Doubling Doses Research Articles

Approaches to assessing genetic risks from exposure to chemicals.

An effort to assess and quantify genetic risks from human exposure to mutagenic chemicals is urgently needed; otherwise genetic toxicology may well lose its credibility. Genetic biomonitoring provides us with an indication of mutagenic effectiveness in human somatic cells. The populations and chemicals selected for such studies form a useful database for genetic risk-assessment studies. Extrapolation to what can be expected in germ cells of exposed individuals should be possible by using good dosimetry (adducts) and a parallelogram approach. The principle is that genetic damage in the inaccessible human germ cells can be estimated by determining the effects on lymphocytes (or other somatic cells) from humans and mice and in germ cells of mice. Worldwide, opportunities for the costly mouse germ cell studies are limited. Knowledge of type of DNA adducts, their persistence and/or removal and dominant lethal studies, will be helpful in predicting stage sensitivity. Extrapolation from a lowest effective dose level is proposed. The available data for ethylene oxide and benzene are reviewed. The risk of heritable translocations in progeny of populations exposed to ethylene oxide is so high that more precise estimates seem desirable. In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out. The molecular changes underlying dominant mutations in man are more limited than is the case for recessive mutations. This raises the question whether mutagenic agents can produce the specific changes leading to recoverable, dominant mutations. Extrapolation from increased mutation rates to predictable increases of human disease, whether by doubling dose or direct methods, have been criticized.

The determinants of airway hyperresponsiveness to hypertonic saline in atopic asthma in vivo. Relationship with sub‐populations of peripheral blood leucocytes

In patients with asthma there is only a weak relationship between airway responsiveness to hypertonic saline and methacholine. We tested the hypothesis that airway responsiveness to hypertonic saline in asthma is related to the presence and activity of inflammatory cells in the peripheral blood. Nineteen atopic asthmatic adults (19-28 yr; PC20 0.06-12.4 mg/ml), not receiving steroid treatment, entered a metacholine and hypertonic saline period in random order. Dose-response curves to doubling doses of inhaled methacholine (0.03-256 mg/ml) or hypertonic saline (0.9-14.4% NaCl) were obtained twice in each period, 7 days apart. The response was measured by FEV1. Methacholine responsiveness was measured by PC20 METH of FEV1 and responsiveness to hypertonic saline was expressed as the percentage fall in FEV1 after 14.4% NaCl (HYP14.4%). Peripheral blood was collected before the second challenge test of each period. Apart from leucocyte counts and serum eosinophilic cationic protein (ECP) level, sub-sets of lymphocytes (CD4+/CD3+, CD8+/CD3+, CD25+/CD4+ and VLA-1+/CD4+) were determined using flow cytometry. HYP14.4% was positively correlated to basophil, eosinophil and monocyte counts (r = 0.64, 0.54 and 0.44, respectively; P < 0.05). The basophil count remained positively related to HYP14.4% when PC20METH or FEV1%pred were entered in multiple linear regression analyses (r = 0.66 and 0.75, respectively; P < 0.05). There were no significant relationships between HYP14.4% or PC20METH on one side and ECP level or T-lymphocyte subsets on the other (P > 0.05). We conclude that airway responsiveness to hypertonic saline is positively related to the number of peripheral blood basophils, eosinophils and monocytes. Basophil count is an independent correlate of responsiveness to hypertonic saline, after correction for methacholine responsiveness and baseline lung function. This fits in with active involvement of basophils in airway narrowing to hypertonic saline in vivo.

