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S D Anderson

Publications and source records attributed to S D Anderson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Inhaled mannitol identifies methacholine-responsive children with active asthma.

Inhaled mannitol has been developed for bronchial challenge testing in adults. This study determined if mannitol could identify children with active asthma and responsive to methacholine, and whether mannitol challenge was faster to complete than methacholine challenge. Twenty-five children (aged 6-13 years) responsive to methacholine and 10 nonasthmatic children unresponsive to methacholine were studied. The methacholine challenge (Cockcroft protocol) was followed by a mannitol challenge on separate days. Twenty-one asthmatic children were positive to mannitol. Three taking inhaled corticosteroids with borderline methacholine responsiveness did not respond to mannitol, and one could not complete the mannitol challenge due to cough. The geometric mean (GM) and 95% confidence interval (CI) for PD(15) for mannitol was 39 mg (19, 78), and PC(20) for methacholine was 0.6 mg/mL (0.35-1.02) (r(p) = 0.75, p < 0.001, n = 21). Responses to mannitol were repeatable: GM PD(15) for the first challenge was 29 mg (CI: 17,50), and for the second challenge, 33 mg (CI: 20, 55) (P = 0.44, n = 9). Mannitol was faster to administer than methacholine (median (range)) 14 min (5-32) vs. 29 min (19-49), respectively (P < 0.001). Time to recover to baseline FEV(1) spontaneously and after bronchodilator administration was similar for both challenges. There were no significant falls in arterial oxygen saturations. During mannitol challenge, the mean (SD) fall in FEV(1) in nonasthmatic children was 3.1% (2.9). We conclude that mannitol identifies children with airway hyperresponsiveness and is faster to perform than the methacholine challenge.

Asthma↗
PubMed2000

Nasal hyperosmolar challenge with a dry powder of mannitol in patients with allergic rhinitis. Evidence for epithelial cell involvement.

BACKGROUND: The responses to airway hyperosmolar challenges probably involve various inflammatory mediators. However, it is not fully understood which cell type/types are the source of these mediators. Potential cell types include mast cell, epithelial cell and the sensory c-fibre nerve cell. OBJECTIVE: To clarify which cell types are involved with the mediator response to hyperosmolarity in the human airway. METHODS: Ten healthy subjects, 11 patients with nonactive allergic rhinitis, and nine with active allergic rhinitis were challenged intranasally with mannitol powder, and with sham provocation, on separate days. Symptoms were assessed by visual analogue scales and nasal patency by measuring the nasal peak inspiratory flow (nPIF). Nasal lavage fluid levels of alpha(2)-macroglobulin (an index of plasma extravasation), substance P (an index of sensory nerve cell activation), tryptase (an index of mast cell activation) and 15-hydroxyeicosatetraenoic acid (15-HETE, an index of epithelial cell activation) were analysed. RESULTS: Immediate, although transient burning was the most prominent symptom in all groups whereas only the patients with active rhinitis experienced a fall in nPIF. Mannitol significantly increased the nasal lavage fluid 15-HETE levels in the allergic patients (P < 0.01 vs the sham challenge), but not in the healthy subjects. The increase in 15-HETE correlated with nasal symptoms for itching (r(s) = 0.65, P = 0.019) and burning (r(s) = 0.72, P = 0.009). Detectable levels of tryptase was found only in five allergic subjects. Lavage levels of substance P and alpha(2)-macroglobulin did not not change. CONCLUSION: Epithelial cell seems to be involved with the mediator response to airway hyperosmolar challenge. The roles of sensory c-fibre nerve cell and mast cell remained less clear.

Adult↗
PubMed2000

Exercise-induced asthma: is it the right diagnosis in elite athletes?

