A novel application of multi-event modeling to estimate class segregation in a highly migratory oceanic vertebrate.

Spatial segregation of animals by class (i.e., maturity or sex) within a population due to differential rates of temporary emigration (TE) from study sites can be an important life history feature to consider in population assessment and management. However, such rates are poorly known; new quantitative approaches to address these knowledge gaps are needed. We present a novel application of multi-event models that takes advantage of two sources of detections to differentiate temporary emigration from apparent absence to quantify class segregation within a study population of double-marked (photo-identified and tagged with coded acoustic transmitters) white sharks (Carcharodon carcharias) in central California. We use this model to test if sex-specific patterns in TE result in disparate apparent capture probabilities (po ) between male and female white sharks, which can affect the observed sex ratio. The best-supported model showed a contrasting pattern of Pr(TE) from coastal aggregation sites between sexes (for males Pr[TE] = 0.015 [95% CI = 0.00, 0.31] and Pr[TE]= 0.57 [0.40, 0.72] for females), but not maturity classes. Additionally, by accounting for Pr(TE) and imperfect detection, we were able to estimate class-specific values of true capture probability (p* ) for tagged and untagged sharks. The best-supported model identified differences between maturity classes but no difference between sexes or tagging impacts (tagged mature sharks p*  = 0.55 (0.46-0.63) and sub-adult sharks p*  = 0.36 (0.25, 0.50); and untagged mature sharks p*  = 0.50 (0.39-0.61) and sub-adults p*  = 0.18 (0.10, 0.31). Estimated sex-based differences in po were linked to sex-specific differences in Pr(TE) but not in p* ; once the Pr(TE) is accounted for, the p* between sexes was not different. These results indicate that the observed sex ratio is not a consequence of unequal detectability and sex-specific values of Pr(TE) are important drivers of the observed male-dominated sex ratio. Our modeling approach reveals complex class-specific patterns in Pr(TE) and p* in a mark-recapture data set, and highlights challenges for the population modeling and conservation of white sharks in central California. The model we develop here can be used to estimate rates of temporary emigration and class segregation when two detection methods are used.

Effects of adjustable and stationary fans with misters on core body temperature and lying behavior of lactating dairy cows in a semiarid climate.

Cows readily seek shade to reduce solar heat load during periods of high ambient temperature. Typically, auxiliary cooling systems are oriented to maximize cooling for shaded cows. However, when a shade structure is oriented north-south, stationary fan and mister cooling systems are unable to track shade as the sun's angle shifts throughout the day, and thus can become ineffective. The FlipFan Dairy Cooling System (Schaefer Ventilation Equipment, Sauk Rapids, MN) employs fans and misters that follow shade and compensate for wind speed by rotating on a horizontal axis. Multiparous, lactating Holstein cows (n=144) on a commercial dairy in Arizona were cooled by a fixed system comprised of stationary fans and misters acting as control or the adjustable FlipFan operated for 16.5 h/d (0830 to 0100 h). Core body temperatures (CBT) of 64 cows (4 pens/treatment; 8 cows/pen; 6d) and lying behavior of 144 cows (4 pens/treatment; 18 cows/pen; 5d) were collected by intravaginal and leg data loggers, respectively. Cows were balanced by milk production, blocked by days in milk, and randomly assigned to pen within block. Pen was the experimental unit. In a second experiment, isothermal maps were developed using a fixed system of thermal data loggers arranged in the shaded areas of the pens at different times of day and were analyzed for differences in the temperature-humidity index (THI) achieved by each cooling treatment. Ambient conditions consisted of a mean temperature of 33.0°C, mean relative humidity of 40.3%, and mean THI of 80.2. Mean 24-h CBT for FlipFan was lower than control (38.9 vs. 39.1±0.04°C). A treatment × time interaction was observed in which CBT of FlipFan was 0.4°C lower than control from 0600 to 0800h and 1500 to 1600h. Cows cooled by FlipFan spent more time lying down compared with those cooled by control (9.5 vs. 8.6 h/d). Cows under FlipFan had more frequent lying bouts than did those under control (12.8 vs. 10.7 bouts/d). Lower CBT and decreased standing time are consistent with the findings of other studies when ambient heat load was reduced. In the second experiment, the FlipFan system achieved a lower THI in the morning and evening (5.9 and 1.7%, respectively), and the THI also tended to be 0.8% lower in the afternoon compared with that of control. Results indicate that FlipFan is more effective than a stationary fan and mister system at decreasing CBT, increasing lying time and bouts, and providing a more desirable microenvironment for cows throughout the day in a semiarid environment.

