log concentration of capsaicin required to elicit two coughs (C2) was significantly lower during infection than recovery but not baseline [median (interquartile range) B = 0.59 (0.28-1.20), I = 0.27 (0-0.89), R = 0.89 (0.28-1.49)]. Log C5 (concentration causing five coughs) was lower during infection than baseline and recovery [B = 1.79 (1.20-2.70), I = 1.49 (0.89-2.08), R = 1.79 (1.20-2.40)]. FEV1 and PC15 methacholine values were unchanged during infection compared to baseline. Subjects with dry cough (n = 14) had lower C5 values during infection than both baseline and recovery, and lower C2 values during infection than recovery; in these subjects, increase in capsaicin sensitivity correlated with cough severity score. Subjects with productive cough or no cough showed no consistent changes during infection. Twenty-six control subjects who reattended without URI showed no change in capsaicin sensitivity. Upper respiratory infection may cause cough as a result of increased sensitivity of capsaicin-sensitive afferent airway nerves without affecting airway calibre or responsiveness.
Administration, Inhalation↗
Abnormal intraepithelial airway nerves in persistent unexplained cough?
Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p < 0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p < 0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p < 0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and healthy humans.
We examined the effects of the alpha 2-receptor agonist clonidine, administered orally and by inhalation, on citric acid- and capsaicin-induced reflexes in guinea pigs and healthy human subjects. In groups (n = 8-10) of conscious guinea pigs, oral clonidine (10 and 100 micrograms/kg) was without effects, whereas inhaled clonidine (10-1,000 microM) caused a concentration-dependent inhibition of citric acid-induced cough (coughs during 3 min: control, 6.5 +/- 0.9; 1,000 microM clonidine, 1.7 +/- 1.0; P < 0.05) and reflex bronchoconstriction (time to onset of bronchoconstriction: control, 191 +/- 24 s; 1,000 microM clonidine, 317 +/- 33 s; P < 0.05). The inhibitory effect of inhaled clonidine on both reflexes was completely reversed by pretreatment with yohimbine but not with prazosin. In 12 healthy human volunteers, oral clonidine (150 mg) caused a significant fall in supine and erect systolic blood pressure and a significant increase in drowsiness as measured on a visual analogue scale 1 and 2 h after administration. Despite these effects, oral clonidine had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. In contrast to the effects in guinea pigs, inhaled clonidine (281 microM) had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. These data suggest that peripheral alpha 2-receptors exert an inhibitory effect on sensory neurotransmission in the guinea pig but not in the healthy human airway, indicating an important difference between the two species.
Administration, Inhalation↗
Capsaicin cough sensitivity decreases with successful treatment of chronic cough.
To assess the role of enhanced cough sensitivity in the pathogenesis of cough, we measured cough severity on a visual analogue scale (VAS) and capsaicin cough sensitivity (the concentration required to elicit two [C2] and five [C5] coughs) in 87 consecutive patients referred with chronic cough. Measurements were repeated after complete investigation and treatment, when patients were entered into one of four study groups: (1) treatment success (primary cause of cough successfully treated with elimination of the cough, n = 48); (2) primary treatment failure (treatment of potential primary cause of cough unsuccessful, n = 12); (3) cough treatment failure subgroup A (potential primary cause of cough identified and successfully treated but no improvement in cough, n = 8); and (4) cough treatment failure subgroup B (no potential primary cause of cough identified, n = 19). All patients in groups 3 and 4 were nonsmokers, had normal chest radiography and negative histamine challenge test, and failed to respond to intensive empirical treatment for rhinitis and gastroesophageal reflux. The VAS cough severity was lower and log C2 and C5 higher after treatment compared with initial values in the treatment success group but not in the other three groups. Enhanced sensitivity of airway nerves that mediate cough is important in the pathogenesis of nonproductive cough, and successful treatment is associated with a reduction in cough sensitivity. While enhanced sensitivity of airway nerves is usually present in patients with identifiable causes of chronic nonproductive cough, it is also found in other patients in whom the cause of cough is unknown.
Adult↗
Cardiopulmonary resuscitation by precordial compression but without mechanical ventilation.