Protective Effect of Inhaled Piretanide on the Bronchial Obstructive Response to Ultrasonically Nebulized H2O: A Dose-Response Study

Inhaled furosemide prevents the obstructive response to several bronchoconstrictor stimuli in asthma. To verify whether this protective effect is also shared by other loop diuretics, we investigated the effect of inhaled piretanide on the bronchial obstructive response to ultrasonically nebulized distilled water (UNW) in ten patients with moderate, stable asthma. In a randomized, single-blind dose-response study, each subject performed an UNW test immediately after nebulization of different doses of piretanide between 12 and 48 mg or placebo. The effect of a single 40-mg dose of inhaled furosemide was also investigated in six subjects. Piretanide caused a significant, dose-dependent increase in UNW PD20 with respect to placebo, corresponding to 0.6±0.2 doubling doses (mean ± SE) after 12 mg, 1.3±0.2 after 24 mg, and 2.0±0.2 after 48 mg, and had a remarkable diuretic effect; 40 mg of furosemide increased UNW PD20 by 2.3±0.3 doubling doses (p<0.01), but showed only a modest diuretic activity. These data indicate that inhaled piretanide is as effective as furosemide in preventing UNW-induced asthma, and this effect is unrelated to their diuretic potency.

Mechanism of bombesin-induced pancreatic secretion in unanesthetized rats

It is unclear whether stimulation of pancreatic enzyme secretion by intravenously administered bombesin is a direct effect on acinar cells or is mediated by release of CCK; this distinction is important for defining the potential role of bombesin-like peptides as regulators of pancreatic secretion. The role of CCK in bombesin-induced pancreatic secretion was examined in rats using CCK radioimmunoassay and the CCK receptor antagonist L-364,718. A biphasic pancreatic response occurred to sequential doubling doses of bombesin (31 to 2000 pmol/kg/h, each for 30 min; n = 9 rats); amylase secretion increased to a peak at 250 pmol/kg/h ( 11.5 ± 1.7 kU/30 min ; 4.2 ± 0.6 kU/30 min , basal) and then declined to basal levels at 2000 pmol/kg/h. The ED 50 dose of bombesin for stimulation was 31 pmol/kg/h, and the maximal response did not differ significantly from that to exogenous CCK-8 ( 10.6 ± 1.5 kU/30 min ) in the same rats. When single doses of bombesin were infused for 2 h (31, 62, 125, 250 pmol/kg/h; one dose per day; order randomized; n = 8), a similar dose-response relationship was seen, both for peak amylase response and cumulative output over basal. L-364,718 (0.5 mg/kg IV) had no effect on the pancreatic response to ED 50 or maximal doses of bombesin. Neither dose of bombesin altered plasma CCK levels. In contrast, other stimulants of pancreatic secretion (food ingestion, soybean trypsin inhibitor) caused marked elevations in plasma CCK levels. These results indicate that the potent stimulation of pancreatic secretion by exogenous bombesin in rats is not mediated by CCK, similar to findings in humans.

Effect of alterations of dietary sodium on the severity of asthma in men.

There is some evidence of a positive association between increased dietary salt consumption and both increased bronchial reactivity and mortality from asthma in men. This study assesses the effects of alterations in dietary salt consumption on the clinical severity of asthma in adult male asthmatic patients. A randomised, double blind, placebo controlled, crossover design was employed. Twenty seven mild to moderate asthmatic patients were established on a low sodium diet (80 mmol/day) at the end of a 4-5 day run in period and then randomised to receive 200 mmol/day slow sodium or matching placebo for five weeks, crossing over to the alternative regime for a further five weeks. Patients used diary cards to record twice daily peak expiratory flow rates, daily symptom scores, and bronchodilator consumption. Spirometry and degree of bronchial responsiveness (methacholine challenge test) were measured at screening and at the end of each treatment period. Twenty four hour urinary sodium excretion was measured at screening and in duplicate for each treatment period. Twenty two patients completed the study. For these patients the mean (95% confidence interval (CI)) difference in 24 hour sodium excretion between treatments was 204 (175 to 235) mmol. Compared with placebo, sodium supplementation resulted in deleterious alterations of all measured parameters. Bronchial reactivity rose on slow sodium with a 0.73 (0.2 to 1.3) doubling dose methacholine difference compared with placebo. Estimated median (95% CI) difference in bronchodilator consumption was 1.3 (0.4 to 2.1) puffs per day, the estimated median difference in symptom score was 0.6 (0.2 to 0.9), and mean forced expiratory volume in one second fell by 0.21 (0.05 to 0.37) 1. The peak expiratory flow rate rose on placebo and fell on slow sodium. Median differences between treatments were 5.6% (2.2% to 9.8%) for morning and 7.8% (3.9% to 12.9%) for evening peak expiratory flow rate. Our results suggest that large increases in dietary sodium result in physiological deterioration and increased morbidity in male asthmatic patients.