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.

Are asthma-like symptoms in elite athletes associated with classical features of asthma?

BACKGROUND: Asthma is frequent in elite athletes and clinical studies in athletes have found increased airway inflammation. OBJECTIVE: To investigate asthma-like symptoms, airway inflammation, airway reactivity (AR) to mannitol and use of asthma medication in Danish elite athletes. METHODS: The study group consisted of 54 elite athletes (19 with doctor-diagnosed asthma), 22 non-athletes with doctor-diagnosed asthma (steroid naive for 4 weeks before the examination) and 35 non-athletes without asthma; all aged 18-35 years. Examinations (1 day): questionnaires, exhaled nitric oxide (eNO) in parts per billion, spirometry, skin prick test, AR to mannitol and blood samples. Induced sputum was done in subjects with asthma. RESULTS: No significant difference was found in values for eNO, AR and atopy between 42 elite athletes with and 12 without asthma-like symptoms. Elite athletes with doctor-diagnosed asthma had less AR (response dose ratio 0.02 (0.004) vs 0.08 (0.018) p<0.01) and fewer sputum eosinophils (0.8% (0-4.8) vs 6.0% (0-18.5), p<0.01) than non-athletes with doctor-diagnosed asthma. Use of inhaled corticosteroids was similar in the two groups (not significant). In all, 42 elite athletes had asthma-like symptoms but only 12 had evidence of current asthma. Elite athletes without asthma had asthma-like symptoms more frequently than non-athletes without asthma (68.6% vs 25.7%, p<0.001). CONCLUSION: Asthma-like symptoms in elite athletes are not necessarily associated with classic features of asthma and alone should not give a diagnosis of asthma. More studies are needed to further investigate if and how the asthma phenotype of elite athletes differs from that of classical asthma.

Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis.

Bronchiectasis is characterised by hypersecretion and impaired clearance of mucus. A 400-mg dose of inhaled mannitol improves mucus clearance however, the effect of other doses is unknown. A total of 14 patients, aged 63.3+/-5.7 yrs, were studied on five visits. Mucus clearance at baseline and with mannitol (160, 320 and 480 mg) was measured using technetium-99m-sulphur colloid and imaging with a gamma camera over 45 min, followed by a further 30 min involving 100 voluntary coughs. A control study assessed the effect of cough provoked by mannitol during the intervention. Whole right lung clearance over 45 min was 4.7+/-1.2 and 10.6+/-2.6% on baseline and control days, respectively, and increased to 16.7+/-4.2, 22.8+/-4.2 and 31+/-4.7% with 160, 320 and 480 mg mannitol, respectively. Clearance over 45 min with 480 mg mannitol was greater than clearance with 320 and 160 mg. Total clearance over 75 min, after mannitol administration and voluntary coughs, was 36.1+/-5.5, 40.9+/-5.6 and 46.0+/-5.2% with 160, 320 and 480 mg mannitol, respectively, all significantly different from baseline (24.1+/-6.0%) and control (13.1+/-3.0%). Total clearance over 75 min with 480 mg mannitol was greater compared with 160 mg. In conclusion, mucus clearance increases with increasing doses of mannitol and can be further increased by cough in patients with bronchiectasis.

Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients.

