Airway Obstruction Worsens in Young Adults with Asthma Who Become Obese.

BACKGROUND: Few studies have examined how developing obesity in early adulthood affects the course of asthma. OBJECTIVE: We analyzed lung function and asthma impairment and risk among nonobese children with asthma, comparing those who were obese in young adulthood with those who remained nonobese. METHODS: We carried out the post hoc analysis of 771 subjects with mild to moderate asthma who were not obese (pediatric definition, body mass index [BMI] < 95th percentile) when enrolled in the Childhood Asthma Management Program at ages 5-12 years. The subjects were then followed to age 20 years or more. For visits at ages 20 years or more, spirometry values as percent predicted and recent asthma symptom scores and prednisone exposure were compared between 579 subjects who were nonobese at all visits and 151 who were obese (adult definition of BMI ≥ 30 kg/m(2)) on at least 1 visit (median number of visits when obese = 4, IQR 2-7). RESULTS: Compared with participants who were nonobese (BMI 23.4 ± 2.6 kg/m(2)), those who became obese (BMI 31.5 ± 3.8 kg/m(2)) had significant decreases in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (P < .0003) and FEV1 (P = .001), without differences in FVC (P = .15) during visits at ages 20 years or more. For each unit increase of BMI, FEV1 percent predicted decreased by 0.29 (P = .0009). The relationship between BMI and lung function was not confounded by sex or BMI at baseline. Asthma impairment (symptom scores) and risk (prednisone use) did not differ between the 2 groups. CONCLUSION: Becoming obese in early adulthood was associated with increased airway obstruction, without impact on asthma impairment or risk.

Asthma controller therapy during pregnancy.

OBJECTIVE: This study was undertaken to educate physicians on the safety of asthma controller use during pregnancy. STUDY DESIGN: A comprehensive literature search using MEDLINE, the Cochrane Controlled Trials Register and Database of Systematic Reviews, EMBASE, and selected bibliographies identified human gestational studies of asthma controller medications from which maternal and fetal outcomes were obtained. The US Food and Drug Administration (FDA) pregnancy category ratings were identified from product package inserts. RESULTS: Human gestational studies were identified for the inhaled corticosteroids (ICSs) beclomethasone, budesonide, and triamcinolone and for cromolyn sodium, theophylline, and salmeterol. Human pregnancy data support an FDA Pregnancy Category B rating for budesonide. Pregnancy Category B ratings for cromolyn, nedocromil, montelukast, and zafirlukast are based primarily on safety in animal reproduction studies. ICSs other than budesonide, theophylline, zileuton, and long-acting beta 2 -adrenergic agonists are Pregnancy Category C. CONCLUSION: Human pregnancy data for many asthma controllers are lacking; nonetheless, data support a range of choices among medications rated Pregnancy Category B.

Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma.

OBJECTIVE: Inhaled corticosteroids are recommended as first-line therapy for pediatric asthma. However, few controlled long-term studies have investigated their effect on bone mineral density (BMD) and growth. METHODS: Children who were aged 6 to 14 years and had persistent asthma were randomized to 24 months' treatment with fluticasone propionate (FP) 200 micro g/d or nedocromil sodium (NS) 8 mg/d (if uncontrolled, maximum doses of 400 micro g/d and 16 mg/d, respectively). BMD was assessed blind and analyzed at a central facility on the basis of dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck at months 0, 6, 12, and 24. Height was measured at months 0, 12, and 24. Efficacy parameters (lung function, asthma control, occurrence of exacerbations) were measured every 3 months. RESULTS: In total, 174 children were randomized to treatment (87 received FP, and 87 received NS). At month 24, the adjusted mean percentage increase in lumbar spine BMD was 11.6% in the FP group compared with 10.4% in NS-treated children (95% confidence interval for treatment difference: -0.7% to 3.1%). The corresponding increases in femoral neck BMD were 8.9% and 8.5%, respectively. There was no significant difference in growth between the 2 groups: adjusted mean growth rates were 6.1 cm/y with FP and 5.8 cm/y with NS. FP was significantly superior for every efficacy parameter investigated and was similarly well tolerated as NS. CONCLUSIONS: The long-term effects of FP and NS on BMD accrual and growth are similar among children with asthma. The benefit:risk ratio of FP may be considered superior to that of NS.

