Drugs acting on the respiratory tract

M. Joerger, K. Hartmann, and M. Kuhn

16

Drugs acting on the respiratory tract

INHALED GLUCOCORTICOIDS

(SEDA-28, 184; SEDA-29, 168; SEDA-30, 193)

The effects of inhaled glucocorticoids on hypothalamic– pituitary–adrenal axis function Adults Ciclesonide, a non-halogenated glucocorticoid, is a prodrug that is converted locally in the airways to produce the active metabolite, desisobutyrylciclesonide. The effect of inhaled ciclesonide on hypothalamic–pituitary–adrenal axis function in adults has been reviewed (1R); the data from four clinical trials suggest that ciclesonide (320–1280 mg/day) has no clinically relevant effect (2C,3C,4C,5c). These data suggest that the systemic availability of ciclesonide is very low and clinically unimportant over a wide dosage range. The systemic availability of ciclesonide and fluticasone propionate have been compared by studying their effects on hypothalamic–pituitary–adrenal axis function (6C). Ciclesonide is deposited in the lungs to a greater extent than fluticasone propionate (52% versus 12–13%), and with less oropharyngeal deposition. However, the results of studies with low or medium doses of fluticasone propionate are controversial; high doses (over 660 mg/day) clearly result in adrenal suppression (7C,8c). Ciclesonide had no significant effect on adrenal Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03116-X r 2009 Elsevier B.V. All rights reserved.

suppression up to daily doses of 1280 mg (2C,5c,9C,10c). The pharmacokinetics of ciclesonide, with its high pulmonary deposition, high plasma protein binding, and rapid clearance, result in a markedly reduced potential for adrenal suppression (6C). The effects of ciclesonide 80 or 320 mg/day and budesonide 200 mg bd have been studied for 12 weeks in 554 asthmatic patients in a randomized multicenter European study; ciclesonide was not associated with adrenal suppression (11C). Mean urinary cortisol excretion was similar to baseline at week 12 with both doses of ciclesonide, but was significantly reduced from baseline with budesonide. These data suggest that therapeutic doses of ciclesonide do not induce adrenal suppression, whereas budesonide 200 mg bd causes potentially clinically relevant adrenal suppression. A meta-analysis of five placebo-controlled, randomized, dose–response studies of at least 4 weeks duration in 732 adult asthmatic patients was performed to assess the effect of fluticasone propionate on adrenal function (12M,13c,14C,15C,16C). The proportion of subjects on placebo with adrenal function below the lower limit of normal, assessed by a cosyntropin stimulation test, was 3.9%. The odds of impaired adrenal function increased by 1.38 (95% CI ¼ 1.01, 1.59) with fluticasone propionate 500 mg/day compared with placebo. However, in the recommended dosage range of 50–500 mg/day, fluticasone propionate had only minimal effects on adrenal function. As none of the studies assessed adrenal effects after more than 3 months, no conclusions on long-term effects can be drawn. As a note of caution, there are only limited data for daily doses of fluticasone propionate over 500 mg, as only two of the five studies included such information (13c,15C).

305

306

Chapter 16

Children The effect of inhaled budesonide on hypothalamic–pituitary–adrenal axis function and skeletal growth has been evaluated in a cross-sectional comparison of 30 controls and 72 asthmatic children, median age 9.4 years who took inhaled budesonide, median daily dose 363 mg, for a median of 18 months (17c). Although there was a significant negative correlation between height standard deviation score and dose of inhaled budesonide, there was a positive correlation between the height velocity standard deviation score and the duration of treatment. This suggests that the negative effect of inhaled budesonide on skeletal growth abates with longer duration of treatment. In a randomized, double-blind comparison of ciclesonide 160 mg/day and fluticasone propionate 88 mg bd for 12 weeks in 556 asthmatic children aged 6–15 years, creatinine-adjusted 24-hour urine cortisol excretion increased from baseline in both groups, by 10% with ciclesonide and by 6% with fluticasone propionate (18C). These results suggest similar systemic availability of the two compounds. Only two patients who took fluticasone propionate had oral candidiasis and one had voice alteration. In a double-blind, placebo-controlled study in 1310 asthmatic children aged 4–11 years, once-daily inhaled ciclesonide 40, 80, and 160 mg caused no significant adrenal suppression, as measured by 24-hour urine cortisol excretion (19C). The discontinuation rates due to treatment-related adverse events were 6.3–8.6% for ciclesonide and 13% for placebo. There were two cases of subcapsular lens opacities in those who used ciclesonide, possibly treatment related. A new laboratory tool with very high sensitivity and specificity for quantifying adrenal function in children taking inhaled glucocorticoids has been described, involving the use of dehydroepiandrosterone sulfate, the corticotropin-dependent adrenal androgen precursor, as a marker (20E).

Musculoskeletal When selecting an inhaled glucocorticoid for childhood asthma, the benefit to harm balance has to

M. Joerger, K. Hartmann, and M. Kuhn

be assessed carefully, the lowest effective dose should be used, and growth should be monitored regularly (21C). In a double-blind, placebo-controlled study, 229 children aged 4–8 years with perennial moderate-to-severe allergic rhini­ tis were randomized to budesonide aqueous nasal spray 64 mg/day or placebo for 1 year to assess growth velocity (22C). There was no difference between the two groups, and this was supported by determination of the 24-hour urinary cortisol:creatinine ratio at baseline and after 1 year. However, there was a small difference in the 1-year growth velocity of 0.27 cm/year in favor of the placebo group (95% CI ¼ –0.07, 0.62 cm/ year), and the authors suggested that some individuals are more susceptible to growth suppression when exposed to inhaled or nasal corticosteroids. The effects of fluticasone propionate and budesonide on relative growth velocity have been compared in a randomized, double-blind study in children aged 6–9 years with persistent asthma (21C). They were randomized for 12 months to either fluticasone propionate 100 mg bd (n ¼ 114) or budesonide 200 mg bd (n ¼ 119). Adjusted mean growth velocity was sig­ nificantly greater with fluticasone propio­ nate than budesonide (5.5 cm/year versus 4.6 cm/year), although the overnight urin­ ary coritsol:creatinine ratio and bone mineral density were similar. In a double-blind, randomized, placebocontrolled study in 332 asthmatic children aged 24–47 months, fluticasone propionate 44 or 88 mg bd for 12 weeks had no effect on growth velocity or 12-hour overnight urinary cortisol excretion (16C). There were similar results in 359 asthmatic children aged 1–4 years randomized to fluticasone propionate 88 mg bd or placebo for 12 weeks (23C). In 24 asthmatic children randomized to beclomethasone dipropionate 100 mg bd or budesonide 100 or 200 mg bd in a doubleblind crossover study, lower leg growth rate over 3 months did not differ between the groups (24c). This observation was corroborated by comparable adrenal func­ tion, assessed by 24-hour urinary cortisol excretion.