BACKGROUND: Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect airway inflammation more closely compared with AHR measured by stimuli that act directly on BSM. METHODS: Fifty-three adult non-smoking asthmatics (28 females, 18-56 years) who were not taking inhaled steroids were challenged with mannitol (up to 635 mg) and methacholine (up to 8 mumol). Induced sputum eosinophils, exhaled nitric oxide (eNO), peak flow variation and clinical severity of asthma according to the Global Initiative for Asthma guidelines were measured in addition to the health-related quality-of-life score using the Juniper asthma quality-of-life questionnaire. FINDINGS: Both AHR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was >20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20 p.p.b., but none had sputum% eosinophils >1%. AHR to mannitol was more closely associated with the percentage of sputum eosinophils (PD(15) to mannitol vs. sputum% eosinophils: r: -0.52, P<0.05), compared with AHR to methacholine (PD(20) to methacholine vs. sputum% eosinophils: r: -0.28, NS). Furthermore, there was a stronger correlation between AHR to mannitol and the level of eNO [PD(15) to mannitol vs. eNO (p.p.b.): r: -0.63, P<0.001], compared with AHR to methacholine [PD(20) to methacholine vs. eNO (p.p.b.): r: -0.43, P<0.05]. INTERPRETATION: In asthma patients not being treated with steroids, AHR to mannitol and to methacholine indicated the presence of airway inflammation. AHR to mannitol reflected the degree of airway inflammation more closely when compared with methacholine.

Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN.

AIMS: To analyze the changes in the prevalence of asthma, bronchial hyperresponsiveness (BHR) and allergies in elite athletes over the past years, to review the specific pathogenetic features of these conditions and to make recommendations for their diagnosis. METHODS: The Task Force reviewed present literature by searching Medline up to November 2006 for relevant papers by the search words: asthma, bronchial responsiveness, EIB, athletes and sports. Sign criteria were used to assess level of evidence and grades of recommendation. RESULTS: The problems of sports-related asthma and allergy are outlined. Epidemiological evidence for an increased prevalence of asthma and BHR among competitive athletes, especially in endurance sports, is provided. The mechanisms for development of asthma and bronchial hyperresponsiveness in athletes are outlined. Criteria are given for the diagnosis of asthma and exercise induced asthma in the athlete. CONCLUSIONS: The prevalence of asthma and bronchial hyperresponsiveness is markedly increased in athletes, especially within endurance sports. Environmental factors often contribute. Recommendations for the diagnosis of asthma in athletes are outlined.

Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN.

AIM: The aims of part II is to review the current recommended treatment of exercise-induced asthma (EIA), respiratory and allergic disorders in sports, to review the evidence on possible improvement of performance in sports by asthma drugs and to make recommendations for their treatment. METHODS: The literature cited with respect to the treatment of exercise induced asthma in athletes (and in asthma patients) is mainly based upon the systematic review given by Larsson et al. (Larsson K, Carlsen KH, Bonini S. Anti-asthmatic drugs: treatment of athletes and exercise-induced bronchoconstriction. In: Carlsen KH, Delgado L, Del Giacco S, editors. Diagnosis, prevention and treatment of exercise-related asthma, respiratory and allergic disorders in sports. Sheffield, UK: European Respiratory Journals Ltd, 2005:73-88) during the work of the Task Force. To assess the evidence of the literature regarding use of beta(2)-agonists related to athletic performance, the Task Force searched Medline for relevant papers up to November 2006 using the present search words: asthma, bronchial responsiveness, exercise-induced bronchoconstriction, athletes, sports, performance and beta(2)-agonists. Evidence level and grades of recommendation were assessed according to Sign criteria. RESULTS: Treatment recommendations for EIA and bronchial hyper-responsiveness in athletes are set forth with special reference to controller and reliever medications. Evidence for lack of improvement of exercise performance by inhaled beta(2)-agonists in healthy athletes serves as a basis for permitting their use. There is a lack of evidence of treatment effects of asthma drugs on EIA and bronchial hyper-responsiveness in athletes whereas extensive documentation exists in treatment of EIA in patients with asthma. The documentation on lack of improvement on performance by common asthma drugs as inhaled beta(2)-agonists with relationship to sports in healthy individuals is of high evidence, level (1+). CONCLUSIONS: Exercise induced asthma should be treated in athletes along same principles as in ordinary asthma patients with relevance to controller and reliever treatment after careful diagnosis. There is very high level of evidence for the lack of improvement in athletic performance by inhaled beta2-agonists.

Visceral leishmaniasis in northern Ethiopia.

