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This chapter provides an overview of some of the issues faced when considering the pharmacological treatment of asthma +/– exercise induced bronchospasm (EIB) in athletes. An understanding of the best approach to the pharmacological treatment of asthma and EIB is vital to any clinician wishing to optimise respiratory care in athletes. Mast cell stabilisers, disodium cromoglycate and nedocromil sodium, attenuate both asthma and EIB when inhaled shortly before exercise. The only precaution should be to avoid physical exercise just after receiving the injection. Ipratropium bromide can also be used, pre-exercise, to prevent EIB, although the effect is not consistent among patients and may be variable, even within the same patient. In the general asthma population, it is well recognised that both inhaler technique and treatment adherence is suboptimal in the vast majority of patients. Patient adherence to prescribed treatment has been also shown to represent a crucial link between effective therapy and improved disease outcomes.

Various studies have shown that flavones have several pharmacological activities including anti-allergy activities. However, the bioavailability of oral flavones is very low, and whether inhaled administration can improve efficacy in respiratory disease models is unclear. In the present study, the anti-allergic activities of inhaling 5,7-dimethoxy-3,4'-dihydroxyflavone (MHF), a synthetic flavonoid, was investigated by comparison with disodium cromoglycate (DSCG) and nedocromil sodium (NS) in rat allergic models. In an anti-DNP-IgE-induced asthmatic model, inhaled MHF dose-dependently inhibited the increase in airway resistance after antigen challenge. In an ovalbumin (OVA)-induced asthmatic model, inhaled MHF showed significant suppression of airway hyperresponsiveness; a decrease in eosinophil and neutrophil counts, IL-4, IL-5 and leukotriene D4 in bronchoalveolar lavage fluid; a reduction in total IgE and OVA-specific IgE levels in serum; and suppression of eosinophil infiltration in lung tissue after antigen challenge. The efficacy of inhaled MHF was comparable to that of NS and DSCG. In conclusion, based on these findings, the report for the first time that that inhaled MHF may be a potential drug for the treatment of allergic asthma.

In this review, we aim to summarize the currently available compounds targeting the different components of the inflammatory cascade triggered by an ocular allergic reaction, from mast cells to eosinophils and lymphocytes, with a special focus on specific signs and symptoms that are related to them.The article gives a review of topical therapies utilized to treat the various forms of allergic conjunctivitis, starting from the first drugs developed in the 1980s up to the new compounds that are currently being developed. These include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory agents, and topical immunosuppressants.The treatment options that have been developed for allergic conjunctivitis in the past 30 years are the result of a better understanding of the pathogenic mechanisms involved in the initiation and perpetuation of the ocular allergic reaction, which is guiding us toward a more specific treatment approach.Several reports and literature reviews have demonstrated that a better knowledge of the immunopathogenesis of the different types of ocular allergy has improved the treatment choice resulting in better clinical outcomes for ocular allergy sufferers. Specifically, the development of novel compounds targeting specific cells and/or cytokines involved in the ocular immune reaction provided safer and more tolerated drugs for both mild-to-moderate and severe forms of allergic conjunctivitis. The correlation of clinical responses to drugs with what we understand about the molecular mechanisms involved could possibly prove useful for developing more standardized treatments in the near future.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect.

G protein-coupled receptor-35 (GPR35) has been shown to be a target of the asthma drugs cromolyn disodium and nedocromil sodium. Gallic acid and caffeic acids are reported to modulate allergic reactions via unknown mode(s) of action. Here we attempt to elucidate whether both phenolic acids share a common mode of action with the two asthma drugs. Label-free dynamic mass redistribution (DMR) assays showed that both phenolic acids triggered robust DMR signals in HT-29 cells, whose characteristics were similar to that of cromolyn disodium. Both phenolic acids resulted in detectable β-arrestin translocation signals in an engineered U2OS cell line stably expressing a C-terminal-modified GPR35, but with lower efficacy than cromolyn disodium. Antiallergic wedelolactone was found to be a potent β-arrestin-biased GPR35 agonist. These results suggest that certain anti-inflammatory phytochemicals including gallic acid and wedelolactone may modulate inflammatory allergic action via their agonism at GPR35. GPR35 may represent a target for the treatment of allergic disorders including asthma.

Introduction: Mast cells are among the first cells to get involved in periodontal inflammation. Their numbers have been shown to be in-creased in cases of gingivitis and periodontal disease. The hypothesis: Since mast cell stabilizers like sodium cromoglycate (SCG) and nedocromil sodium (NS) have been used in the prophylaxis of bronchial asthma without any significant adverse effects and also the fact that drugs like SCG show significant anti-inflammatory activities, it would be logical to use mast cell stabilizers as host modulating drugs for the treatment and prevention of perio-dontal disease. Evaluation of the hypothesis: Safety and efficacy of both SCG and NS are well documented. So, it will be systemically safe to use in humans. However, oral administration SCG or delivery of the drug by means local irrigation will not be very useful because SCG may not be secreted in the gingival crevicular fluid (GCF)(as in the case of oral administraion) or the drug may get washed out from periodon-tal pocket due to the constant flow of GCF(as in the case of irriga-tion). A local or targeted drug delivery of mast cell stabilizers can be used in patients with periodontal disease. Role of mast cells in peri-odontal disease has been dealt in-depth in many studies and arti-cles. However, limited amount of research has been done on using mast cell stabilizers in the prevention and control of periodontal dis-eases. More studies are needed to study the efficacy and effective-ness of mast cell stabilizers as an adjunct to phase I therapy in the control of periodontal disease.

