The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance.

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. alpha-Lactose monohydrate crystals were processed by ball milling for cumulative time durations and their properties evaluated. As expected, milling reduced the median particle diameter while increasing fine particulate (<10 microm) and amorphous levels. Recrystallization of these partially amorphous samples resulted in a reduction in fines, elimination of amorphous material with little change in median diameter. To study the effects of processing on aerosolization performance, blends of lactose monohydrate with a model drug (nedocromil sodium trihydrate), were evaluated using an in vitro multistage liquid impinger (MSLI) model. In general, milling and storage of the carriers at high humidity (prior to blending) had a significant (ANOVA, p < 0.05) effect on the fine particle fractions (FPF; <6.8 microm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R(2) = 0.974 and 0.982 for milled and recrystallized samples, respectively). However, this relationship only existed up to 15% fines concentration, after which agglomerate-carrier segregation was observed and FPF decreased significantly. These results suggest that, after processing, high-dose drug formulation performance is dominated by the presence of fines.

Anti-inflammatory pharmacotherapy for wheezing in preschool children.

Accumulating evidence indicates that there are at least two phenotypes of wheezing in preschool years with distinct natural history. Frequent wheezing in the first 3 years of life with risk factors for asthma (e.g., eczema, maternal asthma) predicts symptoms in older age, while infrequent viral-associated wheezing without risk factors for asthma has a benign prognosis. This systematic review summarizes evidence on the use of anti-inflammatory medications in preschool children with wheezing. Literature search was performed using Medline and the Cochrane Library. Retrieved articles were critically appraised. Episodic use of high-dose inhaled corticosteroids (>1,600 mcg/day of beclomethasone) may ameliorate severity of intermittent viral-associated wheezing. Maintenance inhaled corticosteroids can control symptoms in children with frequent wheezing associated with risk factors for asthma. Inhaled corticosteroids do not alter the natural history of wheezing even when started early in life and could have a negative impact on linear growth rate. Short courses of oral corticosteroids have been proposed as an effective measure to control exacerbations of symptoms although there is little evidence supporting their use. Some studies support the administration of non-steroidal anti-inflammatory medications (leukotriene pathway modifiers, cromones, methylxanthines) for mild frequent wheezing. Maintenance inhaled corticosteroids is the most effective measure for controlling frequent wheezing in preschool children, especially when accompanied by risk factors for asthma. This treatment does not affect the natural history of wheezing, although deceleration of linear growth rate is the most commonly recognized systemic adverse effect.

Protective effects of nedocromil sodium and sodium cromoglycate on gastroduodenal ulcers: a comparative study in rats.

Stabilization of mast cells plays a key mechanism to protect gastrointestinal tract from injury. This study presents a comparative evaluation of mast cell stabilizers nedocromil sodium (NDS) and sodium cromoglycate (SCG) in experimental gastric and duodenal ulcers in rats. Wistar rats of either sex were used in this study. Both NDS and SCG, in the doses of 10, 30 and 100 mg/kg were given intraperitoneally for gastric secretion studies and by gavage for antiulcer studies. Acid secretion studies were undertaken in pylorus-ligated rats. Gastric lesions were induced by water immersion restraint stress (WIRS), indomethacin and ethanol whereas duodenal ulcers were produced by cysteamine. The level of glutathione (GSH) and gastric wall mucus were measured in glandular stomach of rats following ethanol-induced gastric lesions. SCG was more effective than NDS in preventing WIRS- and indomethacin-induced gastric lesions whereas reverse was true in ethanol- and cysteamine-induced ulcers. All the 3 doses of SCG offered almost equal protection against WIRS-induced gastric lesions whereas only medium and high dose of NDS provided significant protection in this model of ulcer. NDS significantly inhibited cysteamine-induced duodenal ulcers whereas SCG failed to do so. Pretreatment with NDS or SCG significantly and dose-dependently protected gastric mucosa against ethanol-induced injury, while the former drug appeared to be more effective. The cytoprotective effects of these two drugs were accompanied by the attenuation of ethanol-induced depletion of gastric wall mucus and GSH. The differential effects of NDS and SCG against various gastric lesions rationalize the possible benefits of a combined therapy (NDS+SCG) for the treatment of complex gastroduodenal ulcers.