BACKGROUND: Visceral leishmaniasis (VL) has been well documented by the Medecins sans Frontieres (MSF) VL treatment programmeme in the Tigray region of Ethiopia, but reports are limited from other facilities in this region where this disease continues to cause substantial morbidity and mortality. OBJECTIVE: To describe the clinical manifestations and treatment outcomes of VL in a government hospital in Axum, Ethiopia. DESIGN: Retrospective analysis of 111 patients treated for visceral leishmaniasis. SETTING: Saint Mary's Hospital, Axum, Ethiopia. SUBJECTS: One hundred and Eleven patients treated for visceral leishmaniasis in a government hospital in Axum, Ethiopia. RESULTS: All patients were male and most reported travel history to Humera, a known endemic area. Patients presented with classic signs and symptoms, including fever, weight loss, splenomegaly and anaemia. Almost one third (15/53) of patients who underwent HIV testing had a positive result. Crude death rate at six months was 13.5 per 100 patients (95% CI: 6.7 - 20.3 per 100 patients). Presence of HIV and other co-infections were associated with increased risk of death. CONCLUSIONS: Clinical manifestations and treatment outcomes in this setting were comparable to that of the MSF programmeme in Tigray, Ethiopia and highlight the importance of HIV testing for patients presenting with visceral leishmaniasis.

A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes.

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled ß2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11ß-prostaglandin F2α (11ß-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11ß-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11ß-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Hemodynamic and metabolic basis of impaired exercise tolerance in patients with severe left ventricular dysfunction.

Hemodynamic and metabolic changes were measured at rest and during exercise in 23 patients with chronic heart failure and in 6 control subjects. Exercise was limited by leg fatigue in both groups and capacity was 40% lower in the patients with failure. At rest, comparing patients with control subjects, heart rate and right atrial and pulmonary wedge pressure were higher; cardiac output, stroke volume and work indexes and ejection fraction were lower; mean arterial and right atrial pressure and systemic resistance were similar. During all phases of exercise in patients with heart failure, pulmonary wedge pressure and systemic vascular resistance were higher and pulmonary vascular resistance remained markedly elevated compared with values in control subjects. Cardiac output was lower in the patients with failure, but appeared to have the same physiologic distribution in both groups during exercise. Although arterial-femoral venous oxygen content difference was higher in patients with heart failure, this increase did not compensate for the reduced blood flow. Even though the maximal oxygen consumption was significantly reduced, femoral venous lactate and pH values were higher than values in control subjects, but femoral venous pH was similar in both groups at their respective levels of maximal exercise. Ejection fraction was lower in those with heart failure at rest and did not increase with exercise. Ventilation in relation to oxygen consumption was higher in patients with failure than in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nifedipine on arterial oxygenation at rest and during exercise in patients with stable angina.

The effects of nifedipine on arterial oxygenation and hemodynamics were studied at rest and during bicycle exercise in 12 men (mean age 55 years, range 41 to 67) with stable exertional angina. The study was conducted double-blind on 2 days, 1 week apart, using a placebo-controlled crossover design. On each day, measurements at rest were made before and 20 minutes after 20 mg sublingual nifedipine or placebo and were followed by measurements made during exercise. Compared with placebo, nifedipine reduced mean arterial pressure, systemic vascular resistance and pulmonary vascular resistance, and increased heart rate and cardiac output at rest and during exercise. It did not alter mean pulmonary artery or pulmonary artery wedge pressures at rest, but decreased them during exercise. Nifedipine decreased arterial oxygen tension (PaO2) from 96 +/- 10 to 90 +/- 13 mm Hg (p less than 0.05) at rest and from 99 +/- 11 to 92 +/- 12 mm Hg (p less than 0.005) at submaximal exercise (33 +/- 21 W), but did not alter it (100 +/- 12 versus 100 +/- 16 mm Hg, p = NS) at maximal exercise (68 +/- 30 W). The reduction in PaO2 was not due to alveolar hypoventilation, because nifedipine did not alter arterial carbon dioxide tension, or to changes in mixed venous oxygen tension, which nifedipine increased at rest (39 +/- 2 versus 43 +/- 3 mm Hg, p less than 0.001) and during submaximal exercise (31 +/- 4 versus 33 +/- 4 mm Hg, p less than 0.03) and maximal exercise (27 +/- 3 versus 31 +/- 3 mm Hg, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that raphe-spinal neurons mediate opiate and midbrain stimulation-produced analgesias.

