[Lung function evolution and respiratory symptoms].
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Animals↗
Biomedical subjects
N A Molfino
Publications and source records attributed to N A Molfino.
Eradication of multiple myeloma and breast cancer cells by TH9402-mediated photodynamic therapy: implication for clinical ex vivo purging of autologous stem cell transplants.
High-dose chemotherapy combined with autologous transplantation using bone marrow or peripheral blood-derived stem cells (PBSC) is now widely used in the treatment of hematologic malignancies as well as some solid tumors like breast cancer (BC). However, some controversial results were recently obtained in the latter case. The presence of malignant cells in the autograft has been associated with the recurrence of the disease, and purging procedures are needed to eliminate this risk. The aim of this study was to evaluate the potential of the photosensitizer 4,5-dibromorhodamine methyl ester (TH9402), a dibrominated rhodamine derivative, to eradicate multiple myeloma (MM) and BC cell lines, while sparing more than 50% of normal pluripotential blood stem cells from healthy volunteers. The human BC MCF-7 and T-47D and MM RPMI 8226 and NCI-H929 cell lines were used to optimize the photodynamic purging process. Cell concentration and the cell suspension thickness as well as the dye and light doses were varied in order to eventually treat 1-2 L of apheresis. The light source consisted of two fluorescent scanning tubes emitting green light centered about 515 nm. The cellular uptake of TH9402 was measured during the incubation and washout periods and after photodynamic treatment (PDT) using spectrofluorometric analysis. The limiting dilution assay showed that an eradication rate of more than 5 logs is obtained when using a 40 min incubation with 5-10 microM dye followed by a 90 min washout period and a light dose of 5-10 J/cm2 (2.8 mW/cm2) in all cell lines. Agitating the 2 cm thick cell suspension containing 20 x 10(6) cells/mL during PDT was essential for maximal photoinactivation. Experiments on mobilized PBSC obtained from healthy volunteers showed that even more drastic purging conditions than those found optimal for maximal eradication of the malignant cell lines were compatible with a good recovery of hematopoietic progenitors cells. The absence of significant toxicity towards normal hematopoietic stem cells, combined with the 5 logs eradication of cancer cell lines induced by this procedure suggests that TH9402 offers an excellent potential as an ex vivo photodynamic purging agent for autologous transplantation in MM and BC treatment.
Breast Neoplasms↗
Risk factors versus mechanisms of death in subjects with asthma.
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Asthma↗
Effect of inhaled furosemide in acute asthma.
We assessed the acute bronchodilator effect of nebulized furosemide when added to conventional therapy of acute emergency department (ED) asthma. Using a double-blind design, 42 patients with acute asthma were randomized to receive 2.5 mg nebulized salbutamol and either 40 mg of nebulized furosemide or saline solution. We recorded clinical variables (respiratory rate, heart rate, and pulsus paradoxus) and peak expiratory flow rates (PEFR) before and 15 and 30 min after therapy. We found no significant difference in PEFR between salbutamol/furosemide and salbutamol/saline-treated patients 15 and 30 min following inhalation. Other endpoints were equally unaffected. However, when we examined separately those patients whose exacerbations were of relative short duration (< 8 hr), PEFR improved significantly more in the furosemide-treated group. At 15 min, PEFR increased by 82 +/- 48% in the furosemide group compared to 35 +/- 40% in the control group (p = 0.03), an effect that was also evident at 30 min when PEFR had increased by 113 +/- 49% in the furosemide group versus 61 +/- 35% in the control group (p = 0.014). Respiratory rate, heart rate, and pulsus paradoxus improved with no differences between the groups. The beneficial effect of furosemide was not evident in patients who reported more prolonged duration (> 8 hr) of asthmatic symptoms. The response to furosemide appeared to be unrelated to concomitant ED therapy with corticosteroids, to baseline pulmonary function, or to patient demographic variables. We conclude that furosemide may offer additive bronchodilator benefits in acute naturally occurring asthma of relative short duration.
Adult↗
Treatment of acute severe asthma with inhaled albuterol delivered via jet nebulizer, metered dose inhaler with spacer, or dry powder.