Efficacy and safety of mometasone furoate vs nedocromil sodium as prophylactic treatment for moderate/severe seasonal allergic rhinitis.

BACKGROUND: The preventive use of medications has been proposed to be effective in the treatment of seasonal rhinitis. OBJECTIVE: To evaluate the efficacy and safety of mometasone furoate and nedocromil sodium nasal sprays as prophylactic treatment for moderate to severe seasonal allergic rhinitis (SAR). PATIENTS: Sixty-one patients were recruited from 3 referral allergy centers. Inclusion criteria were history of SAR for 2 years or longer, sensitization to relevant local pollen (grasses, Parietaria, and olive), and age older than 12 years. METHODS: An open-label, randomized, parallel-group, "real-life" study design was used. Patients received mometasone furoate nasal spray once daily or nedocromil sodium nasal spray 3 times daily starting 2 to 4 weeks before the pollen season and continuing for up to 4 months. Instructions regarding the use of additional medications were given. Diary cards recording symptoms, use of medication, and adverse events were kept by the patients. RESULTS: All 61 patients completed the study. The prophylactic use of mometasone furoate vs nedocromil sodium led to significantly more days without symptoms (75.1% vs 54.5%; P < .001). The mometasone furoate group also had lower nasal symptom scores (mean, 1.4 vs 2.9; median, 0 vs 2; P < .001) and was more satisfied (93.1% vs 43.5%; P < .001). No serious adverse event was recorded, and there was no difference between the treatments in any adverse event. CONCLUSIONS: Prophylactic administration of mometasone furoate before the pollen season is safe and may lead to improved control of SAR compared with the use of nedocromil sodium.

Safety and application of induced sputum analysis in childhood asthma.

BACKGROUND: The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers. OBJECTIVE: At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils. METHODS: Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol. RESULTS: Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity. CONCLUSIONS: Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.

Evaluation of preoperative and postoperative prophylactic regimens for prevention and treatment of diffuse lamellar keratitis.

PURPOSE: To investigate preoperative and postoperative prophylactic treatment with different pharmacological agents before flap cutting and exposure to a diffuse lamellar keratitis (DLK) causative agent. SETTING: Magill Research Center for Vision Correction, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA. METHODS: The study comprised 48 eyes of 24 Dutch-belted rabbits. Three days before a corneal flap was cut and the corneal interface was exposed to Pseudomonas aeruginosa lipopolysaccharide endotoxin, a DLK causative agent, the eyes were randomly assigned to treatment with a mast-cell stabilizer, a nonsteroidal antiinflammatory drug (NSAID), or a corticosteroid or left without treatment as controls. The treatment was maintained throughout the 1-week follow-up. Slitlamp examinations and photographs were performed at 1, 3, 5, and 7 days; DLK was graded by a masked observer from 0 (no DLK) to IV. Corneal interface scrapings were performed in selected eyes on day 7. RESULTS: At the end of the follow-up, 36 eyes were available for evaluation. At 1 week, 100% of the control eyes and the eyes treated with the mast-cell stabilizer developed DLK; in the NSAID-treated and corticosteroid-treated eyes, the DLK rate was 86% and 70%, respectively. At 1 day, the severity of DLK was significantly lower in eyes treated with the mast-cell stabilizer (0.44) and at 7 days, it was significantly lower in corticosteroid-treated eyes (0.3) than in the control group (1.5 and 1.4, respectively) (P<.05, Wilcoxon test). Corneal interface scraping from an eye with grade III DLK showed numerous inflammatory cells. CONCLUSIONS: Preoperative and postoperative treatment with corticosteroids significantly reduced the severity of DLK compared to the untreated control eyes in this animal model. Treatment with a mast-cell stabilizer and an NSAID had less effect on the postoperative course of DLK.