The present experiments were undertaken to assess the role of neurons in the nucleus raphe magnus (NRM) in mediating opiate and stimulation-produced analgesias. A cannode for both electric stimulation and local opiate microinjection was placed in the midbrain preiaqueductal gray region of decerebrate or chloralose-urethane anesthetized cats. Microelectrodes recorded the responses of medullary NRM neurons. Raphe-spinal neurons were identified by antidromic activation from the cerevical spinal cord. Fifteen of 20 raphe-spinal cells tested were excited by electrical stimulation of the midbrain. Of 49 NRM neurons tested, 26 were excited by either systemic or midbrain injection of opiate agonist. Twelve of 33 NRM cells tested by midbrain microinjection were excited. In 10 the effect was reversed by naloxone. Seventeen raphe-spinal neurons were tested; 5 showed naloxone-reversible excitation to either midbrain or intravenous injection of opiates. NRM neurons respond to auditory and somatic stimuli; at least half respond maximally to somatic stimuli of noxious intensity. These findings are consistent with the hypothesis that the raphe-spinal projection mediates opiate and electrical stimulation-produced effects from midbrain sites. The properties of raphe-spinal neurons suggest that they are part of a negative feedback system which monitors and limits the output of spinal dorsal horn pain-transmission neurons.

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.

The use of the treadmill for assessing exercise-induced asthma and the effect of varying the severity and duration of exercise.

Running produces a greater amount of post-exercise bronchoconstriction than other forms of exercise carried out a similar metabolic rates. The treadmill can be used to provide a standardized form of exercise when studying the asthmatic child. The severity of post-exercise bronchoconstriction depends upon the rate of working on the treadmill and the duration of exercise. A maximum response is obtained by six minutes of running at an uphill slope of 10% at a speed of 5 kmph (3 mph). Even with this type of test, there is still considerable variation in the response from time to time and greatest reporducibility is obtained by repeating the test within one week. Treadmill exercise tests may be used in the diagnosis of asthma and in the assessment of its likely severity.

Effect of propranolol and verapamil on oxygen utilization, acidosis and fatigue during exercise in stable angina pectoris.

Oxygen utilization, arterial and venous blood gas levels, hemodynamic values and exercise tolerance were compared before and after administration of propranolol and verapamil in 10 patients with stable angina pectoris. During exercise, propranolol decreased cardiac output (CO) by 22%; O2 extraction was increased and O2 consumption (VO2) did not change. With verapamil treatment, CO modestly increased (7%), O2 extraction decreased and VO2 did not change. In contrast to O2 utilization, the drugs produced opposite changes in mixed venous and arterial blood gas levels. Propranolol decreased mixed venous pH, increased CO2 tension and decreased the pH of arterial blood. Verapamil increased venous pH and decreased CO2 tension; pH of arterial blood did not change. The drugs yielded similar levels of antianginal efficacy, but patients exercised longer during verapamil therapy and were less fatigued. The hemodynamic and metabolic differences suggest that muscle perfusion during exercise influences the onset of fatigue and may help determine the choice of therapy.

Duration of protective effect of terbutaline sulfate and cromolyn sodium alone and in combination on exercise-induced asthma.

For subjects with EIA participating in physical activities throughout the day, prolonged duration of protection is desirable. The purpose of this study was to determine whether in EIA a combination of the recommended aerosol doses of the beta 2-adrenergic receptor agonist, terbutaline sulfate (0.5 mg), and cromolyn sodium (disodium cromoglycate; 2 mg) provides longer protection against EIA than either drug alone. On four separate days, following the administration of either placebo, terbutaline alone, cromolyn sodium alone or terbutaline and cromolyn sodium together, 12 subjects (seven men and five women; aged 18 to 28 years) with EIA performed four identical eight minute treadmill runs, each separated by two-hour intervals. Drug treatments were given double-blind, with the order counterbalanced using a Latin-square design. Pulmonary function was recorded before the drug, immediately before and after exercise, and at 3, 4, 5, 6, 7, 10, 15, and 30 minutes after exercise. Inspired ventilation, heart rate, and environmental conditions were monitored during exercise. A two-way analysis of variance was performed to investigate the main effects of time and drug treatment. Results indicated that in comparison with placebo, EIA was significantly reduced by either cromolyn sodium or terbutaline administered up to two hours (p less than 0.01) and by the combination (cromolyn sodium and terbutaline) up to four hours after inhalation (p less than 0.05). No significant differences were found between the combination and terbutaline during the initial two hours (p less than 0.5). We conclude that a combination of beta 2-adrenergic receptor agonist and cromolyn sodium is the treatment of choice for prolonged effective protection from EIA.

