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Biomedical subjects

R J Hancox

Publications and source records attributed to R J Hancox.

At least 19 recordsLinked to original sources
PubMed2006

Watching television is associated with childhood obesity: but is it clinically important?

OBJECTIVE: To assess the impact of television viewing during childhood and adolescence on body mass index (BMI) in children up to the age of 15 years. DESIGN: Unselected birth cohort, assessed at birth and every 2 years from age 3 to 15 years. SUBJECTS: In all, 1037 individuals were assessed at age 3 years. At age 15 years, 976 (95% of living cohort) continued to participate. MEASUREMENTS: Parental estimates of weekday television viewing between age 5 and 11 years. Self-reports of television viewing at age 13 and 15 years. Weight and height were measured at each age to calculate BMI. RESULTS: BMI and prevalence of overweight at all ages were significantly associated with mean hours of television viewing reported in the assessments up to that age. These associations were stronger in girls than boys. The associations remained significant after adjusting for parental body mass indices and socio-economic status. CONCLUSION: Time spent watching television is a significant predictor of BMI and overweight in childhood. Although the effect size appears small, it is larger than the effect sizes commonly reported for nutritional intake and physical activity. Television viewing should be regarded as an important contributing factor to childhood obesity.

Adolescent↗
PubMed2004

Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults.

OBJECTIVE: This study sought to determine the relationship between levels of the inflammatory marker, C-reactive protein (CRP), cardiovascular risk factors and oral contraceptive use in young adults. DESIGN: Cross-sectional study of a community cohort. SUBJECTS: A total of 822 men and women aged 26 y. MEASUREMENTS: CRP, body mass index (BMI), blood pressure, lipid and lipoprotein levels, smoking status, socioeconomic status, health status, and hormonal contraceptive use in women. RESULTS: Multiple regression analysis showed that obesity was independently related to CRP with an increase in ratio CRP of 1.03 (95% CI 1.01, 1.05) for men and 1.07 (1.05, 1.09) for women associated with a 1 kg/m(2) increase in BMI. In women, combined oral contraceptive use was associated with a ratio change in CRP of 1.52 (1.27, 1.82) compared with nonusers. Other independent determinants of CRP in men and women were apolipoprotein B level, systolic blood pressure and apolipoprotein A1 in men. Univariate analysis showed that the relationship between CRP and BMI, systolic blood pressure and apolipoprotein B was significantly stronger in women than men. CONCLUSION: These findings suggest that obesity is associated with inflammation independent of other cardiovascular risk factors that may contribute to an increased risk for cardiovascular disease in men and women. Elevated CRP related to combined oral contraceptive use may influence the rate of cardiovascular events in young women.

Adult↗
PubMed2004

Relationship between socioeconomic status and asthma: a longitudinal cohort study.

BACKGROUND: There is conflicting information about the relationship between asthma and socioeconomic status, with different studies reporting no, positive, or inverse associations. Most of these studies have been cross sectional in design and have relied on subjective markers of asthma such as symptoms of wheeze. Many have been unable to control adequately for potential confounding factors. METHODS: We report a prospective cohort study of approximately 1000 individuals born in Dunedin, New Zealand in 1972-3. This sample has been assessed regularly throughout childhood and into adulthood, with detailed information collected on asthma symptoms, lung function, airway responsiveness, and atopy. The prevalence of these in relation to measures of socioeconomic status were analysed with and without controls for potential confounding influences including parental history of asthma, smoking, breast feeding, and birth order using cross sectional time series models. RESULTS: No consistent association was found between childhood or adult socioeconomic status and asthma prevalence, lung function, or airway responsiveness at any age. Having asthma made no difference to educational attainment or socioeconomic status by age 26. There were trends to increased atopy in children from higher socioeconomic status families consistent with previous reports. CONCLUSIONS: Socioeconomic status in childhood had no significant impact on the prevalence of asthma in this New Zealand born cohort. Generalisation of these results to other societies should be done with caution, but our results suggest that the previously reported associations may be due to confounding.

Adolescent↗
PubMed2003

Bronchodilator tolerance: the impact of increasing bronchoconstriction.

Chronic exposure to beta-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma. In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 microg q.i.d. or placebo given via Diskhaler for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV1) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 microg, 100 microg and 200 microg was inhaled at 0, 5, and 10 min. FEV1 was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)0-40 FEV1 were compared between treatments and by degree of bronchoconstriction. Regular salbutamol resulted in attenuation of the acute response to beta-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV1 of 0, 15 and 30%, the AUC0-40 FEV1 with salbutamol were 11.2, -14.6 and -35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC0-40 FEV1. Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance.