Airways hyperresponsiveness, bronchodilator response, allergy and smoking predict improvement in FEV1 during long-term inhaled corticosteroid treatment. Dutch CNSLD Study Group

Although most patients with obstructive airways disease show some amelioration with long-term inhaled corticosteroid therapy, the extent of improvement may vary considerably between patients. Patients with mild to moderately severe obstructive airways disease (asthma and COPD) were selected if provocative concentration producing a 20% fall in forced expiratory volume in one second (PC20) < or = 8 mg.ml-1, and forced expiratory volume in one second (FEV1) < 95% confidence intervals (CI) of predicted normal. The independent influences of baseline PC20FEV1, inspiratory vital capacity (IVC), bronchodilator response, smoking habits, and allergy both on the "immediate" (within 3 months) response in FEV1 and the change in long-term (from 3 months onwards) slope of FEV1 with inhaled corticosteroids were analysed. Patients had a larger "immediate" improvement in their FEV1 with inhaled corticosteroids with each doubling doses lower PC20, with each ten-fold higher immunoglobulin E (IgE), and if they did not smoke. Total IgE proved a better independent predictor of "immediate" response than specific IgE for house dust mite, skin tests, or blood eosinophils. A more favourable long-term slope of FEV1 was predicted by a larger baseline bronchodilator response, but not by smoking. In conclusion, PC20, total IgE, and smoking habits are independent predictors of immediate treatment response to inhaled corticosteroids. Bronchodilator response is the single independent predictor of changes in long-term slope of FEV1 with corticosteroid treatment.

Minor acute effect of an inhaled corticosteroid (budesonide) on bronchial hyperresponsiveness to methacholine in children with asthma

Several studies have shown that long-term administration of inhaled corticosteroid reduces airway hyperresponsiveness. This study was performed in order to exclude an acute effect of inhaled corticosteroid. In a double-blind, randomized, cross-over study, children with asthma, who had never used inhaled or oral corticosteroid, received a single dose of 0.8 mg budesonide or placebo on two separate days, with an interval of at least 48 h. On each test day, baseline forced expiratory volume in one second (FEV1) and methacholine responsiveness (expressed as provocative dose producing a 20% fall in FEV1 (PD20) to methacholine, in doubling dose) were measured. Both measurements were repeated 2 and 5 h after administration of the drug. Twenty children were included in the study. FEV1 showed a mean increase of 1% at 5 h on the budesonide day, and a decrease of 2% on the placebo day (p = 0.01). PD20 increased by 0.1 doubling dose on the budesonide day, and decreased by 0.4 doubling dose on the placebo day. These changes are within the measurement variation (p = 0.06). We conclude that a single dose of 0.8 mg budesonide has a minor effect on methacholine responsiveness 5 h after administration in children with asthma. It is unlikely that such an effect interferes with the interpretation of data collected in long-term studies.