Supplementation of fexofenadine therapy with nedocromil sodium 2% ophthalmic solution to treat ocular symptoms of seasonal allergic conjunctivitis.

PURPOSE: Ocular symptoms are often under-treated in patients with allergic rhinoconjunctivitis. The efficacy of fexofenadine hydrochloride 60 mg capsules supplemented with nedocromil sodium 2% ophthalmic solution was evaluated to determine the optimal drug regimen for control of ocular allergic symptoms. METHODS: In this 5-week, open-label, randomized, multicentre comparative study, 89 patients with documented ragweed pollen allergy received fexofenadine b.i.d. with nedocromil rescue, fexofenadine q.d. with nedocromil b.i.d., or fexofenadine rescue with nedocromil b.i.d. during the ragweed pollen season. RESULTS: For all regimens, mean symptom severity scores for itching, burning, tearing, redness, grittiness, discharge, light sensitivity and swelling improved significantly (P < 0.003). Similarly, all groups experienced significant (P < 0.02) improvement in all clinical signs: erythema, oedema, discharge, conjunctival injection and conjunctivitis, as well as quality-of-life scores (P < 0.0001). All regimens reduced overall symptom severity scores after 5 min (P < 0.05) with relief persisting over 12 h (P < 0.03). Improvements in mean symptoms, signs and quality-of-life scores were similar among the treatment groups as were onset and duration of action even though patients in two of the three study arms were taking one-half or less of the recommended fexofenadine dosage. Patients and physicians judged the regimens containing lower fexofenadine dosages (with nedocromil b.i.d.) to be more effective overall than the regimen containing the highest fexo-fenadine dosage (with nedocromil as rescue only). CONCLUSIONS: Supplementation of oral fexofenadine therapy with nedocromil sodium 2% ophthalmic solution relieves ocular symptoms of seasonal allergic rhinoconjunctivitis, allowing control of rhinal symptoms with half the recommended dosage of fexofenadine.

Nedocromil sodium 2% ophthalmic solution for the treatment of ragweed pollen seasonal allergic conjunctivitis.

PURPOSE: To determine the efficacy and safety of nedocromil sodium 2% ophthalmic solution in the treatment of seasonal allergic conjunctivitis. METHODS: A combined analysis of two multicenter, randomized, comparative, double-masked, placebo-controlled clinical trials involving 261 patients diagnosed with seasonal allergic conjunctivitis was used. Patients were randomly assigned to receive either topical 2% nedocromil sodium or placebo twice daily for eight weeks. Diary card scores and clinician assessments of allergic symptoms were recorded throughout the study; efficacy was determined by comparing symptom severity at the peak pollen period with symptom severity at baseline. Clinician and patient evaluations of treatment effectiveness were used as secondary measurements of efficacy. RESULTS: Patients treated with nedocromil sodium experienced improvement in allergy symptoms, with reductions in the summary symptom score, itch, redness, conjunctival injection, and conjunctival edema significantly (p<0.05) greater than those observed in the patients treated with placebo. Clinicians' and patients' opinions of nedocromil sodium treatment effectiveness were significantly (p<0.02) superior to those of placebo treatment effectiveness. CONCLUSION: Nedocromil sodium is effective in the management of seasonal allergic conjunctivitis.

Efficacy and safety of nedocromil sodium 2% ophthalmic solution b.i.d. in the treatment of ragweed seasonal allergic conjunctivitis.

The efficacy and safety of twice-daily nedocromil sodium 2% ophthalmic solution and vehicle were compared in the treatment of ragweed seasonal allergic conjunctivitis. Two separate multicenter, randomized, double-masked, placebo-controlled studies were subjected to a combined analysis. Following a one-week baseline period during the beginning of the ragweed pollen season, 189 patients with seasonal allergic conjunctivitis received either nedocromil sodium or vehicle b.i.d. for eight weeks. Efficacy was evaluated by patient diary cards and clinical eye examinations. Safety was assessed by reports of adverse events. Compared with vehicle, nedocromil sodium produced significantly greater decreases in summary symptom score (p = 0.005), itch (p = 0.005), tearing (p = 0.004), overall eye condition (p = 0.001), and clinician-evaluated conjunctival edema (p = 0.018), and significantly better (p = 0.001), and patient (p = 0.001) opinions of treatment effectiveness at the peak pollen period. Additionally, the superiority of nedocromil sodium compared to vehicle approached statistical significance in redness reduction (p = 0.087) and clinician-evaluated conjunctival injection (p = 0.087). There were no serious treatment-related adverse events in either treatment group. In summary, nedocromil sodium 2% ophthalmic solution b.i.d. was found to be effective and to have a favorable safety profile in the treatment of seasonal allergic conjunctivitis.