Objective— To determine whether the inhibitory action of the antiallergic cromone “mast cell stabilizing” drugs on polymorphonuclear leukocyte (PMN) trafficking is mediated through an annexin-A1 (Anx-A1) dependent mechanism. Methods and Results— Intravital microscopy was used to monitor the actions of cromones in the inflamed microcirculation. Reperfusion injury provoked a dramatic increase in adherent and emigrated leukocytes in the mesenteric vascular bed, associated with augmented tissue levels of myeloperoxidase. Nedocromil, 2 to 20 mg/kg, significantly ( P −/− mice. Short pretreatment of human PMNs with nedocromil, 10 nmol/L, inhibited cell adhesion ( P Conclusion— We propose a novel mechanism to explain the antiinflammatory actions of cromones on PMN trafficking, an effect that has long puzzled investigators.

We report that the asthma drugs cromolyn disodium and nedocromil sodium are potent G-protein-coupled receptor 35 (GPR35) agonists. We utilized calcium flux and inositol phosphate accumulation assays to examine the pharmacology of these asthma drugs on the human, mouse and rat GPR35. The compounds were more potent on the human GPR35 than on mouse and rat receptors. In contrast, zaprinast, a known GPR35 agonist, was more potent on mouse and rat GPR35 than the human ortholog. We show by quantitative PCR that GPR35 is expressed in human mast cells, human basophils and human eosinophils. We also demonstrate that GPR35 mRNA is upregulated upon challenge with IgE antibodies. We show that, unlike zaprinast, a potent phosphodiesterase 5 (PDE5) inhibitor, cromolyn disodium and nedocromil sodium lack inhibitory activity towards PDE5. These findings suggest that GPR35 may play an important role in mast cell biology and be a potential target for the treatment of asthma.

Nedocromil sodium has a number of known hydrate states, a monohydrate, a trihydrate and a heptahemihydrate, including an amorphous state. Effect of grinding on the hydration states of nedocromil sodium crystals was studied. After grinding the trihydrate, heptahemihydrate was observed in the ground sample, even though, the water content in the ground sample was not sufficient to cover the heptahemihydrate’s hydration level. On the other hand, in the ground heptahemihydrate, trihydrate was existed. Apparent activation energies (ΔE) for hydrates, monohydrate→anhydrate, trihydrate→monohydrate and heptahemihydrate→amorphous(anhydrate), were calculated using TG data. ΔE for the dehydration of heptahemihydrate was significantly lower than that of other hydrates. Obtained ΔE data explained the inter-conversion behavior of nedocromil sodium induced by grinding.

Exercise-induced asthma (EIA), now referred to as exercise-induced bronchospasm (EIB), is extremely common. The terms EIA and EIB, although not identical, are often used interchangeably in much of the literature. EIB is now the accepted term to avoid the mistaken impression that exercise causes asthma. Rather, exercise leads to bronchospasm in susceptible individuals, who may or may not have asthma. In this light, all patients with EIA have EIB, but the reverse is not true. This is especially true of athletes who demonstrate airway bronchial hyperactivity that may be a consequence of extreme performance conditions and hyperventilation.

The allergic response is comprised of an early phase and a late phase. The early phase, which occurs within minutes of allergen exposure in sensitized individuals, is characterized by the release of preformed mediators including histamine and proteases. The late phase, which tends to occur within 3–12 h after antigen exposure, involves the recruitment of additional cells to augment the inflammation. These cells may include eosinophils, basophils, monocytes, and lymphocytes (Fig. 37.1).

BackgroundThe purpose of this study was to determine the effects of diphenhydramine HCl and Nedocromil sodium for the prevention of postsurgical adhesion formation in rat model.MethodsSixty adult female rats were anesthetized by 5mg/kg ketamine hydrochloride. After opening the abdominal wall, a 2cm2 peritoneal layer was excised from the left abdominal wall and 10 longitudinal incisions of 2 to 3cm in length were made on the right parietal peritoneum. The abdominal wall was closed with 4/0 atraumatic continuous nylon sutures. Group I was the control group, group II was given 10mg/kg diphenhydramine HCl, group III was given 100mg/kg Nedocromil sodium, and group IV was administered both drugs in the above doses. All the drugs were instilled into the peritoneal cavity after abdominal closure except Nedocromil sodium which was administered in two separate doses 30min before surgery and just after abdominal closure. Relaparatomy was performed 2weeks after the initial surgery and abdominal adhesions were scored. Kruskal–Wallis and Mann–Whitney U-test were used for the statistical evaluation.ResultsThe mean±S.D. (median) of adhesion scores were 2.5±0.90 (2.0), 1.58±0.99 (1.0), 0.92±0.86 (1.0) and 1.75±0.75 (2.0) in group I, II, III and IV, respectively. There were significant differences between the scores of groups I and II (P=0.033), groups I and III (P

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.