West Nile virus infection induces susceptibility of in vitro outgrown murine blastocysts to specific lysis by paternally directed allo-immune and virus-immune cytotoxic T cells

Day 3 post-coitum BALB/c and (BALB/c × CBA/H)F 1 blastocysts were isolated and hatched in replicate wells. Some were treated with interferon-γ (IFN-γ). Whilst others were infected with West Nile Virus (WNV) at 100 plaque-forming units per cell, for 18 h. Controls were mock-treated. Gamma-irradiated (2000 rads) CBA/H, (paternal) WNV-specific and allo(CBA/H)-specific cytotoxic T (Tc) cells were then added to replicates of infected, mock-infected or IFN-γ-treated cultures for 20 h. [ 3H]Thymidine was then added for a further 8 h. [ 3H]Thymidine incorporation was inhibited by 40–50% in WNV-infected cultures exposed to WNV-paternal-specific Tc cells and by 30–40% in WNV-infected cultures exposed to allo-paternal-specific Tc cells compared to similarly exposed, uninfected, or unexposed, WNV-infected, or unexposed, uninfected cultures. No significant differences in [ 3H]thymidine incorporation were found between these controls and IFN-γ-treated cultures exposed to allo-paternal-specific Tc cells or IFN-γ-treated cultures not exposed to Tc cells. Parallel exposure of L929 fibroblasts to the same Tc cells irradiated with 500–8000 rads in doubling doses, showed that irradiation did not alter the efficacy or specificity of the Tc cells. Relevance to maternal anti-viral immune responses during implantation is discussed.

Reanalysis of hanford data: 1944–1986 deaths

Reanalysis of Hanford data by a method, which is new only in the sense that it makes new uses of standard epidemiological procedures, has produced evidence of a cancer risk at low dose levels. By a conservative estimate, about three per cent of the pre-1987 cancer deaths of Hanford workers had occupational exposures to external radiation as the critical (induction) event. These radiogenic cancers were evenly distributed between five diagnostic groups, but as a result of there being much greater sensitivity to "cancer induction by radiation" after, rather than before, 50 years of age, they were concentrated among the cancers which proved fatal after 70 years of age. The reanalysis provides no support for the idea that radiation is more likely to cause leukemia than solid tumors, or the idea that there is reduced cancer effectiveness of radiation at low dose levels (dose rate effectiveness factor or DREF hypothesis), but the estimated proportion of radiogenic cancers was much higher for the 175 nonfatal cancers (which had other certified causes of death) than for the 1,732 fatal cases. Finally, according to the latest publication of the US Committee on Biological Effects of Ionizing Radiation (BEIR V), dose rate is more important than exposure age, and even a single exposure to 10 rem would only increase the normal cancer risk by four percent. Nevertheless, for all recorded exposures of Hanford workers, the estimated doubling dose was close to 26 rem; for exposures after 58 years, it was close to 5 rem, and for exposures after 62 years, it was less than 1 rem.

Effect of a single dose of inhaled salmeterol on baseline airway caliber and methacholine-induced airway obstruction in asthmatic children

Background: Salmeterol is a new inhaled selelctive β 2-adrenergic receptor agonist with a long duration of action. We studied the duration of the bronchodilation and the protective effect against methacholine-induced airway obstruction of a single dose of salmeterol in a double-blind, randomized, placebo-controlled, crossover design. Methods: Seventeen boys and three girls with mild-to-moderate asthma participated in the study. On two separate days either 50 μg salmeterol or placebo was inhaled. FEV 1 and PD 20 methacholine were determined before and 1, 4, 8, 12, and 24 hours after inhalation. Results: Salmeterol resulted in a significant bronchodilation compared with placebo, up to 12 hours ( p = 0.0001). At 24 hours there was a residual effect that approached significance; mean FEV 1 being 8.3% ± 2.4% above baseline ( p = 0.06). Significant protection against airway sensitivity to methacholine after salmeterol inhalation was found at all time points ( p < 0.005). Twenty-four hours after administration mean PD 20 was still 1.22 ± 0.29 doubling dose above baseline. No important adverse effects were noted. Conclusion: We conclude that a single dose of 50 μg salmeterol in children with asthma gives a long-lasting bronchodilation, exceeding 12 hours, which is comparable to the results in adult studies. The duration of the protection against airway sensitivity to methacholine exceeds 24 hours.