Drugs acting on the respiratory tract

Chapter 16

Linear growth has been evaluated in a double-blind study in 360 asthmatic chil­ dren aged 6.4–9.4 years, randomized in equal ratios to beclomethasone 200 mg bd, montelukast 5 mg/day, or placebo for 56 weeks (25C). Mean growth rate was sig­ nificantly lower with beclomethasone than placebo (–0.78 cm; 95% CI ¼ –1.06, –0.49) or montelukast (–0.81 cm). There was an imbalance in bone markers with beclo­ methasone but not montelukast. This study strongly suggests that linear growth is suppressed by beclomethasone 200 mg bd in prepubertal children.

Inhaled glucocorticoids and the risk of fracture

DoTS classification: Reaction: osteoporosis from inhaled glucocorticoids Dose relation: collateral reaction Time course: late Susceptibility factors: elderly patients, female sex (postmenopausal) Until recently, no prospective studies have been large enough or performed for long enough to evaluate adequately the correlation between inhaled glucocorticoids and the risk of fracture (26R). Two large cohort studies have used the UK General Practice Research Database (GPRD) (27c,28c) to address this question, and a third used a Canadian population database (29c). The first UK case–control analysis of 16341 cases (users of inhaled glucocorticoids) and 29889 controls over a mean period of 2.7 years showed an increased risk of hip fractures with the use of inhaled glucocorticoids (OR ¼ 1.19; 95% CI ¼ 1.10, 1.28) after adjusting for the use of oral glucocorticoids (28c). Similarly, in 170818 users of inhaled glucocorticoids compared with 170818 controls there was an increased risk of hip fractures (1.22; 1.04, 1.43), vertebral fractures (1.51; 1.22, 1.85), and non-vertebral fractures (1.15; 1.10, 1.20) (29c). However, the risk of

307 fractures was also increased in 108786 users of bronchodilators compared with controls, suggesting that excess fractures were more likely to be related to the underlying respiratory disease than to the use of inhaled glucocorticoids. In the Canadian study there was no increased risk of upper limb fractures in elderly patients (over 65 years) at daily doses of under 1000 mg of inhaled glucocorticoid in beclomethasone-equivalent units, but there was a dose-related increase in the risk of fractures with daily doses over 1000 mg (29c). The Canadian study compared 133026 elderly patients (65 years and over) using inhaled or nasal glucocorticoids, recruited in 1988–2001, with 191622 controls recruited over at least 4 years. Overall, there were 3326 cases of hip fractures and 6298 cases of upper limb fractures. Although the relative risk was small and the relative risks of the different glucocorticoids remained unclear, these cohort studies provide some evidence that the use of inhaled corticosteroids is associated with a dose-related increase in the risk of fracture. To test the hypothesis of a disease-related increase in the systemic absorption of inhaled glucocorticoids and subsequent bone damage, a large case–control study using data from the GPRD was conducted. Both cases and controls had a history of obstructive airway disease, and each of the 108754 cases was matched with one control patient without a history of a fracture (30C). Higher doses of inhaled glucocorticoids were associated with an increased risk of fracture (OR ¼ 1.95; 95% CI ¼ 1.68, 2.27 in patients exposed to over 1600 mg beclomethasone equivalents per day). However, adjustment for disease severity and bronchodilator use almost completely removed the relationship (OR ¼ 1.19; 95% CI ¼ 1.01, 1.41). In a cohort study of 1671 elderly patients (75 years and over, mean 81; mean time of follow-up 9.4 years) with airflow obstruction, 982 (59%) received a prescription for an inhaled glucocorticoid and 187 patients had a fracture (31C). After adjusting for the effects of age and sex, there was a doserelated increase in fracture risk (OR for a mean daily dose over 601 mg ¼ 2.53; 95%

308

Chapter 16

CI ¼ 1.65, 3.89). The results remained significant after adjusting for oral glucocorticoid exposure, airflow obstruction, historical fracture, and bronchodilator use, and also in the subset of patients with no exposure to oral glucocorticoids (rate ratio ¼ 4.54; 95% CI ¼ 1.23, 17). This large cohort study provides some evidence that inhaled glucocorticoids are an independent susceptibility factor for fractures. However, the fact that most patients used beclomethasone dipropionate (n ¼ 722) and only a few used budesonide (n ¼ 102), might have biased the results, as beclomethasone dipropionate has higher systemic availability than budesonide. The risk of fractures with the use of inhaled glucocorticoids has been assessed in children and adolescents in a cohort study of 3744 patients aged 5–17 years with a fracture and 21757 matched controls using data from the GPRD (32C). Current exposure to inhaled glucocorticoids did not show a substantially altered risk of fracture compared with non-users, even after longterm use (OR ¼ 1.15; 95% CI ¼ 0.89, 1.48). Even current or previous exposure to oral glucocorticoids was not associated with an increased risk of fractures (OR ¼ 1.21; 95% CI ¼ 0.99, 1.49). It can be speculated that in this age group, osteoporosis is of minor etiological importance for bone fractures. Another confounder is increased physical activity in asthmatic children and adults who use inhaled glucocorticoids, which results in increased bone mineral density and a lower risk of fractures.

BETA2-ADRENOCEPTOR AGONISTS (SEDA-28, 188; SEDA-29, 171; SEDA-30, 198)

Comparative studies In the multicenter, double-blind, randomized EXCEL study, salmeterol+fluticasone propionate 50/250 mg bd was compared with formoterol+budeso­ nide 12/400 mg bd in 694 patients with persistent asthma (33C). The incidences and

M. Joerger, K. Hartmann, and M. Kuhn

types of adverse events were similar in the two groups. The most commonly reported treatment-related adverse events were hoarseness/dysphonia (2% in each group), candidiasis of the mouth or throat (2% with salmeterol+fluticasone propionate, 1% with formoterol+budesonide), and headache (1% with salmeterol+fluticasone propionate, 2% with formoterol+budesonide). There were no deaths and only a few patients reported serious adverse events.