Acute Disease↗
PubMed2002

Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship.

Exhaled nitric oxide (eNO) is an easily measured marker of airway inflammation. This study was undertaken to evaluate the usefulness of serial eNO in investigating the dose-response relationship for inhaled beclomethasone (BDP), and to compare eNO with other markers of airway inflammation. Following withdrawal of inhaled corticosteroid (ICS) therapy, 65 patients entered a double-blind, parallel-group, placebo-controlled trial of 50, 100, 200 or 500 microg x BDP x day(-1) for eight weeks. eNO and spirometry were performed weekly and a hypertonic saline challenge with sputum induction was performed at the beginning and end of treatment. The relationship between the dose of ICS and changes in eNO and forced expiratory volume in one second (FEV1) was linear at 1 week and at the end of treatment. A linear dose-response relationship was also seen for sputum eosinophils. Changes in eNO correlated significantly with changes in sputum eosinophils. Changes in the provocative dose of saline causing a 15% fall in FEV1 saline did not differ across the treatment groups nor did they correlate with changes in other measurements. Exhaled nitric oxide may be used to assess the dose-response relationship for the anti-inflammatory effects of inhaled beclomethasone. The relationship found in this study was linear over the dose range 0-500 microg x day(-1) soon after commencing therapy and continued over time.

Administration, Inhalation↗
PubMed2001

The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control.

Exhaled nitric oxide (eNO) levels are increased in untreated or unstable asthma and measurements can be made easily. Our aim was to assess the usefulness of eNO for diagnosing and predicting loss of control (LOC) in asthma following steroid withdrawal. Comparisons were made against sputum eosinophils and airway hyperresponsiveness (AHR) to hypertonic saline (4.5%). Seventy-eight patients with mild/moderate asthma had their inhaled steroid therapy withdrawn until LOC occurred or for a maximum of 6 wk. Sixty (77.9%) developed LOC. There were highly significant correlations between the changes in eNO and symptoms (p < 0.0001), FEV(1) (p < 0.002), sputum eosinophils (p < 0.0002), and saline PD(15) (p < 0.0002), and there were significant differences between LOC and no LOC groups. Both single measurements and changes of eNO (10 ppb, 15 ppb, or an increase of > 60% over baseline) had positive predictive values that ranged from 80 to 90% for predicting and diagnosing LOC. These values were similar to those obtained using sputum eosinophils and saline PD(15) measurements. We conclude that eNO measurements are as useful as induced sputum analysis and AHR in assessing airway inflammation, with the advantage that they are easy to perform.

Adolescent↗
PubMed2001

Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol.

Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied. Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 microg b.i.d. or matching placebo was given for 10-14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 microg, 100 microg, and 200 microg was inhaled via a spacer at 5 min intervals, with a further 400 microg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry. Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0-15) and 45 (AUC0-45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration. It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.

Acute Disease↗
PubMed2001

Long-acting beta-agonist treatment in patients with persistent asthma already receiving inhaled corticosteroids.

International guidelines recommend that long-acting beta-agonists should be considered in patients who are symptomatic despite moderate doses of inhaled corticosteroids. When combined with inhaled corticosteroids they improve asthma symptoms and lung function and reduce exacerbations. The evidence suggests that they are well tolerated. However, they are less effective than inhaled corticosteroids as monotherapy and should not be used alone, although the addition of a long-acting beta-agonist may permit a small reduction in the corticosteroid dose. Both salmeterol and formoterol appear equally effective in improving asthma control. Formoterol, however, has a rapid onset of action and is now being promoted for the relief of acute asthma symptoms. Both drugs provide prolonged protection against exercise-induced bronchospasm. However, this effect rapidly diminishes with continuous therapy and if this is the main aim of treatment, intermittent use may be preferable. When compared with alternative treatments, inhaled long-acting beta-agonists are more effective in controlling asthma symptoms than either theophylline or antileukotriene agents. Bambuterol, an oral prodrug of terbutaline, appears to be as effective as the inhaled long-acting beta-agonists and has the advantage of once daily oral administration. However, the inhaled long-acting beta-agonists are less likely to have systemic adverse effects. There are theoretical concerns that regular beta-agonist treatment may lead to tolerance and a failure to respond to emergency asthma treatment. While there is no doubt that tolerance occurs, there is currently little evidence that this is a clinical problem. Insights into pharmacological as well as therapeutic interactions between inhaled corticosteroids and beta-agonists are providing justification for their use in combination. Guidelines for the management of patients with chronic persistent asthma are likely to require modification to reflect these developments.