It is widely held that mechanical ventilation is essential for cardiopulmonary resuscitation (CPR). However, cardiac output and therefore pulmonary blood flow is reduced to less than one-third of normal during CPR. We therefore reasoned that ventilatory requirements are correspondingly reduced and postulated that gas exchange may be maintained during precordial compression with oxygen passively delivered to the airway in the absence of mechanical ventilation. After tracheal intubation, Sprague-Dawley rats were randomized. Fifteen animals were maintained on positive-pressure ventilation with room air and an additional 15 animals breathed spontaneously. Cardiac arrest was induced by electrical fibrillation. The inspired gas concentration of oxygen was then increased to 100% in both groups. Precordial compression was begun after 4 min of untreated ventricular fibrillation. After an additional 6 min of precordial compression, resuscitation was attempted by DC countershock. During cardiac resuscitation, there were no significant differences in coronary perfusion pressure between mechanically ventilated and spontaneously breathing animals, but arterial PO2 was significantly lower and arterial PCO2 was significantly higher in the absence of positive-pressure ventilation. However, neither resuscitability nor 24-h survival were affected. Postresuscitation myocardial contractility, reflected in the maximally generated dP/dt40, was also not adversely affected. In the unventilated group, only resuscitated animals developed spontaneous gaspings at an average frequency of 17 +/- 2/min-1. The current emphasis on mechanical ventilation as the highest priority for cardiopulmonary resuscitation is therefore not fully supported under the experimental conditions of this study.
Animals↗
Effect of topical beclomethasone on histamine-induced increases in nasal airflow resistance and secretion in perennial rhinitis.
The effects of topical beclomethasone dipropionate on changes in nasal resistance and secretion induced by topical histamine were studied in eight patients with perennial rhinitis. Patients were studied at enrollment, after 3 weeks of beclomethasone (100 micrograms spray to each nasal cavity twice daily), and after 3 weeks of placebo (saline) treatment administered in a double-blind cross-over trial. Nasal airflow resistance (Rnaw) and total protein, albumin, lysozyme and glycoconjugate secretion in nasal lavage fluids were measured after topical application of histamine to the nasal mucosa. Resistance measurements and secretory parameters were similar for the initial study and after placebo treatment. In those studies, histamine (1 and 10 mg) increased both nasal resistance and secretion of total protein, albumin and glycoconjugates. After beclomethasone treatment the rise in respiratory resistance in response to histamine was significantly attenuated (delta Rnaw, +11.57 cm H2O/l/s with placebo, +5.80 with beclomethasone, P < 0.05). Beclomethasone had no effect on histamine-induced secretion. Because nasal resistance is determined mainly by vascular processes, beclomethasone treatment appears to have a prominent action on the vascular bed to reduce mediator-induced vasodilatation in perennial rhinitis.
Administration, Intranasal↗
Decrease of histamine induced bronchoconstriction by caffeine in mild asthma.
BACKGROUND: While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS: To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS: While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS: Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.
Adult↗
Regional blood flow during closed-chest cardiac resuscitation in rats.
Quantitative measurement of regional blood flow during cardiac arrest and resuscitation has been confined to large animals. We report on a rodent model utilizing radioactive microspheres during cardiac arrest and resuscitation for investigation of regional blood flow. Ventricular fibrillation was electrically induced in 10 pentobarbital-anesthetized Sprague-Dawley rats. Resuscitation was attempted by precordial compression followed by external direct current countershock. During precordial compression, cardiac output corresponded to 12% of prearrest flow. Similarly low flows were observed in the myocardium and brain. However, much lower flows were observed in the adrenal glands, kidneys, intra-abdominal viscera, skin, and skeletal muscle. Five of ten animals were successfully resuscitated. During precordial compression, resuscitated animals had significantly higher cardiac output (13.1 +/- 4.1 vs. 8.6 +/- 1.46 ml/min), myocardial blood flow (0.70 +/- 0.24 vs. 0.22 +/- 0.15 ml.min-1.g-1), cerebral blood flow (0.17 +/- 0.04 vs. 0.06 +/- 0.02 ml.min-1.g-1), and adrenal blood flow (1.09 +/- 0.60 vs. 0.27 +/- 0.16 ml.min-1.g-1). Thirty minutes after successful resuscitation, cardiac output and myocardial, cerebral, renal, and adrenal blood flows and blood flow to splanchnic viscera (with the exception of the spleen) had returned to > or = 70% of prearrest flows. These studies confirm the conclusion of earlier investigations in larger animals that visceral blood flow during cardiac arrest and precordial compression is preferentially distributed to the brain and myocardium. Successful cardiac resuscitation is contingent on threshold levels of myocardial blood flow that exceed 0.4 ml.min-1.g-1.