Nedocromil sodium ophthalmic solution 2% twice daily in patients with allergic conjunctivitis.

In a multicenter, open-label evaluation, 1098 patients with ocular itching and a history of perennial or seasonal allergic conjunctivitis instilled one drop of nedocromil sodium 2% twice daily in each eye. Ocular symptoms, signs, and global improvement were assessed at baseline and 1 month; satisfaction scores, quality-of-life variables, and adverse events were also recorded. Significant improvements from baseline (P<.012) occurred in mean severity scores for itching, burning, stinging, watering, swelling, tired eyes, dryness, gritty sensation, eye pain, foreign-body sensation, and light sensitivity. Physicians reported significant reductions (P<.0001) in bulbar conjunctival redness and swelling. Two thirds of patients (634/954) and three fourths of physicians (710/954) reported at least 75% improvement in overall condition after 1 month. The most common adverse events were burning (2.7%) and unpleasant taste (1.4%); headache (1.2%) and adverse events leading to discontinuation (1.3%) were rare. Patients reported significant improvement (P<.001) in their ability to perform daily activities; 65% were more satisfied with nedocromil than with their typical medication. Physicians would prescribe nedocromil again to 80% of the patients. Nedocromil sodium 2% twice daily was effective and safe for the treatment of symptoms of allergic conjunctivitis, significantly improving quality of life and producing high rates of user and physician satisfaction.

Nedocromil sodium eye drops are more effective than sodium cromoglycate eye drops for the long-term management of vernal keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a severe though transient form of ocular allergy, predominant in young males, which requires careful management. Corticosteroids are effective but also cause serious topical side-effects in the eye, such as glaucoma and cataracts. The safer, mast cell stabilizing anti-inflammatories (commonly sodium cromoglycate) therefore have an important role. This parallel group study compared efficacy, tolerability and safety of sodium cromoglycate 2% with nedocromil sodium 2%, administered as one drop per eye four times daily for a period of 5 months. METHODS: Children aged 4-17 years, with a diagnosis of mostly limbal VKC in the last 12 months, entered a 2-week baseline during which they used only artificial tears, and were then randomized to treatment, in groups of 18, on an investigator single-masked basis. Daily symptom diary cards were kept by patients/guardians, and VKC was assessed by the clinician at approximately monthly intervals. Dexamethasone was provided for rescue control of severe symptoms, if needed. RESULTS: A total of 34 patients completed the study. Both trial treatments produced rapid improvements and many ocular signs and symptoms, including Trantas' dots, chemosis, itching, soreness and sticky discharge, were fully controlled by the end of the study. However, nedocromil sodium took effect more quickly, with a significant reduction compared to sodium cromoglycate for itching, grittiness, hyperaemia and keratitis within 6 weeks. In addition, nedocromil sodium was the more efficacious overall (significant vs sodium cromoglycate for hyperaemia, keratitis, papillae and pannus at 22 weeks). Both treatments were well tolerated and without serious adverse effects. Final opinions favoured nedocromil sodium, with full control of VKC recorded for 94% (patient opinion) and 100% (clinician opinion) of this treatment group, compared with 29% and 0%, respectively, in the sodium cromoglycate group. CONCLUSIONS: Nedocromil sodium 2% eye drops is significantly more effective than sodium cromoglycate for treatment of VKC.

Risk of non-fatal cardiac failure and ischaemic heart disease with long acting beta 2 agonists.