Effects of β2-receptor agonists on airway responsiveness

Airway hyper-responsiveness is one of the characteristics of asthma. It may be distinguished by airway hyper-sensitivity and an increase of the maximal response plateau. Short-acting β 2-agonists have an acute protective effect on airway sensitivity, which is shorter in duration than the bronchodilating effect, without affecting the maximal response plateau. Long-term treatment has no beneficial effect on airway responsiveness. A diminishement of the protection against metacholine- and histamine-induced airway obstruction and a rebound increase of this after cessation of continuous treatment have been reported. Single doses of long-acting β 2-agonists give a prolonged protection against methacholine- and histamine-induced airway sensitivity of at least 12 hours. A small decrease in the maximal response plateau has been noted. Currently, there is little data on long-term treatment. One study has described the development of tolerance to the protecting effect on methacholine-induced airway sensitivity after 2 months treatment. However, a protection by 1.0 doubling dose remained and the bronchodilating effect was not influenced. So far, no rebound increase in airway sensitivity has been reported after cessation of continuous treatment.

Effect of an anti-Mo1 MAb on ozone-induced airway inflammation and airway hyperresponsiveness in dogs.

Ozone inhalation causes neutrophil migration into the airway and airway hyperresponsiveness in dogs. The leukocyte adhesion molecule Mo1 (CD11b/CD18) is a heterodimeric glycoprotein the expression of which is necessary for neutrophil adhesion to endothelium. To evaluate the contribution of Mo1 to ozone-induced neutrophil influx and airway hyperresponsiveness, six dogs were treated intravenously with an Anti-Mo1 monoclonal antibody (3.75 mg/kg in normal saline) that binds to both human and canine Mo1, or the diluent alone, 1.5 h before inhaling ozone (3 ppm for 30 min), or dry air. Airway responses to doubling doses of inhaled acetylcholine (ACh) were measured before and after inhalation of ozone. Neutrophil influx was assessed by bronchoalveolar lavage (BAL) performed after the second ACh inhalation. Treatment with anti-Mo1 prevented the ozone-induced influx of neutrophils into BAL. After diluent and inhaled dry air, the neutrophil count in BAL was 1.49 +/- 1.26 (SE) x 10(4) (5.0% of total cells). After diluent and inhaled ozone, the neutrophil count increased to 7.27 +/- 3.22 (SE) x 10(4) (22.6% of total cells) (P < 0.05). After anti-Mo1 and inhaled ozone, the neutrophil count was 1.48 +/- 0.62 (SE) x 10(4) (8.5% of total cells). Treatment with anti-Mo1 also significantly reduced the number of eosinophils in BAL after ozone. Ozone-induced ACh airway hyperresponsiveness was not prevented by treatment with anti-Mo1. These results indicate that expression of Mo1 is necessary for ozone-induced neutrophil migration into the airway lumen.

The effect of amiloride on the airway response to metabisulphite in asthma: a negative report

Frusemide, a loop diuretic, has been shown to potently inhibit several indirect bronchoconstrictor challenges in asthma. The mechanism by which nebulized frusemide protects against indirect bronchoconstrictor stimuli in asthma is not known. One mechanism could be related to inhibition of sodium transport. If this is the case, then amiloride, another inhibitor of sodium transport, should also protect against indirect bronchoconstrictor challenges. Ten subjects with mild asthma were administered either 10(-2) M amiloride or placebo, by nebulizer, in a double-blind crossover fashion. After each inhalation, forced expiratory volume in one second (FEV1) was recorded at 10 min intervals for 30 min, after which a metabisulphite challenge was performed. No significant difference in the response to metabisulphite was seen between placebo and amiloride treatment. The mean difference in provocative dose of metabisulphite producing a 20% fall in FEV1 (PD20) between placebo and amiloride was 1.015 doubling doses, 95% confidence interval (95% CI) -0.201 to 2.231, (p = 0.09). This result does not support the hypothesis that frusemide is acting to protect against bronchoconstrictor challenges in asthma by an effect on sodium transport.