Despite the increasing use of dry powder formulations in the ambulatory setting, there is a paucity of information on the efficacy of this therapeutic modality to treat acute severe asthma. In addition, studies that compared wet nebulization vs metered dose inhalers formulated with chlorofluorocarbon (CFCMDI) attached to holding chambers have yielded discrepant results. Thus, it is unclear which of the three delivery systems would elicit a superior bronchodilator response, particularly in patients with life-threatening asthma. In a prospective, randomized open design, we studied the response to inhaled albuterol (salbutamol) in 27 adult asthmatics presenting to the emergency department (ED) with an FEV1 <30% predicted. Subjects were treated with one of the following regimens (nine subjects in each group): group A, mean (SD) baseline FEV1 of 0.7 (0.2) L, received albuterol solution, 5 mg, via a nebulizer (Puritan-Bennett Raindrop; Lawrenceville, Ga) impelled with oxygen (O2) at 8 L/min; group B, baseline FEV1 of 0.6 (0.15) L, received albuterol, 400 microg, via a CFCMDI attached to a 145-mL valved aerosol holding chamber (Aerochamber; Trudell Medical; London, ON); and group C, baseline FEV1 of 0.6 (0.17) L, received albuterol powder, 400 microg, by another means (Rotahaler; Glaxo; Research Triangle Park, NC). All groups received the respective treatments on arrival in the ED, every 30 min during the first 2 h, and then hourly until the sixth hour. Clinical parameters and FEV1 were recorded on ED admission and 15 min after each dose of albuterol. At the time of ED admission, all patients also received continuous O2 and one dose of I.V. steroids (dexamethasone, 8 mg). The total dose of inhaled albuterol administered during the 6-h treatment was 45 mg of nebulized solution in group A and 3,600 microg of albuterol aerosol and dry powder in groups B and C, respectively. No significant differences were found in the population demographics, baseline FEV1, and arterial blood gas values on air. FEV1 improved significantly in all patients after the 6 h of treatment. The 6-h area under the curve FEV1 improved similarly with the three delivery methods despite differences in the total dose administered. No patient was discontinued during the trial or admitted to hospital and no evidence of cardiovascular adverse events was apparent in any of the study groups. These data support the view that the three delivery methods appear adequate to treat subjects with acute severe asthma.
Administration, Inhalation↗
Analysis of the T cell receptor Vgamma region gene repertoire in bronchoalveolar lavage (BAL) and peripheral blood of atopic asthmatics and healthy subjects.
We analyzed the T cell receptor (TCR) Vgamma repertoire in BAL and peripheral blood (PBL) of three mild stable atopic asthmatics and two non-asthmatic controls. We used the polymerase chain reaction (PCR) to establish the expression of the four Vgamma families, and to detect oligo or monoclonal expansion of gammadelta+ T cells, we resolved the PCR projects on denaturing and non-denaturing gels to find the extent of junctional diversity arising from differences in the lengths of the V(D)J junctions. We also subcloned and sequenced the PCR products to characterize fully the sequence diversity. BAL T lymphocytes from two asthmatic patients (treated with inhaled steroids) expressed only VgammaII and, in one of them, VgammaIIJgamma usage was restricted to JgammaP and JgammaP1 gene segments, contrasting with the VgammaJgamma repertoire found in his respective PBL. Analyses in denaturing and non-denaturing gels showed that the BAL VgammaIIJgammaP and VgammaIIJgammaP1 PCR products resolved into few bands, suggesting deletions at the juctions due to oligoclonal expansion. BAL T lymphocytes from the third asthmatic (not receiving inhaled steroids) expressed VgammaI, II and III, and the sequences of the in-frame TCR transcripts from this asthmatic and one healthy volunteer who expressed a similar BAL VgammaTCR repertoire showed clonal expansion of T cells expressing all three Vgamma families. Our analyses showed that much of the GammaDeltaT cell population found in BAL fluid of humans derives from clonally expanded T cells.