Cardiovascular Beta1- and beta2-adreno­ ceptors co-exist in the heart in a ratio of 3:1 (34R), and beta2-adrenoceptor agonists have direct effects on the heart. Cardiovas­ cular adverse effects, such as heart failure and dysrhythmias, are more frequent in patients with chronic obstructive pulmonary disease (COPD) than in the general popu­ lation, and such patients have a higher risk of hospitalization and death because of these conditions (35C,36C). In a randomized, placebo-controlled study of the cardiac safety of formoterol 12 mg bd for 8 weeks in 204 patients with COPD, 24-hour continuous electrocardio­ graphy (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment (37C). Only six patients (four taking formoterol and two taking placebo) had a predefined, prodysrhythmic event. Holter monitoring showed no significant differences between formoterol and pla­ cebo, for variables such as heart rate, number and rate of ventricular extra beats, ventricular tachycardia events, and supra­ ventricular extra beats. Corrected QT intervals were similar. Cardiovascular adverse events were recorded in one patient taking formoterol (atrial flutter) and four taking placebo (atrioventricular block, palpitation, sinus bradycardia, supraventricular tachycardia). Hyperten­ sion was reported in one patient taking placebo. There were no important differ­ ences between the groups in overall adverse events. Although the results of this study are reassuring, larger studies providing more robust statistical power are required to assess the full benefit to harm

Drugs acting on the respiratory tract

Chapter 16

balance of formoterol in this patient population.

Respiratory adverse effects of long-acting beta2-adrenoceptor agonists The overall safety of long-acting beta2adrenoceptor agonists was reviewed in SEDA-30 (p. 198). Recently, several authors have questioned the long-term safety of these agents (38R,39C,40M,41r). In a meta-analysis of 19 trials in 33826 patients with asthma, long-acting beta2adrenoceptor agonists increased exacerbations of asthma that required hospitalization (OR ¼ 2.6; 95% CI ¼ 1.6, 4.3) and life-threatening exacerbations (OR ¼ 1.8; 95% CI ¼ 1.1, 3.9) compared with placebo (40M,42r). The risk of asthma-related death was increased (OR ¼ 3.5; 95% CI ¼ 1.3, 9.3), with a pooled risk difference of 0.07% (95% CI ¼ 0.01, 0.1) over 6 months, using the placebo group of the SMART-study as a reference. Asthma-related hospitalization was more frequent in patients who used salmeterol (OR ¼ 1.7; 95% CI ¼ 1.1, 2.7) or formoterol (OR ¼ 3.2; 95% CI ¼ 1.7, 6.0), and in both adults (OR ¼ 2.0; 95% CI ¼ 1.1, 3.9) and children (OR ¼ 3.9; 95% CI ¼ 1.7, 8.8). Of the 19 studies, 14 contained data on asthma-related deaths. Inhaled glucocorticoids were used in 54% of the patients who used long-acting beta2adrenoceptor agonists and in 53% of those who used placebo. As a note of caution, the SMART study contributed largely to this meta-analysis, and thus introduced potential bias. This meta-analysis had several limitations, owing to the high number of excluded studies, heterogeneity of asthma severity between studies, co-medication, especially with inhaled glucocorticoids, and treatment compliance (42r). In summary, this meta-analysis has provided evidence that regular treatment with long-acting beta2-adrenoceptor agonists is associated with an increased risk of severe asthma exacerbations and of death from asthma in a small but relevant subgroup of patients.

309 The limitations of the studies that have been conducted so far preclude definitive conclusions about the potential of inhaled glucocorticoids to limit or prevent these adverse outcomes. Salmeterol The double-blind, randomized British Salmeterol Nationwide Surveillance study (SNS) compared salmeterol 50 mg bd and salbutamol 200 mg qd over 16 weeks in 25180 patients with asthma in addition to their usual treatment (43C). Life-threatening, asthma-related events were less frequent with salmeterol (9.9%) than with salbutamol (11.6%); however, combined respiratory- and asthma-related mortality was higher with salmeterol (0.07%) than with salbutamol (0.02%), although this difference did not reach statistical significance. Subsequently, the large randomized, double-blind, placebo-controlled Salmeterol Multicenter Asthma Research Trial was (SMART) (38R,39C,44r,45r,46r) designed to clarify the observation of excess asthma-related mortality in patients using salmeterol. This study compared salmeterol 42 mg bd and placebo added to usual asthma care in 26355 patients over 28 weeks (39C). The primary end-point was a comparison of respiratory-related death or life-threatening experiences. In those who used salmeterol there was a small but significant increase in respiratory-related deaths (24 versus 11; RR ¼ 2.16; 95% CI ¼ 1.06, 4.41) and asthma-related deaths (13 versus 3; RR ¼ 4.37; 95% CI ¼ 1.25, 15.34), and in combined asthma-related deaths or life-threatening experiences (37 versus 22; RR ¼ 1.71; 95% CI ¼ 1.01, 2.89). A retrospective subgroup analysis showed no significant differences in respiratory-related deaths or life-threatening experiences in Caucasian patients. AfroAmerican patients had a significantly increased risk of respiratory-related death or life-threatening experiences (RR ¼ 2.8; 95% CI ¼ 1.18, 6.61) and asthma-related death or life-threatening experiences (RR ¼ 4.65; 95% CI ¼ 1.58, 14). Patients who used salmeterol without inhaled glucocorticoids (53% of all patients) had a higher asthma-related mortality than those