Exercise-induced asthma, as recognized in asthmatic subjects, is an exaggerated airway response to airway dehydration in the presence of inflammatory cells and their mediators. The airway narrowing is primarily caused by contraction of bronchial smooth muscle. The milder airway narrowing documented in response to exercise in elite athletes and otherwise healthy subjects may simply be the result of the physiologic responses and pathologic changes in airway cells arising from dehydration injury. These changes, which include excessive mucus production and airway edema, would serve both to cause cough and to amplify the narrowing effects of normal bronchial smooth muscle contraction, resulting in symptoms. These changes are more likely to occur in healthy subjects who exercise intensely for long periods of time breathing cold air, dry air, or both. Under these conditions, the ability to humidify inspired air may be overwhelmed, causing significant dehydration of the airway mucosa and an increase in osmolarity, even in small airways. In addition to dehydration injury, airway narrowing to pharmacologic and physical agents may occur as a result of injury caused by large volumes of air containing irritant gases, particulate matter, or allergens being inspired during exercise. As a result, the airways may become inflamed, and the airway smooth muscle may become more sensitive. These events could result in the same exaggerated airway response to dehydration, as documented in asthmatic subjects.

Asthma, Exercise-Induced↗
PubMed2000

The mechanism of exercise-induced asthma is ...

Exercise-induced asthma (EIA) refers to the transient narrowing of the airways that follows vigorous exercise. The mechanism whereby EIA occurs is thought to relate to the consequences of heating and humidifying large volumes of air during exercise. In 1978 airway cooling was identified as an important stimulus for EIA; however, severe EIA also occurred when hot dry air was inspired, and there was no abnormal cooling of the airways. In 1986 the thermal hypothesis proposed that cooling of the airways needed to be followed by rapid rewarming and that these two events caused a vasoconstriction and a reactive hyperemia of the bronchial microcirculation, together with edema of the airway wall, causing the airways to narrow after exercise. The osmotic, or airway-drying, hypothesis developed from 1982-1992 because neither airway cooling nor rewarming appeared to be necessary for EIA to occur. As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell volume loss. It is proposed that the regulatory volume increase, after cell shrinkage, is the key event resulting in release of inflammatory mediators that cause airway smooth muscle to contract and the airways of asthmatic subjects to narrow. This event may or may not be associated with airway edema. The osmotic and thermal theories come together by considering that inspiration of cold air not only cools the airways but also increases the numbers of airway generations becoming dehydrated in the humidifying process.

Asthma, Exercise-Induced↗
PubMed2000

Nedocromil sodium inhibits responsiveness to inhaled mannitol in asthmatic subjects.

Nedocromil sodium inhibits the response to exercise-induced asthma (EIA). Mannitol given as a powder by inhalation is an osmotic stimulus that identifies EIA. We studied the acute effect of nedocromil on airway responsiveness to mannitol in 24 asthmatic subjects. After a control day, nedocromil (8 mg) or its placebo was administered randomized, double blind, 10 min before a challenge with progressively increasing doses of mannitol. Nedocromil inhibited the response to mannitol and there was a significant increase in the dose of mannitol required to cause a 15% reduction in FEV(1) (PD(15)) after nedocromil 409 (316,503) mg compared with placebo 156 (106,229) mg (p < 0.001). In the presence of nedocromil 12 subjects no longer recorded a 15% decrease in FEV(1) in response to mannitol. The remaining 12 required a significantly greater dose of mannitol to achieve a 15% decrease in FEV(1) after nedocromil. Following nedocromil, a plateau in responsiveness to mannitol was observed in 14 subjects. Nedocromil significantly inhibits the responsiveness to inhaled mannitol in asthmatic subjects.

Administration, Inhalation↗
PubMed1999

The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.

It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.

Administration, Inhalation↗
PubMed1999

Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis.

Bronchiectasis is a disease characterized by hypersecretion and retention of mucus requiring physical and pharmacologic treatment. Recently we reported that inhalation of dry powder mannitol markedly increases mucociliary clearance (MCC) in asthmatic and in healthy subjects (Daviskas, E., S. D. Anderson, J. D. Brannan, H. K. Chan, S. Eberl, and G. Bautovich. 1997. Inhalation of dry-powder mannitol increases mucociliary clearance. Eur. Respir. J. 10:2449-2454). In this study we investigated the effect of mannitol on MCC in patients with bronchiectasis. Eleven patients 40 to 62 yr of age inhaled mannitol (approximately 300 mg) from a Dinkihaler. MCC was measured over 90 min, in the supine position, on three occasions involving: mannitol or control or baseline, using a radioaerosol technique. On the control day patients reproduced the breathing maneuvers and the number of coughs induced by the mannitol. Mannitol significantly increased MCC over the 75 min from the start of the intervention compared with control and baseline in the whole right lung, central, and intermediate region. Mean (+/- SEM) clearance with mannitol was 34.0 +/- 5.0% versus 17.4 +/- 3.8% with control and 11.7 +/- 4.4% with baseline in the whole right lung (p < 0.0001). The mean number of coughs induced by mannitol was 49 +/- 11. In conclusion, inhalation of dry powder mannitol increased clearance of mucus and thus has the potential to benefit patients with bronchiectasis.