Background: L-selectin (CD62L) is an adhesion molecule involved in leucocyte attachment to endothelium at sites of inflammation, and it has been demonstrated that L-selectin is rapidly shed after neutrophil activation. Recently, it has been reported that there is increasing evidence of neutrophil participation in asthma and the allergic process. Objective: The present study was designed to determine whether an IgE-dependent mechanism can modulate L-selectin expression on the surface of neutrophils. Moreover, we analyse the potential implication of intracellular signal-transduction pathways and whether specific immunotherapy (IT), glucocorticoids and antihistamines might regulate this process. Methods: Peripheral blood neutrophils from three groups of donors (asthmatic group without IT treatment, IT-treated asthmatic group and healthy group) were used. Cells were challenged in vitro with the specific allergen that produced clinical symptoms in asthmatic patients and also with the allergen to which the patients were not sensitive. Neutrophils from healthy donors were also challenged with allergens. Expression of CD62L on the neutrophil surface was analysed by flow cytometry, and soluble CD62L (sCD62L) in culture supernatant by ELISA. In an attempt to discover which IgE receptor is involved, we also challenged the neutrophils with monoclonal antibody to FcɛRI, FcɛRII (CD23) and galectin-3 receptors. Results: When neutrophils from allergic patients were challenged with specific allergens that produce clinical allergy symptoms, L-selectin was down-regulated from the surface of those cells, accompanied by a concomitant up-regulation of soluble L-selectin in the supernatant. The challenge with antibodies against FCɛRI, FCɛRII (CD23) and galectin-3, induces down-modulation of L-selectin on the surface of the neutrophils in all three cases. Calphostin C, wortmannin and manoalide attenuated CD62L down-regulation, suggesting the potential implication of protein kinase C, phosphatidylinositol 3-kinase and phospholipase A2 in the process. IT and glucocorticoids modulated allergen-dependent CD62L down-regulation, whereas antihistamines (terfenadine, loratadine and cetirizine) or nedocromil sodium did not affect the shedding of L-selectin. Conclusions: We present evidence that the neutrophil surface expression of CD62L can be modulated by an allergen-dependent mechanism. The modulation of CD62L expression can be induced through the three receptors of IgE. This process can be affected by IT.

Objective: Inhaled mannitol induces both bronchoconstriction and cough. Nedocromil sodium greatly attenuates mannitol-induced bronchoconstriction. Knowledge about the effect of nedocromil on mannitol-provoked cough might, therefore, clarify the mechanisms of this response. Methodology: Inhalation challenges with mannitol powder were performed after inhalation of 8 mg of nedocromil or its placebo in 24 subjects with asthma. The study was double-blind, randomised, and placebo-controlled. The mannitol-provoked coughs were manually recorded and the mannitol-induced bronchoconstriction was measured with a spirometer. Results: The cumulative dose of mannitol that provoked at least two coughs tended to be higher on the nedocromil day than on the placebo day (34 (22–53) mg vs 26 (18–37) mg, P = 0.051). The cumulative number of coughs per dose of mannitol was slightly, but significantly, lower on the nedocromil than on the placebo day (4.2 (2.8–6.3) coughs/100 mg vs 6.1 (4.0–9.4) coughs/100 mg, P = 0.037). However, when analysed on a constant-dose basis, nedocromil provided no protection for coughing (−1% protection), whereas the protection for bronchoconstriction was clear (55% protection). Conclusions: Nedocromil strongly attenuates mannitol-induced bronchoconstriction but has a negligible effect on mannitol-provoked cough. Therefore, these responses seem to have different pathways in asthma. Recording of both provoked coughs and induced bronchoconstriction during mannitol challenge may provide supplementary information about a patient's disease.

Summary Background In a previous study, iontophoresis of nedocromil sodium into human skin in vivo was shown to reduce histamine-induced itch and flare. In asthma, the Na+/K+/2Cl− cotransporter inhibitors, frusemide and bumetanide, have been reported to have many similar actions to nedocromil sodium. Objective To compare the effects of these drugs in the histamine-induced itch, flare and weal response in human skin in vivo and elucidate their site of action. Methods Nedocromil sodium, frusemide bumetanide and reversed osmosis water (control), were introduced by iontophoresis into the forearm skin of 10 volunteers in each of two single-blind studies. In study 1, histamine (20 μL of 100 μm) or vehicle was injected into the area of iontophoresis 10 min later. In study 2, histamine or vehicle was injected 5 mm outside the area of iontophoresis so the flare developed over the area of iontophoresis. Itch was scored on a visual analogue scale every 20 s for 5 min, flare areas were assessed using scanning laser Doppler imaging up to 10 min and weal was assessed by planimetry at 10 min. Results In study 1, nedocromil sodium, frusemide and bumetanide reduced itch scores by 36%, 48% and 34%, respectively, and flare areas by 17%, 26% and 15% respectively (all P

The conventional model-fitting approach to kinetic analysis assumes a fixed mechanism throughout the reaction and therefore may be too simplistic for many solid-state reactions. Even for a reaction with a fixed mechanism, model fitting sometimes cannot identify the reaction model uniquely. The alternative model-free approach is sufficiently flexible to allow for a change of mechanism during the course of a reaction and therefore provides a more realistic treatment of solid-state reactions kinetics. The application of model-free analysis to solid-state dehydrations was investigated using the two consecutive dehydration reactions of nedocromil sodium trihydrate. The complexity of such reactions is illustrated by the variation of the activation energy as each dehydration proceeds. The 1st-step dehydration follows one-dimensional phase boundary kinetics until the fraction dehydrated reaches 0.75, and deviates from this model thereafter. The 2nd-step dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. The model-free approach is clearly better than the model-fitting approach for understanding the details of these solid-state dehydration reactions.

Ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution are 2 topical antiallergic medications with different modes of action and efficacy profiles. Both solutions are indicated for ocular itching associated with allergic conjunctivitis.This study compared the efficacy, safety, and comfort of ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution for the prevention of ocular itching, using the conjunctival allergen challenge (CAC) model.This was a single-center, double-masked, contralateral, randomized, placebo- and active-controlled CAC clinical trial. Subjects aged10 years with a history of allergic hypersensitivity who responded to the CAC at screening visits 1 and 2 qualified for randomization at visit 3. At visit 3 (day 21) and visit 4 (day 35), subjects received 1 of 3 treatments: ketotifen, nedocromil, or placebo (artificial tears), randomized by eye. Allergen challenges were conducted at 5 minutes posttreatment dose (visit 3) and 12 hours posttreatment dose (visit 4). At each visit, subjects evaluated their ocular itching every 30 seconds for 20 minutes. At visit 4, subjects evaluated the comfort of the medication immediately after instillation, at 30 seconds after instillation, and at l, 2, 5, and 10 minutes after instillation. The subjects were also queried about overall eyedrop comfort by choosing from descriptive terms and about overall eyedrop preference based on comfort and perceived efficacy.Eighty-five subjects were screened for this study. Fifty-nine (28 males, 31 females; mean age, 38.7 years) qualified and were randomized to receive study medications. Ketotifen-treated eyes experienced significantly less ocular itching induced by CAC than nedocromil-treated eyes and those that received placebo at both the 5-minute and 12-hour posttreatment allergen challenges (all P0.05). Nedocromil-treated eyes showed no statistical or clinical differences from placebo at any time point. Ketotifen-treated eyes showed no differences in comfort from those that received placebo but were significantly more comfortable than nedocromil-treated eyes at 1, 2, 5, and 10 minutes after instillation (all P0.05). On the basis of comfort and subjective efficacy, 60% of subjects preferred ketotifen, 21% preferred nedocromil, and 19% preferred placebo.Ketotifen was significantly more effective and comfortable than nedocromil at both 5 minutes and 12 hours after administration in this CAC model.

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

In asthmatic children with persistent symptoms, maintenance therapy with nedocromil sodium, inhaled corticosteroids, or montelukast is associated with a decreased rate of asthma exacerbations. The greatest benefit is seen with use of regular inhaled corticosteroids in preschool- or school-age children, in whom asthma exacerbations, the need for rescue oral corticosteroids, unscheduled urgent medical visits, and hospitalizations are all decreased by approximately 50%. However, maintenance therapy is not beneficial in children with intermittent respiratory virus-induced wheezing without persistent symptoms. (J Pediatr 2003;142:S21-S25)

Background: Airway inflammation plays a central role in the pathogenesis of asthma, even in the mildest forms and at the earliest stages. Therapeutic strategies now aim to relieve bronchoconstriction as well as focus primarily on controlling the underlying inflammatory process. Clinical trials of children and adults with asthma have demonstrated that inhaled corticosteroids and cromones (such as nedocromil sodium [NS]) improve symptoms and lung function, as well as decrease nonspecific bronchial hyperresponsiveness. Objective: The aim of this study was to compare the effects of various anti-inflammatory therapeutic regimens using inhaled fluticasone propionate (FP) and/or NS on airway hyperresponsiveness to methacholine. Methods: Patients with mild, persistent asthma, who tested positive to a Dermatophagoides pteronyssinus skin prick test, were randomly assigned to 1 of 4 treatment groups: (1) FP for 16 weeks; (2) FP for 8 weeks, followed by NS for 8 weeks; (3) NS for 8 weeks, followed by FP for 8 weeks; or (4) NS for 16 weeks. Each patient was evaluated every 4 weeks. Results: Thirty-two patients with asthma (16 men and 16 women; age range, 18–48 years) were included in the study; 8 patients were randomly assigned to each of the 4 treatment groups. During treatment with FP alone, the provocative dose of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second (PD 20 ) was significantly higher than that recorded during treatment with NS alone (P 20 versus baseline values throughout the study. Moreover, when FP was administered as the second drug (after NS), a further increase in PD 20 compared with the values at week 8 occurred at both week 12 ( P P 20 decreased significantly compared with week 8 ( P P Conclusions: Our results suggest that, in this limited population of asthmatic patients who were treated for 16 weeks, FP was effective in increasing the PD 20 and that NS exerted an effective, progressive protective action against bronchial hyperresponsiveness to methacholine, thereby partially limiting the negative consequences of FP withdrawal on airway inflammation.

Inhalation of ultrasonically nebulised distilled water (fog) induces cough; however, the receptor type(s) mediating this reflex are poorly defined. In humans, cough threshold can be determined by inhalation of progressively increasing fog concentrations; the intensity of the associated motor response can be indexed in terms of flow-related variables as well as of the peak and slope of the integrated electromyographic activity of the abdominal muscles. We have evaluated coughing in patients with Parkinson's disease who show a high incidence of serious chest infections. These patients turned out to have a normal cough threshold but reduced expiratory muscle force during reflex coughing; this suggests an impairment in the central mechanisms subserving muscle activation possibly leading to inefficient airway clearing. Recurrent chest infections also affect laryngectomised patients. These patients have a normal cough threshold but reduced muscle force during coughing in response to threshold stimuli. Voluntary coughing is preserved in these patients, and this should be used to facilitate mucus removal. In normal subjects, fog inhalation causes cough and increases in respiratory drive and minute ventilation, mainly accounted for by increases in tidal volume, possibly due to activation of airway rapidly adapting receptors. Nedocromil sodium administration increases cough threshold and attenuates the ventilatory responses. The assessment of sensory and motor components of coughing may represent a useful tool for those investigating cough in humans.