BACKGROUND: The long term safety of beta agonists, particularly in patients with heart disease, has not been fully established. METHODS: This study accessed the results of three cohort studies involving: 12,294 patients receiving at least one prescription for nedocromil between November 1986 and September 1988; 15,407 patients prescribed salmeterol between December 1990 and May 1991; and 8098 patients prescribed bambuterol between February 1993 and December 1995. Details of all dispensed prescriptions for these drugs prescribed by general practitioners in England soon after their launch were provided in confidence by the Prescription Pricing Authority. Questionnaires were sent to the prescriber asking for details of events occurring after the first prescription (prescription event monitoring). Rates and relative risks of non-fatal cardiac failure and ischaemic heart disease were calculated, comparing bambuterol and salmeterol with the reference drug nedocromil. RESULTS: The age and sex adjusted relative risk of non-fatal cardiac failure associated with bambuterol was 3.41 (95% confidence limits (CL) 1.99 to 5.86) when compared with nedocromil. When salmeterol was compared with nedocromil the adjusted relative risk of non-fatal cardiac failure was 1.10 (95% CL 0.63 to 1.91). The adjusted relative risk of non-fatal ischaemic heart disease was 1.23 (95% CL 0.73 to 2.08) and 1.07 (95% CL 0.69 to 1.66) for bambuterol and salmeterol, compared with nedocromil, respectively. However, in the first month of exposure the adjusted relative risk of non-fatal ischaemic heart disease was 3.95 (95% CL 1.38 to 11.31) when bambuterol was compared with nedocromil. CONCLUSIONS: Caution should be exercised when prescribing long acting oral beta agonists to patients at risk of cardiac failure. More definitive evidence would come from prospective randomised trials.

Onset of action, effectiveness and tolerance of levocabastine and nedocromil in topical therapy of seasonal allergic rhinoconjunctivitis. The Deutsche Rhinitis-Studiengruppe.

This study evaluated the effectiviness and the onset of action of levocabastine (CAS 79547-78-7) nasal spray and eyedrops as well as of nedocromil (CAS 69049-74-7) nasal spray and eyedrops in practical relevant circumstances. The study was designed as an open observational study with parallel groups in 10 centres and comprised 102 patients. All patients presented with seasonal allergic rhinitis and evidenced conjunctival symptoms requiring therapy. The patients as well as the investigators were required to rate the symptoms using symptom scores in order to evaluate the effectiveness of the used drugs. The effectiveness according to symptom scores did not differ significantly between investigator's and patient's judgment. Onset of action was within the first hour in 81.6% of the patients treated with levocabastine and in 82.9% of the patients treated with nedocromil. Symptoms were evaluated on a visual analogue scale ranging from 0 to 100. The use of both substances reduced the severity of the reported symptoms by 50% within the first hour. Thus, no significant difference in the onset of action could be observed even though a later onset of action was expected of the stabiliser of mast cell membranes. Both drugs were tolerated well.

Immunomodulation as asthma therapy: where do we stand?

There is increasing evidence that chronic inflammation in asthma is mediated via a network of cytokines emanating from inflammatory and structural cells in the airways. The prominent eosinophilic inflammation that characterizes asthma appears to be orchestrated by cytokines derived from type 2 T-helper (Th2)-like lymphocytes, suggesting that immunosuppressants might be beneficial in the control of asthma. Indeed, one of the critical modes of action of glucocorticoids in controlling asthma may be the suppression of Th2-lymphocyte-derived cytokines, such as interleukin-5 (IL-5). Cyclosporin-A may have a similar immunomodulatory role, but its potential beneficial effects are outweighed by its toxicity, at least when given parenterally. Future immunomodulators need to be more selective, either by means of delivery (inhalation, liposomes) or by a more specific effect on Th2, as opposed to Th1, lymphocytes or their products. Such approaches may include new immunomodulators, such as mycophenolate mofetil, specific cytokine inhibitors (such as interleukin-5 antibodies), endogenous suppressors of Th2 cells (interferon-gamma or interleukin-12), or type 4 phosphodiesterase inhibitors.

[Nedocromil sodium nasal spray in the treatment of seasonal allergic rhinitis]. / Nedocromil sodico spray nasale nel trattamento della rinite allergica stagionale.

We have evaluated the efficacy of nedocromil sodium 1% nasal spray in 29 patients (14 males and 15 females, mean age 23 years) who had been suffering from seasonal allergic rhinitis due to Parietaria for at least three years. Diagnosis was based on medical history, skin prick test and RAST. Nedocromil sodium was given for 4 weeks in May, at the dosage of 4 mg, 4 times a day in each nostril. On a daily diary card patients had to record both the severity of symptoms following an arbitrary score from 0 to 3 and the possible presence of side effects. After 4 weeks of treatment patients obtained a statistically significant improvement of the symptoms considered (p < 0.001). No side effects have been reported and no other drugs have been necessary to control the symptoms.