Inhaled beclomethasone improves the course of asthma and COPD

The effects of inhaled beclomethasone dipropionate (BDP), 800 micrograms daily, on the long-term course of asthma and chronic obstructive pulmonary disease (COPD) were investigated in a prospective, controlled study, over three years. During the first two years, patients were treated with a bronchodilator only (salbutamol or ipratropium bromide). Fifty six patients (28 asthma, 28 COPD), with an unfavourable course of disease during bronchodilator therapy alone (an annual decline in forced expiratory volume in one second (FEV1) of > or = 80 ml.yr-1 in combination with at least one exacerbation.yr-1), were selected for additional treatment with inhaled beclomethasone dipropionate (BDP), 800 micrograms daily, during the third year. The FEV1 and provoking concentration of histamine producing a 20% fall in FEV1 (PC20-histamine) were assessed at six-monthly intervals. In asthma, the annual decline in prebronchodilator FEV1 of -158 ml.yr-1 during bronchodilator therapy alone was followed by a significant increase of 562 ml.yr-1 during months 1-6 of BDP treatment (p < 0.0005). During months 7-12 of BDP, the FEV1 declined slightly with -31 ml.yr-1, which was not statistically different from the annual decline before steroid therapy (p = 0.17). In COPD, the increase of 323 ml.yr-1 during months 1-6 of treatment with BDP was different from the annual decline of -156 ml.yr-1 before BDP (p < 0.05). The PC20-histamine improved by 308 doubling doses during 1-12 months of BDP in asthma (p < 0.05) but not in COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Profile of bronchial responsiveness in children with respiratory symptoms.

A postal questionnaire inquiring into the presence of respiratory symptoms was sent to 3698 children aged 7 and 8 years. Those reporting either cough or wheeze were randomised, and a sample invited to attend for skin testing. A total of 192 symptomatic children, half of whom were atopic and half non-atopic, were randomly selected to enter the study. All children performed and recorded best of three peak expiratory flow measurements twice a day and completed a 10 point respiratory symptom score card each day for one year. They also recorded all treatment taken and made a note of relevant life events. Each child was seen monthly for general assessment and for measurement of nonspecific bronchial responsiveness to methacholine. Of the 192 children, 183 successfully completed the study. For six subjects 11 measurements of the provocation dose required to cause a 20% fall in forced expiratory volume in one second (PD20) were available for analysis and on the remaining 177, greater than or equal to 12 measurements. The prevalence and degree of bronchial hyper-responsiveness (PD20 less than 6.4 mumol) and its relationship to atopy was examined by comparing the percentage of members of each symptom group demonstrating bronchial hyper-responsiveness and the number of occasions on which they did so, and by comparison of minimum and median PD20 values. The range of bronchial responsiveness shown during the study period by each child was expressed as doubling doses of methacholine and compared between symptom groups. Atopy and wheeze were both independently associated with an increased prevalence and greater degree of bronchial hyper-responsiveness when compared with non-atopy and cough respectively, all differences being significant a the 0.001 level.. Thirty three per cent of subjects demonstrated a rnge of methacholine responsiveness of >4 and 13.4% of >6 doubling doses during one year.

Changes of nebulizer output over the years

The effects of long-term use and of cleaning on the output of 30 specimens of DeVilbiss 646 nebulizers were investigated in order to assess their influence on outcome and interpretation of inhalation provocation tests. Output was assessed in a standardized manner based on weight loss on four occasions one year apart. Output was highly reproducible (intraclass correlation greater than or equal to 0.90), and varied considerably between nebulizers, necessitating calibration at least once. Inadequate cleaning diminished nebulizer output by a factor of two (p less than 0.01), while long-term use was associated with a moderate increase in output of 0.28 mg.yr-1 (p less than 0.0001). Bronchial responsiveness can be underestimated by about one doubling dose due to inadequate cleaning, while interchanging nebulizers can lead to overestimation or underestimation by up to one doubling dose. With proper care the increase in output due to wear has no consequences for clinical practice, or for longitudinal studies.

