Cromolyn for Asthma

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Several studies have shown that ICS are more effective than cromolyn in patients with severe asthma (88-90). However, some studies in mild to moderate asthmatics have shown either comparable efficacy (91-93) or an even better response to ICS (94,95). On the other hand, the addition of cromolyn to ICS failed to show any beneficial effect (96). A more recent review of 24 placebo-controlled trials of cromolyn concluded, ''there is insufficient evidence for a beneficial effect of CS as maintenance treatment in children with asthma.'' Further review of this study shows that cromolyn is more effective in older children (97). In addition, a recent review reported no significant difference between DSCG and placebo in children with asthma (98). The use of cromolyn versus placebo administered via face mask with spacer device in 167 children aged one to four years found no difference in the primary outcome measure of symptom-free asthma days between the two groups (99). Long-term studies with cromolyn have reported good asthma control and improvement in lung function with a lower dosage of cromolyn (100,101).

Konig and Shaffer reported that children on cromolyn and ICS for prolonged periods had no evidence of irreversible airway changes in a retrospective study in 175 infants in three treatment groups (102).

One group of mild asthmatics was treated with as needed bronchodilators, moderate asthmatics were treated with CS, and the severe asthmatics were treated with ICS (102). In this study the final pulmonary function tests (PFT) improved in both the cromolyn and ICS groups compared to bronchodilators alone (Fig. 9) (102). However, the overall change in pulmonary function from start to end of a study showed a significant improvement of FVC only in the ICS group (Fig. 10) (103). Overall, the clinical outcomes showed improvements in the frequency of hospitalizations (p < 0.05) in both the cromolyn group and the ICS-treated group. Likewise, a reduction in emergency department (ED) visits (p < 0.05) was observed in the ICS-treated group when compared to the bronchodilator group, despite the perceived mild severity of the latter group. Furthermore, a delay in starting cromolyn was associated with an unfavorable effect in clinical outcomes, whereas no effects were observed with delay of initiation of ICS (102).

A Finnish cross-sectional study of school children was divided into three groups—bronchodilators only, cromolyn, and ICS—reported improved PFT in the cromolyn group (104). This study involved 297 children: 60/297 (20%) on bronchodilators as needed for symptoms, 169/297 (57%) on cromolyn (97/169) or nedocromil (72/169), and 68/297 (23%) or ICS with budesonide (65/68) or beclomethasone (3/68). Thus, the majority of children in this study were on chromones medication. The decrease in at least one of the parameters of pulmonary function (PEF, FVC, FEV1,

Cromolyn For Asthma
Figure 9 Change in pulmonary function from start to end of initial treatment with either b-agonists, sodium cromolyn, or inhaled cartiosteroid. All values are pre-bronchodilator use. Abbreviations: FVC, forced vital capacity; FEF25_75, forced expiratory flow; PRN, as needed. Source: From Ref. 103.

Figure 10 Mean (±SD) within treatment changes in prebronchodilator pulmonary function test results reported as percentage of predicted normal value. Data represent start to end of treatment, regardless of whether the end of treatment was the end of the study or represented a change in therapeutic agent, b-agonist, n — 44; cramolyn sodium, n — 28; inhaled cartiosteroid, n — 26. Open bars, start of treatment results; shaded bars, end of treatment test results. *p < 0.05. Source: From Ref. (102).

Figure 10 Mean (±SD) within treatment changes in prebronchodilator pulmonary function test results reported as percentage of predicted normal value. Data represent start to end of treatment, regardless of whether the end of treatment was the end of the study or represented a change in therapeutic agent, b-agonist, n — 44; cramolyn sodium, n — 28; inhaled cartiosteroid, n — 26. Open bars, start of treatment results; shaded bars, end of treatment test results. *p < 0.05. Source: From Ref. (102).

or the MMEF) was highest in the ICS group and lowest in the chromone group (104). Analysis of the chromone group demonstrated that the FVC and FEV1 were higher in the cromoglycate group (p < 0.05). This study only followed spirometry over one year and had disproportionate numbers of participants in the study groups. Today the ICS have proven to be beneficial and asthma guidelines have changed. The percentage of patients with mild, moderate, and severe asthma on ICS has steadily increased in the last decade.

De Baets et al. (105) compared cromolyn to budesonide in a small double-blind crossover study. This study involved 13 subjects (43-66 months) given inhaled cromolyn 10 mg tid or budesonide 100 mg tid for two months. A significant difference in morning peak flows was demonstrated in the ICS group [160L/min vs. 150L/min (p < 0.03)]. Fewer asthma exacerbations were reported in the ICS group as well, 7 versus 16 on cromolyn (p < 0.005). However, there were no differences in bronchial hyper-responsiveness observed.