Adult↗
Tracheobronchial constriction in asthmatics induced by isocapnic hyperventilation with dry cold air.
Although it is well known that isocapnic hyperventilation (IHV) with dry cold air produces airway constriction in asthmatic subjects, the site of airway narrowing is nuclear. To address this issue, we have quantified the tracheal and bronchial response to IHV with dry cold air in 15 patients with mild asthma and 7 healthy control subjects. We employed the acoustic reflection technique to evaluate changes in airway cross-sectional areas caused by IHV with dry cold air. Airway areas were measured during tidal breathing before and 5 to 10, 30, 60, and 90 min following cold air challenge. For analysis purposes, airway areas were divided into three anatomic segments: extrathoracic tracheal segment, intrathoracic tracheal segment, and main bronchial segment. These segments were assessed at a fixed volume below total lung capacity. Maximal and partial expiratory flow-volume curves were also obtained before each set of area measurements. In normal subjects, IHV with dry cold air caused no significant changes in FEV1, flow at 30% of the vital capacity in the partial curve (V30p), or airway areas. In asthmatics, at 5 to 10 min after challenge, we found that FEV1 decreased by 22 +/- 5% (mean +/- SEM) (p < 0.0001), V30p by 33 +/- 8% (p < 0.003), intrathoracic tracheal area by 10.7% +/- 2% (p < 0.03), and main bronchial area by 14 +/- 3% (p < 0.003). At 30 min, tracheal and main bronchial areas were returned to baseline levels; however, FEV1 and V30p were still significantly decreased, by 13 +/- 3% and 16 +/- 4%, respectively. We conclude that in asthmatics, IHV with dry cold air causes both tracheal and bronchial constriction, and that recovery seems to occur first in the central airways.
Acoustics↗
Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma.
BACKGROUND: It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. METHODS: Asthmatic patients presenting to the ED with acute severe asthma (FEV1 less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 micrograms per puff, or albuterol, 100 micrograms per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled beta 2-agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV1 plateau (i.e., < 10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV1 were assessed after each dose. RESULTS: 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV1 160 mL more than albuterol. The mean (SEM) FEV1 increase from baseline was 0.75 +/- 0.06 L in the fenoterol group and 0.59 +/- 0.06 L in the albuterol group (p < 0.03). Both beta 2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23 +/- 0.04 mmol/L) than in the salbutamol (0.06 +/- 0.03 mmol/L) group (p = 0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011 +/- 0.003 s compared with 0.003 +/- 0.003 s in the albuterol group (p < 0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. CONCLUSIONS: In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 micrograms per puff by MDI valved holding chamber and mask, to a total dose of 3,200 micrograms and salbutamol (100 micrograms per puff) to a total dose of 1,600 micrograms over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.
Acute Disease↗
The effect of pre-exposure to 0.12 ppm of ozone on exercise-induced asthma.
Ozone (O3) is a common air pollutant that has been associated with a dose-dependent increased bronchial responsiveness and airway inflammation. Previous investigations have shown increased airway responsiveness to allergens in asthmatics pre-exposed to 0.12 ppm of O3 for 1 h. In the present study, we investigated whether inhalation of relatively low levels of O3 would modify the degree of exercise-induced bronchoconstriction. We studied 15 "never smokers" with mild stable asthma (7 male and 8 female) (mean age [+/- SD] 25.6 +/- 6.8 years) who had exhibited a fall in FEV1 > 15 percent after a standard 6-min treadmill exercise challenge test on the screening day. This was a double-blind, placebo-controlled study. The patients were randomized to receive either O3 or air (placebo) before performing the exercise challenge again. The average highest 1-h daily O3 concentrations in Toronto during O3 days and air days were 0.017 +/- 0.017 and 0.014 +/- 0.005 ppm, respectively. The O3 concentration inside the chamber averaged 0.122 +/- 0.005 ppm on O3 days and 0.002 +/- 0.001 on placebo days. Partial and complete flow volume curves were done before and after this exposure, and also 5, 10, 15, 20, 30, and 60 min postexercise. The percent fall in FEV1 on the O3 chamber day and on the air chamber day was the same (F = 0.67, p = 0.67, NS) as well as the percent fall in V40p (F = 0.91, p = 0.49, NS). A repeated measures analysis of variance to test the effects of exposure on the time course of the airway response after exercise showed no significant difference between the 2 days. There was also no significant difference in maximal percentage fall in FEV1 (25.6 +/- 8.6) or V40p (62.2+18.6) following O3 exposure, and FEV1 (26.8 +/- 9.4)(p = 0.64) or V40p (65.3+4.31)(p = 0.60) following air. Our data indicate that previous exposure at rest to a concentration of O3 that has previously been shown to augment the bronchoconstriction response to allergens did not increase the bronchoconstriction response to subsequent exercise nor did it change the time course of such bronchoconstriction.