310

Chapter 16

who used concurrent inhaled glucocorticoids (9 versus 0 patients). It is unclear whether the concurrent use of inhaled glucocorticoids together with salmeterol protects patients from harmful effects (47R). Asthma-related life-threatening experiences have also been described after the concurrent use of salmeterol and inhaled glucocorticoids (48r). The inferior outcome in Afro-American patients with asthma receiving salmeterol, as described in the SMART study, may have resulted from interethnic differences in the pharmacogenetic characteristics of the beta2-adrenoceptor (49C). Formoterol There have been three prospective, randomized, placebo-controlled, double-blind pivotal trials of formoterol 12 and 24 mg bd in patients with asthma (50C). Patients who used regular formoterol 24 mg bd had more serious asthma exacerbations than patients who used placebo. In the first study, four (3%) of 135 adults who used formoterol 24 mg bd had serious asthma exacerbations compared with none of the 136 placebo-treated patients (51C). In the second study, five (3.7%) of 136 patients who used formoterol 24 mg bd had serious asthma exacerbations compared with two (1.4%) of 141 placebo-treated patients. In the third study, 11 (6.4%) of 171 children who used formoterol 24 mg bd had serious asthma exacerbations compared with none of the 176 placebo-treated patients (52C). In a post-approval, placebo-controlled, parallel-group, multicenter safety study, 2085 asthma patients were randomized for 16 weeks to formoterol 12 mg bd, formoterol 12 mg bd plus up to 24 mg/day on demand, formoterol 24 mg twice daily, or placebo; there were serious respiratory events in 0.9%, 0.4%, 0.2%, and 0.2% respectively; there were serious asthma exacerbations in 5.9%, 4.4%, 6.3%, and 8.8% (53C). There was no association between high-dose formoterol (24 mg bd) and serious asthma exacerbations. The study had 80% power to detect a 3% difference of serious asthma exacerbations between the groups. In conclusion, to avoid the risk of serious asthma exacerbations, patients with asthma

M. Joerger, K. Hartmann, and M. Kuhn

should not regularly use more than 48 mg of formoterol per day.

Genetic susceptibility factors with the therapeutic use of long-acting beta2-adrenoceptor agonists Data on the relation between beta2-adrenoceptor genotypes and salbutamol treatment were reviewed in SEDA-29 (p. 173) and SEDA-30 (p. 199). New data on the effect of the arginine-16 (Arg16) beta2-adrenoceptor polymorphism on the course of asthma in young patients and on airway hyper-responsiveness in healthy Japanese subjects have since been published. In the first study, a cross-sectional survey, the variants at positions 16 and 27 of the beta2-adrenoceptor gene were determined in 546 children and young asthmatics; the primary outcome measure was asthma exacerbations over the previous 6 months (54C). There was a significantly increased risk of asthma exacerbations when the homozygous genotypes Arg/Arg and Gly/Gly were compared (OR ¼ 2.05; 95% CI ¼ 1.19, 3.53), particularly in patients who had been exposed to salmeterol (OR ¼ 3.40; 95% CI ¼ 1.19, 9.40). Thus, the Arg16 variant of the beta2-adrenoceptor predisposes to exacerbations in asthmatic children and young adults, especially in those exposed to regular salmeterol. This could be explained by genotype-selective down-regulation and impaired receptor coupling by regular salmeterol, and is in agreement with previous studies that showed clinically important increases in asthma exacerbations in homozygous arginine-16 asthmatic patients taking regular salbutamol compared with nonhomozygous patients (55C,56C). This is further in agreement with a more recent retrospective meta-analysis of two randomized, double-blind, placebo-controlled studies that showed no response in salmeterol-treated patients homozygous for Arg16 compared with patients homozygous for Gly16, independent of the additional use of inhaled glucocorticoids (49C).

Drugs acting on the respiratory tract

311

Chapter 16

However, in another randomized, placebo-controlled study there was no effect of the beta2-adrenoceptor Arg16Gly genotype on treatment response in 183 asthmatic patients who used salmeterol 50 mg bd+fluticasone propionate 100 mg or daily montelukast 10 mg for 12 weeks (57C). Even in the run-out period, all the subjects had similar reductions in measures of asthma control, with no differences between beta2-adrenoceptor genotypes. This might be explained by the fact that this analysis did not evaluate the effect of salmeterol as monotherapy, but concurrently with fluticasone propionate. However, salmeterol as a single agent is not recommended in asthmatic patients. In a study of the association between nonspecific airway hyper-responsiveness and the beta2-adrenoceptor polymorphism at position 16 in 120 asymptomatic healthy Japanese subjects those who carried the Gly16 allele were significantly more responsive to methacholine than those who carried the Arg16 allele (58C). These results are in agreement with a comprehensive meta-analysis of 28 previously published genetic studies that showed a strong association between the Gly16 allele and nocturnal asthma and asthma severity (59M). Overall, the cumulative data suggest that the beta2-adrenoceptor variant at position 16 has a significant impact on airway hyperresponsiveness in individuals who have not been exposed to beta2-adrenoceptor agonists and on beta2-adrenoceptor down-regulation in asthmatic individuals exposed to beta2adrenoceptor agonists. Prospective studies on the safety and activity of beta2-adrenoceptor agonists in patients who carry the Arg16 allele should clarify the latter.

Dosage regimens High-dose formoterol and salbutamol The safety and tolerabil­ ity of high-dose formoterol and salbutamol has been assessed in a two-way, crossover, double-blind study in 17 adults with mild­ to-moderate COPD, randomized to either formoterol 24 mg or salbutamol 600 mg (60c). The treatment was switched after washout for 4–7 days. High-dose formoterol and

salbutamol were equally well tolerated, with no reports of serious adverse events. Both were associated with hypokalemia (mean minimum values 3.4 and 3.3 mmol/l respectively), hyperglycemia (mean maxi­ mum values 9.0 and 8.7 mmol/l), and small increases in mean QTc interval (mean maximum 439 ms with both). There were no relevant between-treatment differences in adverse events or laboratory values. However, the study was very small (n ¼ 17), and conclusions should be made with caution. Furthermore, extrapulmonary adverse events were monitored only up to 3 hours after the dose, despite the fact that formoterol has a considerably longer dura­ tion of action than salbutamol. Combined salmeterol and fluticasone propionate In a randomized, double-blind placebo-controlled comparison of salme­ terol 50 mg bd alone, or fluticasone propio­ nate 500 mg bd alone or the combination in a single inhaler, for 3 years in 6112 patients with COPD, the hazard ratio for death with the combination compared with placebo was 0.825 (95% CI ¼ 0.68, 1.0), corre­ sponding to a difference of 2.6% or an 18% reduction in the risk of death. There was no significant difference in the prob­ ability of fractures (6.3% with the combina­ tion, 5.1% with placebo, 5.1% with salmeterol, and 5.4% with fluticasone) (61C). There was no excess of cardiac disorders in patients treated with the combination or salmeterol alone, and there were no significant differences in bone mineral density or cataracts between the groups.