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

Mast cells have been implicated in chronic inflammatory conditions resulting in fibrosis, such as Crohn disease. However, a link between inflammation, fibrosis and mast cells has not been demonstrated in human or animal intestinal diseases. This work was undertaken to analyze whether mast cells play a role in inflammation and fibrosis in the TNBS-induced rat colitis.Rats were rectally instilled 2,4,6,-trinitrobenzene sulfonic acid in ethanol, and immediately or 4 days later injected daily i.p. with nedocromil sodium, a mast cell stabilizer, compound 48/80, a mast cell activator, or saline. Rats were sacrificed 5 days post-TNBS, or on day 21. Intestinal inflammation and fibrosis were assessed by gross and histopathological evaluation. Colonic mast cell numbers (toluidine blue) and collagen (type I mRNA expression) were evaluated. Mast cell sonicate was added to rat colon fibroblasts. Fibroblast proliferation (3H-thymidine), collagen synthesis (3H-proline) and contractile activity (tridimensional collagen lattice contraction) were then assessed.Nedocromil reduced inflammation and fibrosis possibly by decreasing mast cell numbers and activation and consequent collagen production. Compound 48/80 slightly enhanced the severity of the disease by activating mast cells. Mast cells increased fibroblast proliferation, collagen production and contractile activity.Mast cells are involved in the gastrointestinal tract inflammation and fibrosis of the TNBS-colitis rats.

To evaluate nedocromil sodium 2% ophthalmic solution for the treatment of sea-sonal allergic conjunctivitis, 24 golfers with documented ragweed-pollen allergy instilled eyedrops twice daily for 4 days prior to golf-course intervention and 15 minutes before playing a round of golf during peak ragweed season. Ocular symptoms were scored at baseline (7 days before golfing), prior to instillation on the day of golf, and 30 minutes, and 1, 4, 8, and 12 hours after tee-off. Physician assessment was performed prior to tee-off, before tee-off on the ninth hole, and at the end of the 18th hole. Itching, burning, grittiness, tearing, redness, and light sensitivity were significantly decreased after nedocromil administration, as were erythema, edema, conjunctival hyperemia, and overall findings in the conjunctiva. Symptom severity scores fell approximately 30 minutes after instillation, with improvements persisting 8 and 12 hours after treatment. Most patients (92%) rated the treatment moderately or completely effective, and 83% were willing to continue its use. Physician assessments of effectiveness agreed with those of the patients. In this open-label study, nedocromil sodium eyedrops relieved the ocular symptoms of seasonal allergic conjunctivitis for up to 12 hours, well beyond a usual round of golf.

Nedocromil sodium and levocabastine are widely used for the treatment of ocular allergy, but their mechanisms of action are unclear.We sought to compare the efficacy and mechanisms of action of nedocromil sodium and levocabastine in reducing conjunctival symptoms after ocular allergen challenge.We performed a double-blind, placebo-controlled study in which 48 subjects were randomized to 3 groups to receive nedocromil sodium (2%), levocabastine (0.05%), or placebo eye drops twice daily for 2 weeks before ocular challenge with 10 microL of ryegrass extract. Symptoms and tear histamine and PGD(2) concentrations were determined before challenge and at 10, 20, 30, 60, 180, and 360 minutes after challenge. Bulbar biopsy specimens were taken at 6 and 24 hours after challenge to assess conjunctival inflammatory cell numbers, adhesion molecule expression, and mast cell-associated IL-4, IL-5, IL-6, IL-13, and TNF-alpha levels.Both drugs significantly reduced total symptom scores (P.05) at all times after challenge compared with placebo. Itching, hyperemia, and lacrimation were most affected. Nedocromil sodium treatment reduced tear concentrations of histamine (by 77%) and PGD(2) (by 70%) at 30 minutes after challenge (both P.05). In biopsy specimens nedocromil sodium reduced the number of 3H4-positive mast cells (purportedly the secreted form of IL-4) by 49% at 6 hours and 59% at 24 hours (both P.05). Levocabastine reduced intercellular adhesion molecule 1 expression by 52% at 6 hours and 45% at 24 hours (both P.05).Nedocromil sodium and levocabastine both reduced the conjunctival symptoms after ocular allergen challenge but appeared to work by different mechanisms. Nedocromil sodium reduced mast cell function, whereas levocabastine appeared to have primarily antihistaminic actions, although it also reduced the expression of intercellular adhesion molecule 1.

We examine the respiratory, bronchomotor, cardiac, and vascular responses to histamine and ragweed allergen delivered to the bronchi or alveoli compartments and the potential role of sensory nerves and reflexes mediating the histamine-induced responses. The masses of aerosols deposited in the bronchi and alveoli were quantitated using radioaerosol techniques. Activation of sensory nerves and/or histamine-induced mediator release were characterized by depositing nedocromil sodium aerosol prior to histamine challenge. The histamine-induced responses due to vagosympathetic transmission were determined by performing bilateral vagotomy. Both histamine and ragweed increased respiratory rate, ventilation, and bronchomotor tone whether deposited in the bronchial or alveolar regions. However, these responses were not elicited when histamine was administered intravenously. Precipitous allergen-induced decreases in heart rate and systolic and diastolic pressure were maximal 72 sec following ragweed deposition in alveolar regions of the lungs. Increases in respiratory rate were mediated via the vagus whether delivered to the bronchi, alveoli, or vasculature. Histamine-induced increases in respiratory rate and bronchomotor tone were attenuated by nedocromil. When histamine was delivered to the alveolar regions, increases in lung resistance appeared to be mediated primarily via the vagus and when delivered to the bronchial airways primarily by its action on smooth muscle or local reflexes. Histamine-induced hypotension and bradycardia appear to be mediated by the direct action of histamine on the cardiovascular system rather than through a vagally mediated reflex.