Adrenal insufficiency in an adult on inhaled corticosteroids; recovery of adrenal function with inhaled nedocromil sodium.

BACKGROUND: Whereas oral corticosteroids and high-dose inhaled corticosteroids may be associated with suppression of the hypothalamic-pituitary-adrenal axis, medium-dose inhaled corticosteroids have not been reported to be associated with clinically significant adrenal insufficiency in the adult. OBJECTIVE: A case study of adrenal responsiveness after prolonged medium-dose inhaled corticosteroids and after replacement of steroid therapy by inhaled nedocromil sodium is described. METHODS: Standard 250-microg dose ACTH (cosyntropin) stimulation tests were followed after replacement of inhaled triamcinolone acetonide therapy by nedocromil sodium. RESULTS: A 55-year-old woman who had been on inhaled triamcinolone acetonide, 1600 microg/day for 12 years, presented with symptoms of adrenal hypofunction upon inhaled corticosteroid taper. An ACTH stimulation test confirmed adrenal insufficiency. She was switched to inhaled nedocromil sodium with improvement in her clinical syndrome and normalization of her ACTH stimulation test. CONCLUSION: Withdrawal from prolonged use of inhaled medium-dose corticosteroids may be associated with clinically significant adrenal insufficiency in adults. Steroid sparing agents may be considered for those on long-term inhaled corticosteroid therapy.

[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.

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.

Current practice: diagnosis and treatment in primary healthcare.

In a primary healthcare facility, there are certain 'rules of thumb' that can be recommended for the diagnosis and treatment of conjunctivitis. The type of discharge is a crucial factor in the differential diagnosis and can also be a clue towards the management in primary care. It is important to identify whether the conjunctivitis is an isolated case or part of another disease, and if it is acute or chronic, and I would suggest taking a smear or culture sample whenever possible. When the aetiology is not clear, I would try antibiotics. If the patient is allergic, and an allergic conjunctivitis is suspected, the best management today is to use mast cell stabilisers, and combine these with conservative measures of frequent washings, and compresses. If the aetiology remains doubtful, or if there is no obvious improvement using these treatments, the patient should be re-evaluated and/or referred to an ophthalmologist or specialist eye centre. The use of corticosteroids for conjunctivitis should certainly be avoided in primary healthcare. Conjunctivitis is often self-limited and the drug-induced consequences of improper management can be far more devastating than the disease itself.

Nedocromil sodium 2% eye drops for twice-daily treatment of seasonal allergic conjunctivitis: a Swedish multicentre placebo-controlled study in children allergic to birch pollen.

This was a multicentre, double-blind, randomized group comparative study in which 77 children, aged 6-16 years, received 2% nedocromil sodium eye drops and 72 received placebo, one drop into each eye twice daily. The treatment period was 4 weeks, covering the peak birch pollen season. Prior to the start of the season, patients who had attended the clinic the previous 2 years because of seasonal allergic conjunctivitis (SAC) to birch pollen, entered a one week baseline period during which symptoms were assessed, dairy cards completed, and routine sampling of blood and urine carried out. The double-blind treatment period then commenced at the onset of the birch pollen season. Patients/parents kept daily diary record cards of eye symptom severity and concomitant therapy. Conjunctivitis was mild in both treatment groups but nedocromil sodium was more effective than placebo in controlling symptoms. During the 2-3 weeks of peak pollen counts, this therapeutic effect was statistically significant for itching (P < 0.01), watering (P < 0.05) and total symptom score (P < 0.01), but was not significant for grittiness (P = 0.08) or redness (P = 0.06). Global opinions of efficacy showed no difference between treatments, due to a high placebo effect (however, the diary card data indicated a significant improvement with nedocromil sodium). We therefore conclude that nedocromil sodium 2% eye drops, administered twice daily, is an effective treatment for SAC in children.