Administration, Inhalation↗
PubMed2000

Home ventilation: the Green Lane Hospital experience.

AIMS: To describe the characteristics and outcomes of patients treated with domiciliary nocturnal support ventilation (NSV). METHODS: Case-note review of all patients treated with home NSV by Green Lane Hospital. RESULTS: 111 patients received home NSV between 1990 and 1999. 59 had respiratory failure due to obesity-hypoventilation syndrome (OHS), most of whom were Maori or Pacific Island people. Their mean BMI was 53 kg/m2. They frequently presented acutely, and often in extremis. After a median duration of 22 months treatment, 37 patients continued treatment. Four have died, but none from respiratory failure. Other causes of respiratory failure included: neuromuscular disease (26), kyphoscoliosis (19) and obstructive sleep apnoea (8). Patients who did not have OHS were mostly of New Zealand European ethnicity, required lower ventilation pressures than patients with OHS, and had better arterial blood gases on treatment. After a median follow-up of 35 months, however, fourteen have died. 33 continued on treatment. Both OHS and non-OHS patients had high deprivation scores according to NZdep96. This was most apparent for patients with OHS. CONCLUSIONS: OHS is an important cause of respiratory failure in New Zealand, particularly affecting Maori and Pacific people. The prognosis of OHS treated with NSV appears to be good despite significant co-morbidity.

Adult↗
PubMed2000

Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment.

There is uncertainty about the development of airway tolerance to beta-agonists and the phenomenon of rebound bronchoconstriction on beta-agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows. The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500-1000 microg four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed. Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23.1 l min(-1) (95% CI = 18.8, 27.4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19.2 and 13.41 min(-1) [increases of 25.0 and 17.31 min(-1) in comparison with the corresponding values during placebo (P<0.01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0.01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21.6 l min(-1) (P<0.05 compared to placebo). The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the beta-receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of beta-agonist treatment could conceivably lead to a deterioration in asthma control.

Administration, Inhalation↗
PubMed2000

Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism.

BACKGROUND: Polymorphisms of the beta(2) adrenoceptor influence receptor function in vitro and asthma phenotypes in vivo. However, their importance in determining responses to inhaled beta agonist treatment has not been clearly defined. METHODS: In a retrospective analysis of previously published data we have examined relationships between polymorphisms at codons 16 and 27 of the beta(2) adrenoceptor and clinical outcomes in a randomised, placebo controlled, crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma. Genotyping was obtained for positions 16 and 27 in 108 and 107 patients, respectively. For position 16, 17 patients (16%) were homozygous Arg-Arg, 40 (37%) were heterozygous Arg-Gly, and 51 (47%) were homozygous Gly-Gly. RESULTS: Within the homozygous Arg-16 group major exacerbations were more frequent during salbutamol treatment than with placebo (1.91 (95% CI 1.07 to 3.12) per year versus 0.81 (95% CI 0.28 to 1.66) per year; p = 0.005). No significant treatment related differences occurred for heterozygous Arg-Gly patients (salbutamol 0.11 (95% CI 0.01 to 0.40), placebo 0.54 (95% CI 0.26 to 1.00) exacerbations per year) or homozygous Gly-16 patients (salbutamol 0.38 (95% CI 0.17 to 0.73), placebo 0.30 (95% CI 0.12 to 0.61) exacerbations per year). No adverse changes occurred for any position 16 subgroup with salmeterol. There was no significant relationship between position 27 genotypes and treatment related outcomes. CONCLUSION: Homozygous Arg-16 patients are susceptible to clinically important increases in asthma exacerbations during chronic dosing with the short acting beta(2) agonist salbutamol.

Adolescent↗
PubMed2000

Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma.