Adult↗
Trends in pharmacotherapy for chronic airflow limitation in Argentina: 1983-1990.
Reported increases in worldwide asthma mortality have prompted the publications of guidelines and consensus statements on the management of airway disease. Overreliance in bronchodilator therapy and lack of anti-inflammatory treatment have been the major findings and the guidelines are aimed at correcting these problems. The Argentinean population appears to have increased prevalence and severity of conditions characterized by chronic airflow limitation and there is no data, to our knowledge, that has analyzed how the treatment of such conditions has been conducted in the past years. Drug sales data in Argentina were surveyed retrospectively to estimate prescriptions dispensed for the treatment of airway disease for the years 1983 to 1990 inclusive. The number of prescriptions of all airway drugs increased significantly (p < 0.01) in the 8-year period except for oral beta 2-agonists and disodium cromoglycate (DSCG). Prescriptions for these agents were 42.7% and 69% less frequent respectively. Thus, oral beta 2-agonists declined from being the single most frequently prescribed class of drugs (40% of prescriptions) in 1983 to the third most frequently prescribed (22%) in 1990. Concurrently, prescriptions of inhaled beta 2-agonists in all forms rose significantly comprising 27% in 1983 and 46% in 1990 becoming the most commonly prescribed airway therapy. Despite this apparent trend away from oral bronchodilator therapy, theophylline prescriptions comprised a significantly higher percentage of prescriptions in 1990 as compared to 1983 (30% vs 20%).(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Agonists↗
[Treatment of asthma in Argentina].
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Adrenergic beta-Agonists↗
Near-fatal asthma.
The prevalence of patients with acute severe asthma appears to be increasing in many countries. In the present review, we summarize data in the literature relating to the prevention and treatment of fatality-prone asthmatics. The underlying assumption is that increased understanding of near-fatal asthma will increase our understanding of the pathophysiology of severe asthma, and lead to interventions that could reduce the mortality rate from asthma. Recognition of acute life-threatening asthma attacks by any physician is mandatory, since lack of such diagnosis and appropriate treatment has been shown to have devastating consequences. The characteristics that allow identification of asthmatics prone to die in ambulatory settings (i.e. previous admissions, type of therapy, etc.) as well as the principal precipitating factors of acute near-fatal and fatal attacks of asthma are reviewed. Predisposing factors, such as lack of appropriate treatment, lack of compliance or poor preventive measures are debated. Finally, we discuss current therapeutic approaches in emergency facilities, based on the major pathophysiological findings in near-fatal asthma.
Asthma↗
Tracheobronchial dilation during isocapnic hypoxia in conscious humans.