[Nedocromil sodium as a topical treatment of allergic conjunctivitis due to grasses]. / Nedocromil sodico come trattamento topico della congiuntivite allergica da graminacee.

Thirty-two patients (20 males and 12 females, mean age 31 ys) with seasonal allergic conjunctivitis to grass pollen, were selected for this study. Nedocromil sodium 2% ophthalmic solution was given at the dosage of 1 drop four times a day for four weeks during the month of June. On a daily diary card each patient had to report the severity of the symptoms: itchy eyes, lacrimation, red eyes and photophobia, following an arbitrary score from 0 to 3 (0 = no symptom, 1 = mild, 2 = medium, 3 = severe). After four weeks of treatment we observed a statistically significant improvement of the symptoms considered. Patients did not take other medications and did not report any side effects. Nedocromil sodium is therefore a valid alternative in the treatment of allergic conjunctivitis to grass pollen.

A comparative study of the clinical efficacy of nedocromil sodium and placebo. How does cromolyn sodium compare as an active control treatment?

Nedocromil sodium and cromolyn sodium are the only two currently available nonsteroid anti-inflammatory agents for treatment of asthma. Clinical differences between the two agents remain under continuous investigation with reports differentiating the two on the basis of atopy of the patient and reversibility of bronchoconstriction. This study investigated the efficacy of nedocromil sodium (4 mg, qid) for treatment of mild-to-moderate asthma in comparison to placebo using cromolyn sodium (2 mg, qid) as an active control treatment. Patients were primarily allergic asthmatics (with at least 15% reversibility) previously maintained on a regimen of regular bronchodilator therapy. During a 2-week run-in period, the patient's slow-release theophylline therapy was removed, and the patients were randomized to treatment after deterioration of asthma control (asthma symptom summary score of 3 for 7 of the 14 days). After 8 weeks of treatment, patients were returned to as occasion requires bronchodilator therapy, as per the 2-week baseline period. The results demonstrate that patients treated with nedocromil sodium showed statistically significant improvements during the primary time period (mean weeks 3 through 8) over placebo-treated patients as evidenced by all indexes of asthma symptoms, pulmonary function measures, and decreased bronchodilator reliance (p<0.05). Patients treated with cromolyn sodium demonstrated similar improvements over placebo-treated patients. Comparisons between nedocromil sodium and cromolyn sodium showed the two agents to be comparable in this group of primarily allergic patients with reversible disease. Between-group differences were noted for 3 of the 13 variables (nighttime asthma, FEV1, and forced expiratory flow rate between 25 % and 75% of the FVC) in favor of cromolyn sodium when the data were pooled during the primary time period. The number of patients missing 1 or more days from work/school/regular activity due to asthma was significantly fewer compared with placebo, and favoring nedocromil sodium over cromolyn sodium. No differences were observed among the three treatments for adverse events. This study demonstrated that in primarily allergic patients with reversible airways disease, nedocromil sodium and cromolyn sodium are both significantly more effective than placebo for treatment of mild-to-moderate asthma.

Nedocromil in the outpatient management of asthma.

OBJECTIVE: To more closely approximate the use of a nonsteroidal inhaled anti-inflammatory medication for asthma, nedocromil sodium, under actual ambulatory practice conditions. DESIGN: Large, open-label trial. PATIENTS: One thousand two hundred one patients from 286 primary care and specialty centers. INTERVENTION: Four weeks of treatment with nedocromil sodium (4 mg delivered from the valve and 3.5 mg delivered from the mouthpiece of a metered inhalor [2 puffs, four times daily]). MAIN OUTCOME MEASURES: Asthma symptom scores, peak expiratory flow rate, a lifestyle assessment measures questionnaire, and mean number of days missed per month from work or school. RESULTS: Statistically significant improvements were seen after 1 and 4 weeks of treatment for cough, daytime and nighttime asthma, morning tightness, peak expiratory flow rate, and all four measured lifestyle assessment factors (P < .001). An additional clinically relevant outcome measure, mean number of days missed per month from work or school, was reduced by 75% (P < .001). No serious adverse reactions were reported. CONCLUSION: This study reproduces the high level of efficacy and safety of nedocromil that was previously reported in placebo-controlled clinical studies.

The use of twice daily nedocromil sodium in the treatment of asthma.