Adrenal Glands↗
Potent leukotriene D4 receptor antagonist ICI 204,219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction.
ICI 204,219 is a potent and specific leukotriene D4 receptor antagonist that blocks both the early and late responses to allergen challenge in humans when given orally at a dose of 40 mg. Here we report our findings with an inhaled formulation of ICI 204,219 against allergen-induced bronchoconstriction. A group of 10 atopic subjects (mean age 25.6 +/- 4.2; 6 females; FEV1 > 90% of predicted; on inhaled beta 2-agonists only) were studied on 2 separate days 2 to 3 wk apart. In a randomized placebo-controlled trial they inhaled eight puffs of a standard metered dose inhaler containing either ICI 204,219 (200 micrograms/puff, total dose 1,600 micrograms) or propellant alone. They underwent bronchial allergen challenge 30 min later using a single concentration of allergen previously shown to lower the FEV1 by > or = 15%. FEV1 was monitored hourly for 10 h, and urine was collected for LTE4 determination. Inhalation of ICI 204,219 was well tolerated, with no adverse clinical or biochemical effects. There was no significant effect of ICI 204,219 inhalation on basal airway caliber (change in FEV1 30 min after inhalation was -149 +/- 67 ml after placebo versus 3 +/- 38 ml after ICI 204,219; p = 0.08). The early response to allergen was significantly inhibited by ICI 204,219 (the maximum fall in FEV1 was -21.2 +/- 6.1% after ICI 204,219 compared with -38.8 +/- 6.5% on placebo; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
A comparative evaluation of propofol and midazolam as sedative agents in fiberoptic bronchoscopy.
Propofol, a new intravenous sedative agent, was investigated in 41 asthmatic patients undergoing day-case (outpatient) fiberoptic bronchoscopy. The study design was a randomized comparison between propofol and midazolam, which is a well-established intravenous sedative agent. The age, weight, and American Society of Anesthesiologists physical status and lung function of the two groups were not significantly different. Mean (SD) induction dose of propofol was 104.7 (30.1) mg with a maintenance dose of 121.9 (38.5) mg. Corresponding values of midazolam were 9.3 (3.1) mg and 3.7 (2.3) mg. The required level of sedation was achieved significantly faster with propofol, mean (SD) 125.4 (39.8) s, compared with midazolam, 179.4 (55.2) s (p < 0.001). Significantly faster recovery was noted with propofol compared with midazolam in terms of time to recall name and date of birth 2.3 (1.7) min vs 6.3 (8.6) min, (p < 0.045). Alertness scored with the digital symbol substitution test (DSST) returned to prebronchoscopy values in the propofol group at 30 min, DSST score = 35.9 (18.2) vs 13.4 (9.1), in the midazolam group (p < .0001) and was still significantly higher at 90 min-39.4 (17.9) and 23.1 (13.8) (p < 0.01). We conclude that propofol is a useful sedating agent in fiberoptic bronchoscopy with similar efficacy to midazolam but with a faster onset of action and a more rapid recovery. These represent significant advantages for day-case procedures.
Ambulatory Care↗
Ipratropium bromide delivered orally by metered dose inhaler does not decrease salivary flow in normal subjects.
A randomised placebo-controlled cross-over group study was conducted to ascertain the occurrence and duration of xerostomia induced by 240 micrograms (high dose) and 120 micrograms (low dose) of ipratropium bromide (IPB) delivered by metered dose inhaler (MDI) into the mouth in normal subjects. Salivary output was higher with both doses of IPB than with placebo though the differences were not statistically significant. IPB was less palatable than placebo as indicated on visual analogue scale (VAS) and the taste of the drug may have caused a reflex increase in salivary output from the major salivary glands which would have masked any possible local effect of the drug on the smaller submucosal glands of the mouth. IPB delivered into the oral cavity by MDI is therefore not a suitable treatment for hypersalivation.
Administration, Inhalation↗
Ocular hazards of nebulized bronchodilators.
Three cases of pupillary dilatation associated with the development of acute glaucoma, precipitated by the use of nebulized bronchodilators are described. We suggest measures to reduce the risk of this complication.
Adult↗
Adaptation of cough reflex with different types of stimulation.
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Adaptation, Physiological↗