Background: The purpose of this study was to determine the clinical effect of nedocromil sodium and its relationship with serum levels of inflammatory mediators by monitoring lung function and noninvasive markers of airway inflammation, such as eosinophil blood counts; serum ECP, sIL-2R, IL-4 and sICAM; and total IgE. Anti-inflammatory medications cause a reduction in the markers of airway inflammation, decrease the intensity of airway hyperresponsiveness, and improve clinical symptoms of asthma. Among the available choices is nedocromil sodium, which is favored in the treatment of asthmatic children due to its very mild side-effects. It has been previously shown to improve the clinical parameters of asthma, but there are limited data on its effect on inflammatory mediators in the serum of asthmatic children. Methods: In this double-blind, randomized, placebo-controlled 8-week trial, 39 children, aged 9–16 years, with moderate atopic asthma were randomly allocated to receive either nedocromil sodium, two puffs twice daily, 0.002 g/puff, or placebo, two puffs twice daily. The primary end points were the clinical parameters of asthma measured by asthma symptom score, FEV1, and PC20H. Other end points included the serum levels of various inflammatory markers – ECP, sIL-2R, IL-4, sICAM, and IgE. Results: Clinical and inflammatory parameters improved with the use of nedocromil sodium, compared with placebo. Nedocromil significantly decreased serum levels of inflammatory markers, as shown in the following table. No correlation was found between any of the measured parameters. Conclusions: Nedocromil sodium provided effective anti-inflammatory treatment for children with moderate atopic asthma.

This study was designed to test the hypothesis that nedocromil sodium inhibits sensory nerve function to reduce flare and itch in human skin. Nedocromil sodium (2%) or water (control) was introduced into the volar forearm skin of eight non-atopic volunteers by iontophoresis (8 mC) and histamine (20 microl of 1 microM and 300 nM) injected intradermally 10 min later at the same site. Itch was assessed on a visual analogue scale every 20 s for 5 min. Weal and flare areas and mean blood flux within the flare were assessed by scanning laser Doppler imaging at 10 min. The results showed that nedocromil sodium reduced itch scores, totalled over 5 min, by approximately 74.0% (P

The objective of this review was to compare the effects of prophylactic doses of nedocromil sodium (NCS) and sodium cromoglycate (SCG) on postexercise lung function, in persons diagnosed with exercise-induced bronchoconstriction.Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register, plus hand searching for trials in journals, bibliographies of relevant studies and review articles. Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were pooled using odds ratios (OR) for dichotomous outcomes or weighted mean differences (WMD) with 95% confidence intervals (95% CI) for continuous outcomes.No significant differences were noted between NCS and SCG with respect to the maximum per cent decrease in forced expiratory volume in one second (WMD=−0.88; 95% CI −4.50–2.74), complete protection (OR=0.95; 95% CI 0.50–1.81), clinical protection (OR=0.71; 95% CI 0.36–1.39), unpleasant taste (OR=6.85; 95% CI 0.77–60.73), or sore throat (OR=3.46; 95% CI 0.32–37.48). Subgroup analyses based on age, dosages of medications and timing of exercise postinhalation were consistent with the overall pooled analyses.No significant differences were evident between the effects of nedocromil sodium and sodium cromoglycate during the immediate postexercise period in adults and children with exercise-induced bronchoconstriction, with regards to maximum per cent decrease in forced expiratory volume in one second, complete protection, or clinical protection. Side-effect profiles were similar.

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

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of ∼1 μm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the “micronized” nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12–76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1160–1169, 2000

A six-stage model is proposed to describe the overall process of sorption of water vapor on and into anhydrous nedocromil sodium. The way in which temperature, pressure, and time affect the rate of reaction for each of the stages has been analyzed. Experimental data for the measured rates, where temperature, pressure, and time are variables, are compared with the predictions obtained from each of the six stages. The most useful comparator is a graphical representation of reduced time versus hydration rate. The theoretical equations presented as a shape analysis of the experimental curves show the process to have different controlling mechanisms in three temperature regions: up to 27 degrees C, hydration is controlled by a nucleation and growth mechanism; between 27 and 31 degrees C, the process is dominated by diffusion of water molecules into the crystal; and >31 degrees C, neither nucleation nor diffusion are controlling but some, as yet, undetermined physical processes.

Nedocromil sodium inhibits the response to exercise-induced asthma (EIA). Mannitol given as a powder by inhalation is an osmotic stimulus that identifies EIA. We studied the acute effect of nedocromil on airway responsiveness to mannitol in 24 asthmatic subjects. After a control day, nedocromil (8 mg) or its placebo was administered randomized, double blind, 10 min before a challenge with progressively increasing doses of mannitol. Nedocromil inhibited the response to mannitol and there was a significant increase in the dose of mannitol required to cause a 15% reduction in FEV(1) (PD(15)) after nedocromil 409 (316,503) mg compared with placebo 156 (106,229) mg (p0.001). In the presence of nedocromil 12 subjects no longer recorded a 15% decrease in FEV(1) in response to mannitol. The remaining 12 required a significantly greater dose of mannitol to achieve a 15% decrease in FEV(1) after nedocromil. Following nedocromil, a plateau in responsiveness to mannitol was observed in 14 subjects. Nedocromil significantly inhibits the responsiveness to inhaled mannitol in asthmatic subjects.