Previous studies have shown that the regular administration of short acting beta-agonists can be associated with adverse effects on airway caliber and bronchial hyperresponsiveness (BHR) and that this may occur through a proinflammatory mechanism. The aim was to explore possible adverse effects of high-dose beta-agonist therapy and to assess any adverse interaction with corticosteroids. We undertook a randomized, crossover study to investigate the effects of 6 wk of treatment with regular terbutaline (1 mg four times a day), regular budesonide (400 microg twice a day), combined treatment, and placebo in subjects with mild to moderate asthma. Major endpoints were PD(15) saline, PD(20) methacholine, and induced sputum differential cell counts. Thirty-four subjects were randomized and 28 completed the study. PD(15) saline decreased on terbutaline alone compared with placebo treatment and on combined treatment compared with budesonide alone (mean fold decrease of 0.57 [95% CI = 0.36, 0.90] and 0.65 [95% CI = 0.43, 0.97], respectively). PD(20) methacholine was not affected by the use of terbutaline either alone or in combination with budesonide. The percentage of eosinophils in induced sputum increased during terbutaline treatment alone compared with placebo (median 8.3% versus 4.4%, p = 0.049). The addition of terbutaline to budesonide did not affect the percentage of eosinophils compared with budesonide treatment alone. These findings support the hypothesis that short-acting beta-agonists have a permissive effect on airway inflammation and that when used in high dose there may be an unfavorable interaction with inhaled corticosteroids.

Administration, Topical↗
PubMed2000

The influence of polymorphism at position 16 of the beta2-adrenoceptor on the development of tolerance to beta-agonist.

Polymorphism at position 16 of the beta2-adrenoceptor alters receptor down-regulation in vitro. Our aim was to compare the development of tolerance to beta-agonist in homozygous Gly-16 patients with patients harboring the "wild" genotype (homozygous Arg-16) during regular treatment with salmeterol. In a prospective, randomized, double-blind, placebo-controlled, cross-over study, 20 subjects with mild to moderate asthma (10 Gly-16, 10 Arg-16) received 2 weeks of treatment with inhaled salmeterol 100 microg b.i.d. Thereafter, dose responses to inhaled salbutamol were constructed for forced expiratory volume in 1 sec (FEV1), heart rate, QTc interval, serum potassium and glucose, and finger tremor. The protective effect of salbutamol against adenosine monophosphate (AMP) challenge was also measured. Salmeterol resulted in a significant reduction in the area under curve (AUC) for FEV1 (p = 0.01), heart rate (p = 0.01), QTc interval (p = 0.01), and tremor (p = 0.05), and in the maximum responses for FEV1 (p = 0.05), heart rate (p = 0.02), and glucose (p = 0.02). The protective effect of salbutamol against AMP was reduced by 3.61 doubling doses (p < 0.001). However, differences between Gly-16 and Arg-16 patients were small and nonsignificant. Thus, although tolerance is influenced in vitro by polymorphism of the beta2-adrenoceptor, the magnitude of between-genotype differences in vivo is unlikely to be significant.

Adrenergic beta-Agonists↗
PubMed1999

Tolerance to beta-agonists during acute bronchoconstriction.

Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction. Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 microg, b.i.d.), both drugs or placebo in a randomized, double-blind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 microg at 5 min intervals) was then measured. Dose-response curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates. There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide. Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations.

Acute Disease↗
PubMed1999

Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma.

BACKGROUND: Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken. METHODS: Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment. RESULTS: Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness. CONCLUSIONS: In this group of mild to moderate asthmatic subjects the combination of beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid.

Administration, Inhalation↗
PubMed1999

Effects of inhaled beta agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma.

BACKGROUND: Inhaled corticosteroids and beta agonists are the most commonly used treatments in asthma and are often used together. Recent evidence suggests that many of the anti-inflammatory actions of corticosteroids are mediated by cross-talk between the activated glucocorticoid receptor (GR) and other transcription factors such as the pro-inflammatory nuclear factor kappa B (NFkappaB). Beta agonists can activate the transcription factor cAMP response element binding protein (CREB). A mutual inhibition between GR and CREB occurs in vitro which raises the possibility of a negative interaction between corticosteroid and beta agonist drugs. A study was undertaken to determine whether these interactions occur during treatment with beta2 agonists and corticosteroids in asthma. METHODS: Seven subjects who were participating in a randomised, placebo controlled, crossover study of six weeks treatment with inhaled budesonide (400 microg twice daily), terbutaline (1 mg four times daily), and combined treatment were recruited. Biopsy samples of the bronchial mucosa were obtained after each treatment and analysed for the DNA binding activity of GR, CREB, and NFkappaB. RESULTS: Budesonide increased GR activity (p<0.05) and decreased NFkappaB activity (p<0.05). No treatment combination altered CREB activity and terbutaline had no significant effects on any transcription factor. CONCLUSIONS: Inhaled corticosteroids have significant effects on GR and NFkappaB activity in bronchial mucosa. A negative interaction between inhaled corticosteroids and beta agonists was not found.

Administration, Inhalation↗