Administration, Inhalation↗
PubMed1998

Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.

Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether toxicity arises from superoxide-mediated oxidative stress. Aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components or aberrant catalysis by misfolded mutants underlies a portion of mutant-mediated toxicity.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant.

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1(G85R) mutant-mediated toxicity to motor neurons.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma.

We investigated airway responsiveness to mannitol, a new hyperosmolar challenge, in persons hyperresponsive to airway drying. We studied 36 asthmatic subjects, 18 to 40 yr of age, responsive to exercise (n = 23) and eucapnic hyperventilation (n = 28) defined by a 10% fall in FEV1. Fifteen subjects performed both challenges. All subjects performed a challenge with dry powder mannitol, encapsulated and delivered via a Dinkihaler until a 15% decrease in FEV1 was documented or a cumulative dose of 635 mg was delivered. All subjects responsive to eucapnic hyperventilation and all but one subject responsive to exercise were responsive to mannitol. Sixty-nine percent of subjects had a positive response to mannitol after less than 155 mg (6 capsules) and 94% less than 320 mg (10 capsules). The provoking dose of mannitol required to cause a 15% fall in FEV1 (PD15) was related to the severity of the response to exercise (Pearson's correlation coefficient [rp] = 0.68, p < 0.01) and eucapnic hyperventilation (rp = 0.68, p < 0.01) in subjects who were not taking inhaled corticosteroids. The mean (+/- SD) maximum percent fall in FEV1 after mannitol was 24.4 +/- 6.2% and recovery to bronchodilator occurred within 10 min in most subjects. The mannitol test is simple, inexpensive, faster to perform than hyperpnea with dry air and could become an office-based test. Further studies are now required to determine the sensitivity of mannitol to identify exercise-induced asthma in a random population.

Adolescent↗
PubMed1997

Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods.

Generation of a three-dimensional pharmacophore model (hypothesis) that correlates the biological activity of a series of farnesyl protein transferase (FPT) inhibitors, exemplified by the prototype 1-(4-pyridylacetyl)- 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 44342, 1, with their chemical structure was accomplished using the three-dimensional quantitative structure-activity relationship (3D-QSAR) software program, Catalyst. On the basis of the in vitro FPT inhibitory activity of a training set of compounds, a five-feature hypothesis containing four hydrophobic and one hydrogen bond acceptor region was generated. Using this hypothesis as a three-dimensional query to search our corporate database identified 718 compounds (hits). Determination of the in vitro FPT inhibitory activity using available compounds from this "hitlist" identified five compounds, representing three structurally novel classes, that exhibited in vitro FPT inhibitory activity, IC50 < or = 5 microM. From these three classes, a series of substituted dihydrobenzothiophenes was selected for further structure-FPT inhibitory activity relationship studies. The results from these studies is discussed.

Alkyl and Aryl Transferases↗
PubMed1997

Dry gas hyperpnea changes airway reactivity and ion content of rabbit tracheal wall.

Dry air hyperventilation provokes airway narrowing in asthmatics. The mechanism is thought to involve the release of inflammatory mediators in response to airway osmolarity. The response to inhaled histamine on lung mechanics and the ion content of the airway subepithelial connective tissue after dry gas hyperventilation was investigated in rabbits. Resistance increased more after histamine given after hyperventilation with dry gas compared to humid gas (P < 0.05). Compliance decreased after histamine for both dry and humid gas hyperventilation. The Na, Cl and K content was decreased in the tissue at 4 min (P < 0.001) and nearly returned to resting content at 8 min of hyperventilation with dry gas. The results suggest that dehydration occurred and was followed by oedema formation in the tracheal wall. Thus, the effects of inhaled histamine on airway resistance was amplified. The mechanism involved may be part of the normal defence of the airway to protect against desiccation during hyperventilation with dry air. This response may be exaggerated in asthmatics.