The use of cromolyn therapy in early infancy and childhood has given conflicting data. While some studies have suggested that cromolyn may not be effective in the first year of life, one report verified that children under one year did show improvement with cromolyn (106-108). A reduction in symptoms and bronchodilator use has been observed with the use of cromolyn in a group of premature infants and children (109). In contrast, a recent review by the Cochrane database concluded that ''cromolyn sodium cannot be recommended for the prevention of chronic lung disease in preterm infants'' (110). The enigma of persistent wheezing after bronchiolitis has led investigators to experiment with preventive therapy during active disease. Reijonen et al. (111) reported that a single subsequent wheezing episode was lower in a group of children with bronchiolitis treated with cromolyn or budesonide. Prevention of the high cost of care from hospitalization favored the use of both medications in a subgroup of atopic children.

Another method used to assess the efficacy of therapy is to match pharmacy records to outcomes of emergency visits or need for hospitalization. Such investigations are fraught with numerous confounding variables but point out important trends in subjects using medication. One study reviewed inhaled anti-inflammatory medication dispensing through an analysis of automated pharmacy records of 11,195 children ages 3 to 15 years with a diagnosis of asthma (112). The outcome measures were ED visits and hospitalization for asthma. The adjusted relative risk (RR) for ED visits with the use of either cromolyn or ICS were 0.4 (95% CI 0.3, 0.5) and 0.5 (95% CI 0.4, 0.6), respectively. For hospitalizations, the adjusted RR with cromolyn and ICS were 0.6 (95% CI 0.4, 0.9) and 0.4 (95% CI 0.3, 0.7), respectively. Thus, a record of the patient obtaining one of these agents (use can not be demonstrated) is highly associated with prevention of ED visits and hospitalization for asthma (112).

A second investigation of pharmacy records analyzed the number of hospitalizations for asthma in 16,941 members from a Health Maintenance Organization (HMO) related to the use of ICS, cromolyn, and p-agonists (113). The primary outcome measure was time to the first hospitalization for asthma after dispensing. Dispensing one cromolyn inhaler was associated with a significant decreased RR of hospitalization of 0.8 (95% CI 0.6-0.9) for ages 0 to 17 years but was not protective in adults with RR of 0.8 (95% CI 0.6-1.1) forages 18 to 44 years and RR of 0.8 (95% CI 0.6-1.3) for ages >45 years. For ICS the overall RR was 0.5 (95% CI 0.4-0.6). Furthermore, the RR for the dispensing of >8 canisters of p-agonists was 4.3 (95% CI 3.1-6.0). This study was limited to one specific HMO and excluded patients on Medicaid/Medicare (113).

Recently a study done by the Severe Asthma Research Committee in Japan compared cromolyn to salbutamol (114). This study investigated 232 children with persistent asthma classified as either severe (64%) or moderate (35%). DSCG (20mg) nebulized solution mixed with salbutamol was compared to either agent of DSCG and salbutamol alone. The primary outcome measure was the change in daily asthma symptom score.

The combination medication improved this score by 39% when compared to salbutamol and 38% compared to DSCG. Although the individual agents resulted in improvement, the combination was superior.

Similar studies with DSCG and bronchodilators also showed an improvement in asthma symptoms. DSCG powder combined with isopre-naline resulted in a 59% improvement with the combination medication compared to only a 44% improvement with isoprenaline alone (115). A reduction of 33% to 35% in asthma severity classification was observed in 189 patients treated with cromolyn (p < 0.00005) (116).

For adult patients there were two critical clinical trials involving cromolyn performed through the Medical Research Council (MRC) and the Drug Committee of the American Academy of Allergy (AAA). The MRC trial involved 103 patients in four groups—cromolyn, isoproterenol, cromolyn and isoproterenol, and placebo—for 12 months (117). After eight weeks, the dose of cromolyn was reduced from 20 mg tid to a twice-daily dosage and finally to a daily dose. At the end of the study no outcome difference was found between patients receiving the full or reduced dosage. Although pivotal, the power of the study to make this observation may be problematic given the low number of subjects and multiple treatment arms.

The AAA trial involved 252 patients comparing cromolyn with placebo in a crossover design over eight weeks (118). The investigators observed a significant treatment effect in 80% of the patients receiving the placebo first.

Blumenthal et al. (119) reported on a group of patients controlled on cromolyn spincaps that were switched to placebo. After four weeks, the patients with worsening asthma were treated with cromolyn or placebo. The patients treated with cromolyn had significant improvement in their daily symptom scores for overall asthma severity and pulmonary function parameter of FVC and PEF when compared to the placebo treated subjects (119).

Ideally, inhaled chromone therapy would reduce the need for oral corticosteroid use in asthma. In an early study, the addition of cromolyn to oral corticosteroids resulted in a 41% reduction in dose after six months and withdrawal of steroids in 25% of patients after 1.5 years (120).

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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