The effect of the spacers (Fisonair, Breath-A-Tech, Volumatic and Nebuhaler) on the in vitro aerosol characteristics of two propellant-driven metered dose inhalers (MDIs), Tilade (nedocromil sodium) and Intal (disodium cromoglycate), was studied. The measurement was carried out on a Marple-Miller impactor operating at 30 l/min. Five actuations were collected for the drug assay. The results showed that Tilade (label claim 2 mg active per actuation) and Intal (label claim 5 mg active per actuation) generated aerosols with a fine particle mass (FPM, i.e. mass of particles 5 microm in the aerosol) of 0.34 mg (S.D. 0.01, n = 4) and 0.02 mg (S.D. 0.01, n = 4) per actuation, respectively. For both inhalers, large volume spacers increased (Fisonair > Nebuhaler > Volumatic) while small volume spacer (Breath-A-Tech) decreased the FPM. The FPM (per actuation) for Tilade with Fisonair, Nebuhaler, Volumatic and Breath-A-Tech was 0.52 (0.03), 0.45 (0.03), 0.41 (0.04) and 0.09 (0.04) mg, respectively, while for Intal the corresponding values were 0.41 (0.02), 0.32 (0.04), 0.28 (0.03) and 0.08 (0.01) mg. Thus, the fine particle mass can be either increased or decreased, depending on the spacer selected. In addition, all spacers significantly reduced the coarse particle (> or = 10 microm) mass, with Fisonair, Breath-A-Tech, Nebuhaler and Volumatic producing only 7.6, 0.4, 5.2 and 2.6, respectively of that from Tilade alone and 15.6, 0.7, 5.4 and 4.1%, respectively of that from Intal alone. The general trends for Tilade and Intal were similar but not quantitatively identical. The proper choice of spacers is therefore important for the optimal delivery of Tilade and Intal.

Nedocromil sodium is a nonsteroidal anti-inflammatory drug used to control asthmatic attacks. Our hypothesis is that nedocromil sodium inhibits virus-induced airway inflammation, a common trigger of asthma. We nebulized nedocromil sodium into beagle dogs (n = 10, mean +/- SEM ages: 149 +/- 13 days) before and after inoculation with canine adenovirus type 2 (CAV2). Control dogs (n = 10) received saline aerosols and were either infected with CAV2 (Sal/CAV2, n = 7, mean +/- SEM ages: 140 +/- 11 days) or were not infected (Sal/Sal, n = 3, ages: 143 +/- 0 days). All dogs were anesthetized with choralose (80 mg/kg i.v.), intubated, and mechanically ventilated. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed using standard techniques. Pulmonary function tests revealed no significant change between the nedocromil sodium and non-nedocromil-treated groups. The percentage of infected bronchioles was quantitated as the number of inflamed airways of 40 bronchioles examined times 100 for each dog. Nedocromil-treated dogs had significantly (p < 0.05) less mucosal inflammation (mean +/- SEM, 39% +/- 5%), epithelial denudation (36% +/- 5%), and BAL neutrophilia (11 +/- 3) than did Sal/CAV2 dogs (51% +/- 6%, 57% +/- 4%, and 33% +/- 8%, respectively). We concluded that pretreatment with nedocromil sodium aerosols attenuated CAV2-induced airway inflammation in these beagle puppies.

The effects of intravenous administration of nedocromil sodium were investigated in active and passive models of conjunctival immediate hypersensitivity in rats. In the active sensitization model, animals were immunized with ovalbumin 21 days prior to ocular instillation of a solution containing ovalbumin. Nedocromil sodium administered prior to antigen challenge significantly inhibited emergence of conjunctival edema and erythema (P < .05) and reduced mast cell degranulation (P < .02). In the passive-sensitization model, the conjunctiva in one eye was injected with ovalbumin antiserum 48 hours prior to intravenous administration of ovalbumin. Nedocromil sodium administered prior to antigen challenge significantly and dose-dependently reduced appearance of the signs of conjunctivitis (P < .01) as well as vascular leakage (P < .05). These data indicate that intravenous nedocromil sodium is effective in animal models of allergic conjunctivitis and may have potential for wider therapeutic application. These data are also consistent with results of clinical studies in which nedocromil sodium relieved symptoms of allergic conjunctivitis and further support a role for nedocromil sodium in the prevention of allergic conjunctivitis.

Purpose. Nedocromil sodium (NS), which is used in the treatment ofreversible obstructive airway diseases, such as asthma, has been foundto exist in the following solid phases: the heptahemihydrate, thetrihydrate, a monohydrate, an amorphous phase, which contains variableamounts of water, and a recently discovered methanol + water (MW)solvate. Our aim was to apply 13C solid-state nuclear magneticresonance (NMR) spectroscopy and solid-state Fourier transform infrared(FTIR) spectroscopy to the study of specific interactions in the varioussolid forms of NS.

OBJECTIVE: To assess the proportion of patients with moderate or severe persistent asthma who are on prophylactic therapy when first evaluated at a specialized outpatient center. METHODS: Descriptive study of 306 patients with persistent asthma and ages ranging from four to fifteen years old, seen from June/1995 to August/1998, at the Respiratory and Allergic Diseases section of the Child and Adolescent Institute, an outpatient reference center located in the town of Juiz de Fora (MG), Brazil. Data from the Institute's registry, chiefly those related to the use of prophylactic medications, such as inhaled steroids, sodium chromoglycate, nedocromil sodium, sustained-release theophylline, long acting inhaled beta2-agonist and ketotifen were used to fill in a standardized protocol. RESULTS: Of the 306 patients, 87.3% had persistent moderate and 12.7% had persistent severe asthma. Only 14.4% were on some kind of controller medication. When only the use of inhaled antiinflammatory drugs (sodium cromolyn, nedocromil sodium and steroids) was considered, this proportion decreased to 4.6%. There was not statistical significance (p

Matrix metalloproteinases (MMPs) are particularly potent in degrading basement membrane collagen associated with lung injury in inflammatory processes. We have investigated the effects of betamethasone, cyclosporin, and nedocromil on MMP2 and MMP9 activities, on TNF-alpha and IL-10 release, as well as on the recruitment of inflammatory cells in the bronchoalveolar lavage (BAL) fluid after aerosol administration of lipopolysaccharide (LPS) in mice. When mice were pretreated with betamethasone (5 mg/kg, po), MMP2 and MMP9 activities, TNF-alpha in BAL fluids, and the enhanced neutrophil number of LPS-exposed mice were reduced, whereas the level of IL-10 was increased. Pretreatment of mice with cyclosporin (10 mg/kg, po) did not significantly reduce MMP activities, but cyclosporin inhibited neutrophil recruitment, inhibited increase TNF- alpha and inhibited IL-10 decrease. Nedocromil sodium (30 mg/kg, ip) had no influence on the LPS-induced MMP activities, on neutrophil recruitment, or on IL-10 level, but this drug elicited a significant inhibition of TNF- alpha level. These results showed that treatment with the antiinflammatory drugs cyclosporin and nedocromil sodium did not lead to reduction of MMP release. However, since betamethasone reduced the LPS-induced pulmonary inflammation and production of MMPs, these results suggest that corticosteroids may decrease tissue remodelling associated with acute lung injury.