Airway Resistance↗
PubMed1997

Effect of inhaled frusemide and oral indomethacin on the airway response to hypertonic saline challenge in asthmatic subjects.

BACKGROUND: Inhaled frusemide inhibits airway narrowing and causes a transient increase in forced expiratory volume in one second (FEV1) during hypertonic saline challenge. This inhibitory effect could be secondary to prostaglandin release during challenge. The involvement of prostaglandins in the inhibitory action of frusemide during challenge with 4.5% NaCl was investigated by premedicating with indomethacin, a prostaglandin synthetase inhibitor. METHODS: Fourteen asthmatic subjects (eight women) aged 26.6 (range 18-56) years participated in a double blind, placebo controlled, crossover study. The subjects attended five times and inhaled 4.5% NaCl for 0.5, 0.75, 1, 1.5, 2, 4, 8, 8, and 8 minutes, or part thereof, or until a provocative dose causing a 20% fall in FEV1 (PD20 FEV1) was recorded. Indomethacin (100 mg/day) or placebo were taken three days before all visits, except control day. The FEV1 was measured and frusemide (38.0 (6.4) mg, pH = 9) or vehicle (0.9% NaCl, pH = 9) were inhaled 10 minutes before the challenge. Bronchodilation was calculated as the percentage rise in FEV1 from the prechallenge FEV1 to the highest FEV1 recorded during the challenge. RESULTS: Frusemide caused a fold increase in PD20 FEV1 compared with the vehicle which was similar in the presence of both indomethacin and placebo (3.7 (95% CI 2.0 to 7.3) versus 3.3 (2.0 to 5.4)). Frusemide, but not vehicle, also caused a transient percentage rise in FEV1 during challenge with 4.5% NaCl which was not blocked by indomethacin (3.6% (1.2 to 6.0)) or placebo (3.1% (1.0 to 5.2)). CONCLUSIONS: Inhaled frusemide inhibited airway narrowing and caused a transient increase in FEV1 during challenge with 4.5% NaCl. These effects were not blocked by indomethacin, which suggests that the inhibitory action of frusemide is not secondary to prostaglandin release.

Adolescent↗
PubMed1997

A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol.

We developed a bronchial provocation test (BPT) with a dry powder preparation of mannitol. The mannitol was inhaled from gelatin capsules containing 5, 10, 20, or 40 mg to a cumulative dose of 635 mg, and was delivered via an inhalator, Halermatic, or Dinkihaler device. We studied the airway sensitivity to inhaled mannitol, the repeatability of the response, and the recovery after challenge in 43 asthmatic subjects 18 to 39 yr of age who had a 20% decrease in FEV1 in response to inhaling a 4.5% NaCl. We compared this with the airway response to methacholine in 25 subjects. The geometric mean (GM) for the dose of dry mannitol required to reduce the FEV1 by 15% of the baseline value (PD15) was 64 mg, with a 95% confidence interval (CI) of 45 to 91. Subjects responsive to mannitol had a PD20 to metacholine of < 7.8 mumol, with a GM of 0.7 mumol (CI: 0.4 to 1.2). For the first of two challenges to mannitol the PD15 was 59 mg (CI: 36 to 97) and for the second the PD15 was 58 mg (CI: 35 to 94) p = 0.91 (n = 23). Spontaneous recovery to within 5% of baseline occurred within 60 min and within 10 min after 0.5 mg terbutaline sulfate was inhaled. Arterial oxygen saturation (SaO2) remained at 93% or above during mannitol challenge. Subjects tolerated the inhalation of the mannitol well. A dry powder preparation of mannitol may be suitable to develop for bronchial provocation testing.

Administration, Inhalation↗
PubMed1997

Inhalation of dry-powder mannitol increases mucociliary clearance.

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.

Administration, Inhalation↗
PubMed1997

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects.

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.

Administration, Inhalation↗