ANTICHOLINERGIC DRUGS (SEDA-28, 190; SEDA-29, 174; SEDA-30, 203)

Tiotropium bromide

(SEDA-28, 190; SEDA-29, 174; SEDA-30, 203) Inhaled ipratropium bromide has gained widespread acceptance in the treatment of

312

Chapter 16

COPD. Common recognized unwanted effects include urinary retention, dry mouth, constipation, tachycardia, palpitation, and narrow-angle glaucoma. In an analysis of pooled adverse event data from 19 randomized, double-blind, placebo-con­ trolled trials in 4435 patients who used tiotropium bromide and 3384 who used placebo, contributing to 2159 person-years of exposure to tiotropium bromide and 1662 person-years of exposure to placebo, dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported adverse events (62C). There was a higher relative risk of dry mouth (RR ¼ 3.60; 95% CI ¼ 2.56, 5.05) and a lower relative risk of dyspnea (RR ¼ 0.64; 95% CI ¼ 0.50, 0.81) and COPD exacerbation (RR ¼ 0.72; 95% CI ¼ 0.64, 0.82) with tiotropium. Allcause mortality (RR ¼ 0.76; 95% CI ¼ 0.50, 1.16), cardiovascular mortality including myocardial infarction and cardiac arrest (RR ¼ 0.57; 95% CI ¼ 0.26, 1.26), and respiratory mortality (RR ¼ 0.71; 95% CI ¼ 0.29, 1.74) were not over-represented in those who used tiotropium bromide. However, urinary retention was signifi­ cantly more frequent in the patients who used tiotropium bromide (RR ¼ 11; 95% CI ¼ 1.26, 95). The results of this analysis support the current safety profile of tiotropium, dry mouth and urinary reten­ tion being the most frequent adverse events. A meta-analysis of comparisons of tio­ tropium bromide with placebo, ipratropium bromide, or long-acting beta2-adrenoceptor agonists over at least 12 weeks nine clinical trials in a total of 8002 patients were included (63C). Dry mouth was significantly more common with tiotropium bromide than placebo (OR ¼ 4.6; 95% CI ¼ 3.0, 7.1), ipratropium (OR ¼ 2.1; 95% CI ¼ 1.05, 4.2), and salmeterol (OR ¼ 4.7; 95% CI ¼ 2.4, 9.2); urinary retention was more common with tiotropium bromide than placebo (OR ¼ 2.5; 95% CI ¼ 0.5, 14) and salmeterol (OR ¼ 3.0; 95% CI ¼ 0.1, 75), but not significantly so, and no comparative data were available for ipratropium. There was also a consistent but statistically insignificant increase in

M. Joerger, K. Hartmann, and M. Kuhn

constipation in patients who took tiotro­ pium compared with placebo. The results of this meta-analysis were in agreement with the data from a pooled clinical trial analysis (63C).

LEUKOTRIENE MODIFIERS (SEDA-28, 191; SEDA-29, 174; SEDA-30, 203)

Montelukast Musculoskeletal Linear growth has been evaluated in a double-blind study in 360 asthmatic children aged 6.4–9.4 years, randomized in equal ratios to beclomethasone 200 mg bd, montelukast 5 mg/day, or placebo for 56 weeks (25C). Mean growth rate was significantly lower with beclomethasone than placebo (–0.78 cm; 95% CI ¼ –1.06, –0.49) or montelukast (–0.81 cm). There was an imbalance in bone markers with beclomethasone but not montelukast. Montelukast should be considered for prepubertal asthmatic children, as it is effective in controlling multiple aspects of mild-to-moderate chronic asthma in children and adults (64C). Susceptibility factors Adults Montelu­ kast 10 mg/day was well tolerated in a multicenter phase IV study in 6158 patients with both asthma and allergic rhinitis over 4–6 weeks (65C). There were 21 treatmentrelated adverse events in 14 patients (0.23%), of which headache, gastrointest­ inal infections, and sleepiness were the most common; none was serious. Children The safety of montelukast has been studied in an open, non-comparative, prospective, 12-month trial in 50 children (mean age 5.4 years) with mild persistent asthma (66c). Patients aged 2–4 years received montelukast 4 mg/day and patients over 4 years 5 mg/day for 12 weeks. Of the 50 children, 19 had mild adverse effects, such as loss of appetite (16%), raised liver function tests (18%), and headache (10%).

Drugs acting on the respiratory tract

313

Chapter 16

None of these mild adverse events required withdrawal. The effect of montelukast 5 mg/day for 4 weeks in exercise-induced bronchocon­ striction has been studied in a double-blind, randomized, placebo-controlled trial in 32 asthmatic children aged 6–12 years (67c). Montelukast was significantly more protective than placebo against exerciseinduced bronchoconstriction after 3, 7, and 28 days, and there was no significant difference in the percentage fall in FEV1 between different days. These data provide reassurance that montelukast does not lead to tolerance to the bronchoprotective effect in children with mild persistent asthma.

PHOSPHODIESTERASE TYPE IV INHIBITORS Phosphodiesterase type IV is a major reg­ ulator of cyclic adenosine monophosphate metabolism in many cell types, including smooth muscle, proinflammatory calls, and immune cells (68R). Inhibitors of phospho­ diesterase type IV inhibit the synthesis of tumor necrosis factor alpha in monocytes, monocyte-derived dendritic cells, and macrophages and inhibit CD4+ T cell pro­ liferation and production of cytokines (e.g., interleukin 2 and interleukin 4), leukotriene B4 synthesis, and the formation of reactive oxygen species (69R). In early preclinical and clinical studies inhibition of phosphodiester­ ase type IV resulted in bronchodilatation, neuromodulation, and reduced numbers and activation of inflammatory cells relevant to obstructive lung disease (70E).

Cilomilast Cilomilast is an orally active, potent, selective inhibitor of phosphodiesterase type IV. Gastrointestinal The safety of cilomilast has been assessed in a randomized,

double-blind, placebo-controlled study in 647 patients with COPD, who were rando­ mized to oral cilomilast 15 mg bd or placebo for 24 weeks (71C). The numbers of adverse events that led to withdrawal were similar in the two groups (placebo 16%, cilomilast 22%). Similar proportions of subjects in each group had at least one adverse event (cilomilast 87%, placebo 82%). A higher proportion of those who received cilomilast had gastrointestinal adverse events (e.g., diarrhea, nausea, abdominal pain) com­ pared with placebo (49% versus 25%), but there was a higher proportion of serious gastrointestinal adverse events in patients who took placebo compared with cilomilast (1.9% versus 0.2%). Gastrointestinal events that interfered with daily activities were reported more often after cilomilast than placebo (17% versus 8% respectively). There were no clinically relevant cardio­ vascular adverse events.