The duration of action of the combination of fenoterol hydrobromide and ipratropium bromide in protecting against asthma provoked by hyperpnea.

We compared the duration of the protective effect of two beta-adrenoceptor agonists, fenoterol (200 micrograms) and salbutamol (200 micrograms), the anticholinergic agent ipratropium (80 micrograms), and the combination of fenoterol (200 micrograms) and ipratropium (80 micrograms) against challenge by eucapnic voluntary hyperventilation (EVH). Twelve patients with asthma performed EVH for two or four min at 60 percent maximal voluntary ventilation, 30 min, 2 and 4 h after treatment. All treatments (Rx) produced significant bronchodilation after 30 min. The Rx containing a beta-adrenoceptor agonist maintained this bronchodilation for at least 2 h. While all the Rx with a beta-adrenoceptor agonist significantly reduced the fall in forced expiratory volume in one second after EVH at 30 min, only the combination of fenoterol and ipratropium provided significant protection after 2 h. We advise that the duration of protective effect of beta-adrenoceptor agonists is short and patients with moderate to severe exercise-induced asthma may be better controlled by combination therapy.

Duration of protection by inhaled salmeterol in exercise-induced asthma.

Beta-adrenoceptor agonists such as albuterol are very effective in preventing exercise-induced asthma (EIA) when they are given as an aerosol immediately before exercise. However, their duration of protection against EIA is usually less than 2 h. This may be due partly to their rapid clearance from the airways. Salmeterol is a highly lipophylic compound that is thought to bind to an exoreceptor near the beta-receptor. The objective of this study was to compare the protective effect of salmeterol with albuterol against EIA. Exercise was performed 0.5, 2.5, 4.5, and 6.5 hours after administration of the active drugs. Subjects attended the laboratory on four days within six weeks and cycled for 8 min breathing dry compressed air. We studied 17 asthmatic subjects (aged 19 to 49 years) with moderate to severe EIA. Salmeterol (50 micrograms) or albuterol (200 micrograms) was given from a metered dose inhaler via a spacer (Volumatic). On the control day, the mean work load +/- 1 SD was 174 +/- 47 W, ventilation (VE) was 77.9 percent +/- 11.2 percent of the target ventilation (60 percent maximum voluntary ventilation [MVV]), and heart rate was 170 +/- 14 beats per minute. This intensity was maintained for all tests. FEV1 was measured before and after exercise and was expressed as percent predicted and as percentage of the preexercise value (percentage of fall). Thirty minutes after treatment, both drugs were effective in inhibiting EIA--percentage of fall in FEV1, 17 +/- 12 after salmeterol; percentage of fall in FEV1, 15 +/- 15 after albuterol. At 2.5, 4.5, and 6.5 hours, the reduction in FEV1 was significantly less (p less than 0.01) after salmeterol compared with albuterol. At 6.5 hours, the percentage of fall in FEV1 was 20 +/- 10 after salmeterol and 36 +/- 12 after albuterol. Salmeterol also had a more prolonged action as a bronchodilator and values for FEV1 were significantly higher compared with those on albuterol at 4.5 and 6.5 hours. At 6.5 hours, the FEV1 percent predicted was 96 +/- 10 after salmeterol and 84 +/- 12 after albuterol (p less than 0.01). We conclude that the extent of protection against EIA and the bronchodilation induced by both drugs was similar, but that salmeterol has a longer duration of action compared with albuterol. The reason for its superior duration of action may be due to a slower clearance of the drug from the airways.