To assess the effects of isocapnic hypoxia on the pharynx, glottis, extrathoracic trachea (ET), intrathoracic trachea (IT), and main bronchi (MB), we measured the cross-sectional areas of these airways by acoustic reflection technique in 15 healthy volunteers. Measurements were made during tidal volume breathing while subjects were normoxic [arterial O2 saturation (SaO2) > 95%] or were made hypoxic by a rebreathing procedure. Under hypoxemic conditions, airway cross-sectional areas increased significantly at ET, IT, and MB levels (P < 0.001). The magnitude of this dilation was similar for both levels of hypoxemia studied (SaO2 80-85% and 70-75%); at the milder of the two hypoxemic conditions, ET cross-sectional area increased by 12.4 +/- 4.2% (SE), IT by 10.2 +/- 5.9%, and MB by 19.1 +/- 3.2%. No significant changes were found in the pharyngeal or glottic areas. Dilation was not produced by normoxic isocapnic hyperventilation, and the use of hypoxic airway gas mixtures did not artifactually alter acoustic reflection measurements in a mechanical model. Vagal airway tone, as reflected by airway constriction during pauses in tidal breathing, was unaffected by isocapnic hypoxia. We conclude that isocapnic hypoxia produces dilation of the trachea and major bronchi, an effect unaccounted for by an alteration in the ventilatory pattern.
Adult↗
Assessment of airway tone in asthma. Comparison between double lung transplant patients and healthy subjects.
We investigated the hypothesis that asthmatic patients have an increased cholinergic tone by measuring tracheobronchial cross-sectional areas during transient voluntary apnea. This allowed us to assess bronchomotor tone without the influence of changes in lung recoil or lung volume. Three groups of subjects with potentially different levels of tracheobronchial tone were studied: 14 healthy volunteers (N), 18 stable asthmatic patients (A), and 10 double lung transplant recipients (T). Using the acoustic reflection technique, we measured changes in tracheobronchial cross-sectional areas during short periods (5 to 10 s) of voluntary apnea. In a subset of subjects, studies were repeated before and after the inhalation of the muscarinic antagonist ipratropium. During breath-holding, glottis and extrathoracic trachea remained unchanged but intrathoracic tracheal area decreased by 30 +/- 8% (mean +/- standard error of the mean) in N, by 27 +/- 3% in A, and by 9 +/- 4% in the T group. Bronchial areas decreased by 24 +/- 8% in N, by 45 +/- 3% in A, and by 10 +/- 4% in T. These differences among groups were statistically significant at the tracheal and bronchial levels (p < 0.05), and ipratropium significantly inhibited this airway constriction (p < 0.05) only in the asthmatic group. Assuming that changes in cross-sectional airway areas voluntary apnea reflect airway tone, these results support the view that in humans this tone is mainly vagally controlled and that it is significantly increased in asthmatic compared with nonasthmatic subjects.
Administration, Inhalation↗
[Echogram of the upper airway].
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Acoustics↗
The effects of air pollution on allergic bronchial responsiveness.
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Air Pollution↗
Heterogeneous airway tone in asthmatic subjects.
We examined the effect of volume history on the dynamic relationship between airways and lung parenchyma (relative hysteresis) in 20 asthmatic subjects. The acoustic reflection technique was employed to evaluate changes in airway cross-sectional areas during a slow continuous expiration from total lung capacity to residual volume and inspiration back to total lung capacity. Lung volume was measured continuously during this quasi-static maneuver. We studied three anatomic airway segments: extra- and intrathoracic tracheal and main bronchial segments. Plots of airway area vs. lung volume were obtained for each segment to assess the relative magnitude and direction of the airway and parenchymal hysteresis. We also performed maximal expiratory flow-volume and partial expiratory flow-volume curves and calculated the ratio of maximal to partial flow rates (M/P) at 30% of the vital capacity. We found that 10 subjects (group I) showed a significant predominance of airway over parenchymal hysteresis (P < 0.005) at the extra- and intrathoracic tracheal and main bronchial segments; these subjects had high M/P ratios [1.53 +/- 0.27 (SD)]. The other 10 subjects (group II) showed similar airway and parenchymal hysteresis for all three segments and significantly lower M/P ratios (1.16 +/- 0.20, P < 0.01). We conclude that the effect of volume history on the relative hysteresis of airway and lung parenchyma and M/P ratio at 30% of vital capacity in nonprovoked asthmatic subjects is variable. We suggest that our findings may result from heterogeneous airway tone in asthmatic subjects.
Adolescent↗
Changes in cross-sectional airway areas induced by methacholine, histamine, and LTC4 in asthmatic subjects.
To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.
Analysis of Variance↗