Roflumilast Roflumilast, an oral inhibitor of phospho­ diesterase type IV, has anti-inflammatory activity and a pharmacokinetic profile that favors once-daily dosing. A dose of 500 mg/ day reduced exercise-induced asthma and attenuated allergen-induced asthmatic reac­ tions (72c). Dose-ranging studies In a randomized, double-blind phase 2/3 study of roflumilast 100, 250, or 500 mg/day for 12 weeks in 693 patients with mild-to-moderate asthma, 57% of the patients taking 500 mg/day, 48% of those taking 250 mg/day, and 46% of those taking 100 mg/day had adverse events (73C). Most of the adverse events that were considered to be treatmentrelated were mild to moderate and resolved spontaneously with continued treatment. All serious adverse events (18 cases in 693 patients) were considered by the investigator to be unrelated or probably not related to roflumilast. The most fre­ quently reported treatment-related adverse events were headache, diarrhea, and nausea, which were more common in patients who

314

Chapter 16

took roflumilast 500 mg/day. Most episodes of headache, diarrhea, and nausea occurred within the first week of treatment (53%, 65%, and 75% of events respectively) and lasted for less than 2 weeks in 79%, 83%, and 75% of events respectively. There were no clinically relevant changes in routine laboratory parameters. Comparative studies Roflumilast 500 mg/ day and beclomethasone dipropionate 200 mg bd for 12 weeks have been compared in 499 patients with persistent asthma in a double-blind, randomized, non-inferiority study (74C). The most frequent adverse events were worsening asthma (9%) and nausea (6%) with roflumilast and worsening asthma (4%) and upper respiratory tract infections (4%) with beclomethasone dipro­ pionate. Most of the adverse events were mild to moderate in intensity. All the serious adverse events (1% in each group) were considered to be unrelated to the treatment. Placebo-controlled studies The safety of roflumilast 250 and 500 mg/day for 24 weeks has been assessed in 1411 patients with COPD in a multicenter, double-blind, randomized, placebo-controlled study (75C). Improvement in health-related qual­ ity of life was greater with roflumilast 250 and 500 mg/day than with placebo, although the differences were not signifi­ cant. Adverse events that were thought to be probably treatment related were reported in 12 patients taking placebo (4%), 46 patients taking roflumilast 250 mg/day (8%), and 92 patients taking roflumilast 500 mg/day (17%). Diarrhea was the most common followed by nausea. Headache was least likely to have been treatment related. There were no apparent changes in vital signs, electrocardiography, or clinical laboratory parameters during treatment with roflumilast. The withdrawal rate due to adverse events was higher with roflumilast 500 mg/day (15%) than roflumi­ last 250 mg/day (10%) or placebo (8%). The most frequent serious adverse event was exacerbation of COPD in each group. There was no pattern or trend associating

M. Joerger, K. Hartmann, and M. Kuhn

the incidence or cause of serious adverse events with roflumilast.

Non-prescription cough and cold medicines The US FDA has reviewed the safety and effectiveness of non-prescription cough and cold medicines in children and wants to determine whether the benefits from these products justify the risks of harms, especially in children under 2 years of age (76S). Some of the serious reported adverse events appear to be related to the amounts used. The FDA has issued a Public Health Advisory to warn that an over-the-counter medicine can be harmful if more than the recommended amount is used, if it is given too often, or if more than one cough and cold medicine contain­ ing the same active ingredient is used. Parents are advised to follow the directions for use on the product label carefully. The Advisory lists a set of facts that parents need to know about using cold and cough products in children, including the follow­ ing highlights:  Do not use cough and cold products in children under 2 years of age unless given specific directions to do so by a healthcare provider.  Too much medicine can lead to serious adverse effects, particularly in children aged 2 years and younger.  For liquid products, parents should use the measuring device (dropper, dosing cup, or dosing spoon) that is packaged with each formulation and that is marked to deliver the recommended dose; a kitchen teaspoon is not an appropriate measuring device for giving medicines to children.  If a measuring device is not included with the product, parents should obtain one at the pharmacy.  If a child’s condition worsens or does not improve, stop using the product immedi­ ately and take the child to a health-care provider for evaluation.

Drugs acting on the respiratory tract

315

Chapter 16

References 1. Meltzer EO, Derendorf H. The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide. Ann Allergy Asthma Immunol 2006;97(2):149–57. 2. Derom E, Van DVV , Marissens S, Engel­ statter R, Vincken W, Pauwels R. Effects of inhaled ciclesonide and fluticasone propio­ nate on cortisol secretion and airway responsiveness to adenosine 5'monopho­ sphate in asthmatic patients. Pulm Pharma­ col Ther 2005;18(5):328–36. 3. Lipworth BJ, Kaliner MA, LaForce CF, Baker JW, Kaiser HB, Amin D, Kundu S, Williams JE, Engelstaetter R, Banerji DD. Effect of ciclesonide and fluticasone on hypothalamic–pituitary–adrenal axis func­ tion in adults with mild-to-moderate persis­ tent asthma. Ann Allergy Asthma Immunol 2005;94(4):465–72. 4. Szefler S, Rohatagi S, Williams J, Lloyd M, Kundu S, Banerji D. Ciclesonide, a novel inhaled steroid, does not affect hypothala­ mic–pituitary–adrenal axis function in patients with moderate-to-severe persistent asthma. Chest 2005;128(3):1104–14. 5. Weinbrenner A, Hüneke D, Zschiesche M, Engel G, Timmer W, Steinijans VW, Bethke T, Wurst W, Drollmann A, Kaatz HJ, Siegmund W. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002;87(5):2160–3. 6. Kaliner MA. Pharmacologic characteristics and adrenal suppression with newer inhaled corticosteroids: a comparison of ciclesonide and fluticasone propionate. Clin Ther 2006; 28(3):319–31. 7. Chervinsky P, van As A, Bronsky EA, Dockhorn R, Noonan M, LaForce C, Pleskow W. Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma. The Fluticasone Propio­ nate Asthma Study Group. J Allergy Clin Immunol 1994;94(4):676–83. 8. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, Fahy JV, Fish JE, Ford JG, Israel E, Kiley J, Kraft M, Lazarus SC, Lemanske Jr RF, Mauger E,

9.

10.

11.

12.

13.

14.

15.

16.