High-dose nedocromil sodium as an addition to inhaled corticosteroids in the treatment of asthma.

In a double-blind placebo-controlled trial nedocromil sodium in a dose of 8 mg four times daily or matching placebo was added to the treatment of 29 asthmatic patients. All patients were taking inhaled corticosteroids in a dose of up to 1000 micrograms daily. The trial agents were given for 6 weeks after a 2-week run-in period. Twenty-four patients completed the study, three withdrew because of adverse effects, two on placebo. Daytime asthma symptoms were significantly reduced on nedocromil compared to placebo (-0.46 vs. +0.09, P = 0.03). Night-time asthma and morning tightness were not changed significantly. Bronchodilator use in the night and day were lower on nedocromil but the differences were not significant. Morning peak flow rates were higher on nedocromil (+22.2 vs. +0.08, P = 0.06) and physicians opinions of overall effectiveness favoured nedocromil (U = 35.0, P = 0.04). These results confirm that nedocromil sodium may be a useful addition in asthma to low to medium doses of inhaled corticosteroids. The effects of 32 mg nedocromil daily were comparable to previous reports with lower doses.

Group comparative trial of 2% nedocromil sodium with placebo in the treatment of seasonal allergic conjunctivitis.

A double blind group comparative trial comparing 2% nedocromil sodium with placebo in treating seasonal allergic conjunctivitis over a four week period is reported. Sixty-four patients were analysed. During the period of peak pollen challenge, statistically significant differences in favour of nedocromil sodium for itching and soreness were demonstrated. During a longer period of a less high pollen count, a significant difference in favour of nedocromil sodium was shown only for the symptom of soreness.

[Nedocromil in treating chronic bronchial asthma of a moderate course]. / Nedokromil w leczeniu przewleklej astmy oskrzelowej o sredniociezkim przebiegu.

Randomized, double blind, placebo controlled clinical studies aimed at evaluating the efficiency of nedocromil sodium (Tilade) in the form of metered dosimeter aerosol. Studies involved patients with moderate chronic bronchial asthma controlled with beta 2-agonists and theophylline in the form of sustained release preparations. Forty patients completed the studies. All patients were examined clinically (staging of the symptoms and doses of drugs) and spirometrically prior to and after 4 and 8 weeks of the treatment with nedocromil sodium. Statistically significant clinical improvement and spirometric improvement as well in patients treated with nedocromil sodium were noted. It may be concluded that nedocromil sodium is effective and well tolerated adjuvant therapy in the bronchial asthma.

Nedocromil sodium in contact-lens-associated papillary conjunctivitis.

Forty-five patients with contact-lens-associated papillary conjunctivitis (CLAPC) were included in a 6-week double-masked group comparative study of unpreserved 2% nedocromil sodium eye drops and placebo. Data were collected by diary card recording of symptoms and duration of lens wear, assessment of symptoms at clinic visits, biomicroscopic appraisal of signs on the globe and the upper tarsal conjunctiva, and laboratory analysis of tear and serum IgE levels. All assessments were made by the same clinician throughout the study. Diary card records demonstrated that there was significantly less itching in the nedocromil sodium group compared with the placebo group during weeks 1-3 of the study (p < 0.01), but not during weeks 4-6. Findings for duration of lens wear were inconclusive, due to differences between the groups at admission. Biomicroscopic assessment showed a significant difference in mucus found on the upper tarsal surface in favour of nedocromil sodium by the end of the study (p < 0.02). Twenty-one patients experienced adverse events during the study. The most common were taste and/or stinging on insertion of the drops. No significant difference was seen for tear or serum IgE between the two treatment groups during the study.