Separate and combined effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness in asthma

We have investigated separate and interactive effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness. Twelve allergic subjects with asthma were treated in a double-blind, crossover, randomized study with budesonide, 1.6 mg daily for 3 weeks, prednisone, 40 mg daily, for 8 days, and placebo. After each period, dose-response curves were measured on 4 study days with doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo until a plateau in FEV 1 was reached. A histamine challenge was then performed, and the provocation concentration causing a 20% fall in FEV 1 (PC 20) was calculated. The budesonide and prednisone regimens were equipotent. FEV 1 was 81.2% of predicted after budesonide, 81.0% predicted after prednisone, and 67.5% predicted after placebo, bronchodilatation thus being 13.7% predicted (budesonide) and 13.5% predicted (prednisone). PC 20 improved with 2.17 doubling concentrations (DCs) after budesonide, and 1.86 DCs after prednisone, compared with that of placebo. Salbutamol caused stronger bronchodilatation than ipratropium (26.2% versus 14.7% predicted) and a better protection against histamine challenge (3.95 versus 1.12 DC). The effects of corticosteroids and bronchodilators on FEV 1 and PC 20 were, in general, additive. This study emphasizes different modes of action on both airflow obstruction and airway hyperresponsiveness by corticosteroids and bronchodilators, and it demonstrates no enhancement of bronchodilator action by corticosteroids.

A comparative study in atopic subjects with asthma of the effects of salmeterol and salbutamol on allergen-induced bronchoconstriction, increase in airway reactivity, and increase in urinary leukotriene E 4 excretion

Salmeterol (SM) is a novel β 2-adrenoceptor agonist with a duration of action in excess of 12 hours. Evidence from in vitro studies has also demonstrated that, unlike the short-acting β 2-agonists, such as salbutamol (SB), it may have some anti-inflammatory properties. With a randomized, double-blind, crossover design, we have compared the inhibitory effects of SM (50 μg) and SB (200 μg) delivered by metered-dose inhaler on allergen-induced bronchoconstriction, changes in airway reactivity, and urinary leukotriene (LT) E 4 excretion in 12 atopic subjects with mild asthma. The immediate bronchoconstriction to allergen was significantly reduced by both β 2-agonists ( p < 0.005), when reduction was expressed either in terms of maximum fall in FEV 1 at 15 minutes after allergen (percent fall in FEV 1, mean ± SEM: 6.2 ± 4.9, SM; 5.7 ± 2.5, SB; 40.4 ± 6.3, placebo) or the area under the FEV 1 time curve (AUC) for the first 120 minutes after allergen. Four hours after challenge, results in the SB-treated and placebo-treated groups were not significantly different and demonstrated a small persistent bronchoconstriction compared to bronchodilatation in the SM-treated group (percent fall in FEV 1, respectively, 9.3 ± 3.7, 14.3 ± 7.1, and −6.3 ± 2.7; p < 0.005, SM versus SB; p < 0.02, SM versus placebo). Expressed in terms of AUC, only SM significantly reduced bronchoconstriction in the period 120 to 240 minutes after allergen ( p < 0.01). The changes in airway reactivity 4 hours after allergen were (doubling doses of histamine, median, and range) −1.34 (−4.06 to 0.56) placebo; −0.20 (−3.29 to 1.14) SB; and 1.39 (−1.22 to 5.60) SM ( p < 0.005, SB and SM versus placebo; p < 0.005, SM versus SB). There were no differences between groups in urinary LTE 4 excretion for either the 0 to 120-, 120 to 240-, or total 0 to 240 minute collection periods after allergen inhalation ( p > 0.1). Therefore, although both drugs have inhibitory effects on allergen-induced bronchoconstriction, neither drug significantly reduced allergen-induced cysteinyl leukotriene production. This finding suggests that the major effect of inhaled β 2-agonists in allergen challenge is relaxation of airway smooth muscle and not the inhibition of mediator release from pulmonary inflammatory cells.

Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study.

To examine the effect of bronchodilator treatment given continuously versus on demand on the progression of asthma and chronic bronchitis and to compare the long term effects of a beta 2 adrenergic drug (salbutamol) and an anticholinergic drug (ipratropium bromide). Two year randomised controlled prospective 'crossover' study in which patients were assigned to one of two parallel treatment groups receiving continuous treatment or treatment on demand. 29 general practices in the catchment area of the University of Nijmegen. 223 patients aged greater than or equal to 30 with moderate airway obstruction due to asthma or chronic bronchitis, selected by their general practitioners. 1600 micrograms salbutamol or 160 micrograms ipratropium bromide daily (113 patients) or salbutamol or ipratropium bromide only during exacerbations or periods of dyspnoea (110). No other pulmonary treatment was permitted. Decline in ventilatory function and change in bronchial responsiveness, respiratory symptoms, number of exacerbations, and quality of life. Among 144 patients completing the study, after correction for possible confounding factors the decline in forced expiratory volume in one second was -0.072 l/year in continuously treated patients and -0.020 l/year in those treated on demand (p less than 0.05), irrespective of the drug. The difference in the decline in patients with asthma was comparable with that in patients with chronic bronchitis (asthma: 0.092 v -0.025 l/year; chronic bronchitis: -0.082 v -0.031 l/year). Bronchial responsiveness increased slightly (0.4 doubling dose) with continuous treatment in chronic bronchitis, but exacerbations, symptoms, and quality of life were unchanged. Salbutamol and ipratropium bromide had comparable effects on all variables investigated. Continuous bronchodilator treatment without anti-inflammatory treatment accelerates decline in ventilatory function. Bronchodilators should be used only on demand, with additional corticosteroid treatment, if necessary.

Paternal Exposure to Radiation and Offspring Cancer in Mice: Reanalysis and New Evidences

Parental exposure to radiation could induce various kinds of tumors in the next generation. In ICR mice, a large and significant increase of adult types tumor was observed in the F1 offspring after X-ray exposure at spermatozoa and spermatid stages, and less clear increase was observed after spermatogonial exposure. Mature oocytes were resistant upto 1 Gy, but very sensitive to tumor induction at higher doses. While there was no difference in the tumor incidence between acute and fractionated (0.36 Gy at 2 hr intervals) irradiation at post-gonial stages, a large reduction of tumor incidence was observed after spermatogonial and mature oocyte exposure, suggesting some repairs of X-ray damages in these germ cells. Acute lymphocytic leukemia was not induced in ICR and LT mice after spermatogonial exposure, while a large increase of adult type cancers was observed in F1 offspring. However, 1.9-3.2 fold and 4.5-7.4 fold increases of leukemia incidence were observed in ICR and LT mice, when spermatozoa stage was treated with the X-ray doses of 0.36-5.04 Gy and 3.6-5.04 Gy, respectively, indicating the large difference in the sensitivity of developing germ cells to leukemia induction by radiation in the F1 offspring. In contrast to ICR and LT mice, N5 strain developed about 10 or 18 times higher incidence of leukemia in the offspring after spermatogonial or spermatozoa exposure to 5.04 Gy of X-rays, respectively, showing a marked difference in the sensitivity to the leukemia induction by radiation between mouse strains. These differential sensitivities between germ cell stages and also between mouse strains reconcile the difference between two population studies in Hiroshima/Nagasaki and Sellafield. However, there were large diffirences in the doubling doses for leukemia induction between the mouse experiments and Sellafield study in human.