Peters SP, Sorkness CA. Asthma Clinical Research Network of the National Heart Lung, and Blood Institute. Significant varia­ bility in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immu­ nol 2002;109(3):410–8. Chapman KR, Patel P, D'Urzo AD, Alex­ ander M, Mehra S, Oedekoven C, Engel­ stätter R, Boulet LP. Maintenance of asthma control by once-daily inhaled cicle­ sonide in adults with persistent asthma. Allergy 2005;60(3):330–7. Postma DS, Sevette C, Martinat Y, Schlos­ ser N, Aumann J, Kafe H. Treatment of asthma by the inhaled corticosteroid cicle­ sonide given either in the morning or evening. Eur Respir J 2001;17(6):1083–8. Hansel TT, Benezet O, Kafé H, Ponitz HH, Cheung D, Engelstätter R, Barnes PJ. A multinational, 12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma. Clin Ther 2006;28(6):906–20. Masoli M, Weatherall M, Holt S, Shirtcliffe P, Beasley R. Inhaled fluticasone propio­ nate and adrenal effects in adult asthma: systematic review and meta-analysis. Eur Respir J 2006;28(5):960–7. Kellerman D, Stricker W, Howland W. Effects of inhaled fluticasone propionate on the HPA axis of patients with asthma. Eur Respir J 1996;9(Suppl. 23):162s. Li JT, Goldstein MF, Gross GN, Noonan MJ, Weisberg S, Edwards L, Reed KD, Rogenes PR. Effects of fluticasone propio­ nate, triamcinolone acetonide, prednisone, and placebo on the hypothalamic-pituitary­ adrenal axis. J Allergy Clin Immunol 1999; 103(4):622–9. Sorkness CA, Laforce C, Storms W, Lin­ court WR, Edwards L, Rogenes PR. Effects of the inhaled corticosteroids fluticasone propionate, triamcinolone acetonide, and flunisolide and oral prednisone on the hypothalamic–pituitary–adrenal axis in adult patients with asthma. Clin Ther 1999; 21(2):353–67. Wasserman SI, Gross GN, Schoenwetter WF, Munk ZM, Kral KM, Schaberg A,

316

17.

18.

19.

20.

21.

22.

23.

24.

25.

Chapter 16 Kellerman DJ. A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma. J Asthma 1996; 33(4):265–74. Priftis KN, Papadimitriou A, Gatsopoulou E, Yiallouros PK, Fretzayas A, Nicolaidou P. The effect of inhaled budesonide on adrenal and growth suppression in asthmatic chil­ dren. Eur Respir J 2006;27(2):316–20. Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol 2006;41(10):954–61. Gelfand EW, Georgitis JW, Noonan M, Ruff ME. Once-daily ciclesonide in chil­ dren: efficacy and safety in asthma. J Pediatr 2006;148(3):377–83. Dorsey MJ, Cohen LE, Phipatanakul W, Denufrio D, Schneider LC. Assessment of adrenal suppression in children with asthma treated with inhaled corticosteroids: use of dehydroepiandrosterone sulfate as a screen­ ing test. Ann Allergy Asthma Immunol 2006;97(2):182–6. Ferguson AC, Van Bever HP, Teper AM, Lasytsya O, Goldfrad CH, Whitehead PJ. A comparison of the relative growth velocities with budesonide and fluticasone propionate in children with asthma. Respir Med 2007; 101(1):118–29. Murphy K, Uryniak T, Simpson B, O'Dowd L. Growth velocity in children with peren­ nial allergic rhinitis treated with budesonide aqueous nasal spray. Ann Allergy Asthma Immunol 2006;96(5):723–30. Qaqundah PY, Sugerman RW, Ceruti E, Maspero JF, Kleha JF, Scott CA, Wu W, Mehta R, Crim C. Efficacy and safety of fluticasone propionate hydrofluoroalkane inhalation aerosol in pre-school-age chil­ dren with asthma: a randomized, doubleblind, placebo-controlled study. J Pediatr 2006;149(5):663–70. Wolthers OD. Short-term growth and adre­ nal function in children with asthma treated with inhaled beclomethasone dipropionate hydroflouroalkane-134a. Pediatr Allergy Immunol 2006;17(8):613–9. Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, Dass

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

M. Joerger, K. Hartmann, and M. Kuhn

SB, Knorr BA. Pediatric Montelukast Linear Growth Study Group. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Ann Allergy Asthma Immunol 2006;96(6):800–7. Mortimer KJ, Harrison TW, Tattersfield AE. Effects of inhaled corticosteroids on bone. Ann Allergy Asthma Immunol 2005; 94(1):15–21. van Staa TP, Leufkens HG, Cooper C. Use of inhaled corticosteroids and risk of frac­ tures. J Bone Miner Res 2001;16(3):581–8. Hubbard RB, Smith CJ, Smeeth L, Harrison TW, Tattersfield AE. Inhaled corticoster­ oids and hip fracture: a population-based case–control study. Am J Respir Crit Care Med 2002;166(12 Pt 1):1563–6. Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169(1):83–8. de Vries F, van Staa TP, Bracke MS, Cooper C, Leufkens HG, Lammers JW. Severity of obstructive airway disease and risk of osteoporotic fracture. Eur Respir J 2005;25(5):879–84. Hubbard R, Tattersfield A, Smith C, West J, Smeeth L, Fletcher A. Use of inhaled corticosteroids and the risk of fracture. Chest 2006;130(4):1082–8. Schlienger RG, Jick SS, Meier CR. Inhaled corticosteroids and the risk of fractures in children and adolescents. Pediatrics 2004; 114(2):469–73. Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R. EXCEL: a randomised trial comparing salmeterol/fluticasone propio­ nate and formoterol/budesonide combina­ tions in adults with persistent asthma. Respir Med 2006;100(7):1152–62. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circula­ tion 2000;101(5):558–69. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005;128(4):2640–6. Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring Jr E, She D. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Sas­ katchewan Canada cardiovascular disease in

Drugs acting on the respiratory tract

37.

38.

39.

40.

41.

42.

43.

44.

45. 46.

47.

48.