The efficacy and safety of nedocromil sodium inhalation aerosol (4 mg of Tilade administered by metered-dose inhaler) given twice daily was compared with placebo in 112 patients with mild-to-moderate asthma who had been receiving maintenance therapy with oral or inhaled bronchodilators or both. After a 2-week run-in period and a subsequent 2-week baseline period, patients were randomized to active treatment (n = 56) or placebo (n = 56) for 8 weeks. All maintenance bronchodilators were withdrawn before the baseline period, and patients entered the treatment period only after demonstrating a specified level of asthma symptoms. Twice daily administration of nedocromil sodium improved all asthma symptoms in these patients who had symptoms as a result of the withdrawal of their maintenance theophylline and/or oral and inhaled beta 2-agonist bronchodilators. During the primary time period (treatment weeks 5 to 8), statistically significant between-group differences favored nedocromil sodium for the asthma summary score (primary variable, p = 0.001), daytime asthma (p = 0.001), and sleep difficulty caused by asthma (p = 0.006). Furthermore, significant reductions in the use of as-needed rescue medications were reported in the nedocromil sodium group (p = 0.003) compared with the placebo group. Final overall opinions of treatment effectiveness expressed by physicians (p = 0.016) and patients (p = 0.002) strongly favored nedocromil sodium.

Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol.

In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 micrograms of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a beta 2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated.

Clinical experience with Tilavist: an overview of efficacy and safety.

A programme of clinical studies was carried out to determine the basic efficacy and safety of 2% nedocromil sodium eye drops (Tilavist) in treating allergic conjunctivitis, in 2,905 patients from 3-76 years of age. Results of all the double-masked placebo comparative studies completed to date-five in vernal keratoconjunctivitis (VKC), five in perennial (PAC) and 16 in seasonal allergic conjunctivitis (SAC)-have been assessed in a statistical overview analysis. Nedocromil sodium, administered four times daily to 153 patients with VKC, was significantly more effective than placebo (155 patients) and in the clinicians' opinion gave good control in 76% of cases, compared with 46% for placebo (p < 0.001). Patients with chronic symptoms of PAC also responded better to nedocromil sodium given four times daily (n = 146) rather than twice daily (n = 86), and significantly more patients (p < 0.001) were effectively controlled by four times daily treatment with nedocromil sodium (72%) than with placebo (47%; n = 156). Twice-daily dosage with nedocromil sodium (n = 677) was adequate for SAC, however, and the treatment was statistically better than placebo (p < 0.01-p < 0.001) whether dosed twice or four times daily. Speed of action was assessed in seven SAC studies in which 79% of all patients (n = 295) using nedocromil sodium had experienced relief of symptoms when questioned, half of them within 15 minutes and 74% during the first hour after dosing. Test treatments were well-accepted by both adults and children, and there were no major adverse events. Minor irritations reported more frequently with nedocromil sodium than placebo were stinging or burning of the eyes on application of the drops and a distinctive taste, noted by 5% of the active treatment group (n = 1,552).

Comparative therapeutic studies with Tilavist.

Comparative clinical trials which include known therapies as well as placebos are essential in constructing a solid basis from which to 'launch' any new drug. This applies especially to eye drops for treatment of seasonal allergic conjunctivitis, where the symptomatology, already dependent on the vagaries of the natural pollen challenge season, is further influenced by a positive washing action of the placebo eye drops. Tilavist (2% nedocromil sodium ophthalmic solution) has therefore been compared with sodium cromoglycate eye drops and non-sedating antihistamine tablets, both mainstays in the treatment of seasonal allergy, in a series of double-masked, placebo-controlled, mainly multicentre studies. Nedocromil sodium, twice or four times daily, proved as effective overall as sodium cromoglycate (2% or 4% four times daily) in three seasonal trials, and was the more effective treatment in a study of patients with vernal keratoconjunctivitis. Its efficacy was most evident during peak periods of pollen challenge, when neither placebo nor sodium cromoglycate eye drops controlled breakthrough symptoms. Three further seasonal studies showed nedocromil sodium eye drops to be as effective as standard oral doses of astemizole and terfenadine, whilst a faster onset of action than terfenadine was reported in one multicentre study.