Chapter 16

COPD patients. Ann Epidemiol 2006;16(1): 63–70. Campbell SC, Criner GJ, Levine BE, Simon SJ, Smith JS, Orevillo CJ, Ziehmer BA. Cardiac safety of formoterol 12 microg twice daily in patients with chronic obstruc­ tive pulmonary disease. Pulm Pharmacol Ther 2007;20(5):571–9. Martinez FD. Safety of long-acting beta­ agonists—an urgent need to clear the air. N Engl J Med 2005;353(25):2637–9. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multi­ center Asthma Research Trial: a compar­ ison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15–26. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of longacting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006;144(12):904–12. Ernst P, McIvor A, Ducharme FM, Boulet LP, FitzGerald M, Chapman KR, Bai T. Canadian Asthma Guideline Group. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med 2006;145(9):692–4. Glassroth J. The role of long-acting betaagonists in the management of asthma: analysis, meta-analysis, and more analysis. Ann Intern Med 2006;144(12):936–7. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306(6884):1034–7. Vassiliou V, Zipitis CS. Long-acting bronch­ odilators: time for a re-think. J R Soc Med 2006;99(8):382–3. O'Byrne PM, Adelroth E. Beta2 deja vu. Chest 2006;129(1):3–5. Lurie P, Wolfe SM. Misleading data ana­ lyses in salmeterol (SMART) study. Lancet 2005;366(9493):1261–2. Donohue JF, Fromer L. Long-acting betaagonists role in asthma management. J Fam Pract 2006;Suppl:1–6. Weinberger M, Abu-Hasan M. Life-threa­ tening asthma during treatment with salme­ terol. N Engl J Med 2006;355(8):852–3.

317 49. Wechsler ME, Lehman E, Lazarus SC, Lemanske Jr RF, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E. National Heart, Lung, and Blood Institute's Asthma Clinical Research Net­ work. Beta-adrenergic receptor polymorph­ isms and response to salmeterol. Am J Respir Crit Care Med 2006;173(5):519–26. 50. Mann M, Chowdhury B, Sullivan E, Nicklas R, Anthracite R, Meyer RJ. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 2003;124(1): 70–4. 51. Bensch G, Lapidus RJ, Levine BE, Lumry W, Yegen U, Kiselev P, Della Cioppa G. A randomized, 12-week, double-blind, pla­ cebo-controlled study comparing formoterol dry powder inhaler with albuterol metereddose inhaler. Ann Allergy Asthma Immunol 2001;86(1):19–27. 52. Bensch G, Berger WE, Blokhin BM, Soco­ lovsky AL, Thomson MH, Till MD, Castell­ sague J, Della Cioppa G. International Study Group on Foradil Evaluation in Pediatric Asthma. One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Ann Allergy Asthma Immunol 2002;89(2):180–90. 53. Wolfe J, Laforce C, Friedman B, Sokol W, Till D, Della Cioppa G, van As A. Formoterol, 24 microg bid, and serious asthma exacerbations: similar rates com­ pared with formoterol, 12 microg bid, with and without extra doses taken on demand, and placebo. Chest 2006;129(1):27–38. 54. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Argi­ nine-16 beta2 adrenoceptor genotype pre­ disposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006;61(11):940–4. 55. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax 2000; 55(9):762–7. 56. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. The effect of polymorphisms of the beta(2)­

318

57.

58.

59.

60.

61.

62.

63.

64.

65.

Chapter 16 adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162(1):75–80. Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman M, Anderson WH, Dorinsky PM. Salmeterol response is not affected by beta2-adrenergic receptor geno­ type in subjects with persistent asthma. J Allergy Clin Immunol 2006;118(4):809–16. Fukui Y, Hizawa N, Takahashi D, Maeda Y, Jinushi E, Konno S, Nishimura M. Associa­ tion between nonspecific airway hyperre­ sponsiveness and Arg16Gly beta2­ adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects. Chest 2006;130(2):449–54. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the associa­ tion of beta2-adrenergic receptor poly­ morphisms with asthma phenotypes. J Allergy Clin Immunol 2005;115(5):963–72. Rosenkranz B, Rouzier R, Kruse M, Dobson C, Ayre G, Horowitz A, Fitoussi S. Safety and tolerability of high-dose formoterol (via Aerolizer) and salbutamol in patients with chronic obstructive pulmon­ ary disease. Respir Med 2006;100(4):666–72. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. TORCH investigators. Salme­ terol and fluticasone propionate and survi­ val in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775–89. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest 2006;130(6):1695–703. Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstruc­ tive pulmonary disease: a meta-analysis. Thorax 2006;61(10):854–62. Williams B, Noonan G, Reiss TF, Knorr B, Guerra J, White R, Matz J. Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older. Clin Exp Allergy 2001;31(6):845–54. Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respir Med 2006;100(11): 1952–9.

M. Joerger, K. Hartmann, and M. Kuhn

66. Ghosh G, Manglik AK, Roy S. Efficacy and safety of montelukast as monotherapy in children with mild persistent asthma. Indian Pediatr 2006;43(9):780–5. 67. de Benedictis FM, del Giudice MM, Fore­ nza N, Decimo F, de Benedictis D, Capristo A. Lack of tolerance to the protective effect of montelukast in exercise-induced bronch­ oconstriction in children. Eur Respir J 2006; 28(2):291–5. 68. Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157(2):351–70. 69. WilliamsBundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 2001; 297(1):280–90. 70. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, Kroegel C, Morell F, Hansel TT, Rennard SI, Compton C, Amit O, Tat T, Edelson J, Pavord ID, Rabe KF, Barnes NC, Jeffery PK. Antiinflammatory effects of the phospho­ diesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168(8): 976–82. 71. Rennard SI, Schachter N, Strek M, Rickard K, Amit O. Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiester­ ase 4. Chest 2006;129(1):56–66. 72. van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, et al. Roflumilast, an oral, once-daily phos­ phodiesterase 4 inhibitor, attenuates aller­ gen-induced asthmatic reactions. J Allergy Clin Immunol 2005;116(2):292–8. 73. Bateman ED, Izquierdo JL, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, Leichtl S, Bredenbröker D. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol 2006;96(5):679–86. 74. Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, Rost KD,

Drugs acting on the respiratory tract

Chapter 16

Harnest U, Kroemer B, Albrecht A, Bre­ denbröker D. Comparison of roflumilast, an oral anti-inflammatory, with beclometha­ sone dipropionate in the treatment of persistent asthma. Allergy 2006;61(1):72–8. 75. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD.

319 Roflumilast—oral anti-inflammatory treat­ ment for chronic obstructive pulmonary disease: a randomised controlled trial. Lan­ cet 2005;366(9485):563–71. 76. Anonymous. Non-prescription cough and cold medicines. Caution needed with use in. WHO Pharm Newslett 2007;4:5.