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.

BACKGROUND—Current guidelines on the treatment of childhood asthma recommend the introduction of an anti-inflammatory drug in children who have persistent symptoms and require regular treatment with a bronchodilator. The efficacy and safety of inhaled nedocromil sodium (Tilade Mint aerosol) administered using a Fisonair spacer at a dose of 4 mg three times daily was compared with placebo in the treatment of asthmatic children aged 6-12 years who are symptomatic and recovering from an acute exacerbation of asthma. METHODS—A group comparative, double blind, placebo controlled trial was performed in children who were recovering from an acute episode of asthma following treatment in the emergency department of the hospital or in children referred from their general practitioner following a wheezing episode and documented evidence of at least two previous episodes of wheezing. A two week baseline period on existing bronchodilator treatment was followed by a 12 week treatment period on either nedocromil sodium (2 mg/puff) or placebo. Both treatments were administered using a Fisonair spacer at a dose of two puffs three times daily. Changes from baseline values in daytime asthma and night time asthma symptom scores, usage of rescue bronchodilators, mean peak expiratory flow (PEF) recorded twice daily on diary cards, patients' opinion of treatment, and withdrawals due to treatment failure were measured during the primary treatment period (last six weeks of treatment). RESULTS—One hundred and forty two children aged 6-12 years entered the baseline period. Sixty three were withdrawn due to failure to meet the entry criteria (18) or the criteria for asthma symptom severity (15) or reversibility (9), because they developed uncontrolled asthma (2), because they took disallowed treatment (2), or for other non-trial related reasons (17). Seventy nine patients (46boys) of mean age 8.8 years entered the treatment period. There were significant differences in the changes from baseline values during the last six weeks of treatment in favour of nedocromil sodium compared with placebo in the primary variables of daytime asthma and night time asthma, morning and evening PEF, and the usage of rescue inhaled bronchodilators; 53% of patients reported nedocromil sodium to be very or moderately effective compared with 44% placebo. Improvement in asthma symptoms, PEF, and reduction in use of rescue bronchodilators did not reach statistical significance until after six weeks of treatment. Twenty two patients were withdrawn or dropped out during the treatment phase, 12 due to uncontrolled asthma or persistence of asthma symptoms, four due to suspected adverse drug reactions (nedocromil sodium 3 (headaches 2, angio-oedema/urticaria 1), placebo 1(persistent cough)), and six due to non-treatment related reasons. Seventy one adverse events were reported by 27patients in the nedocromil group and 75 by 30 patients in the placebo group. CONCLUSIONS—Asthma symptoms, use of bronchodilators, and lung function can be improved significantly in children recovering from an acute exacerbation of asthma or wheeze and currently receiving treatment with bronchodilators alone by the addition of inhaled nedocromil sodium at a dose of 4 mg three times daily administered using a Fisonair holding chamber.

Second generation antihistamines (anti H1) are effective for seasonal and perennial rhinoconjunctivitis curative or preventive treatment in children. They are better tolerated than first generation drugs. They probably do not act specifically against asthma itself, but are nevertheless useful for relief of nasal obstruction, which is an asthmogenic factor frequently linked with bronchial asthma. The therapeutic relevance of oral ketotifen and inhaled chromones (sodium cromoglycate, nedocromil sodium) is unequally considered among pediatricians. However, their efficacy has been clearly demonstrated as a ground treatment in mild-to-moderate asthmatic children. Chromones are also useful in preventing exercise-induced asthma. Because of their low cost and the lack of potential side effects, and according to the guidelines established in 1997 by the National Heart, Lung and Blood Institute, they should be prescribed at first sight in these indications.

Allergic eye conditions, particularly seasonal allergic conjunctivitis (SAC), are common. Itching, oedema and hyperaemia are relieved with topical H1-antagonists or sodium cromoglycate. The newer mast-cell stabilizing agent nedocromil sodium has a similar safety profile to sodium cromoglycate, but is more potent and has a more convenient twice-daily dosing regimen. When several placebo-controlled studies of its use in the treatment of SAC were analysed, it was found that 80% of patients reported symptom relief. In a further study, nedocromil sodium eyedrops (twice-daily dosing) had similar overall efficacy to sodium cromoglycate eyedrops (four-times-daily dosing) in subjects with SAC during the birch season, but during the period of highest pollen challenge, only the former agent was significantly more effective than placebo. Another study found that nedocromil sodium had efficacy equivalent to levocabastine over 7 days, but tended to have a more rapid onset of action. In patients with perennial allergic conjunctivitis (PAC) unresponsive to sodium cromoglycate, both clinicians and patients reported significantly better control of symptoms with nedocromil sodium eyedrops than with placebo. Recently, in a long-term study of treatment for vernal keratoconjunctivitis (VKC), it was found that nedocromil sodium 2% eyedrops produced a more rapid and marked improvement in symptoms than sodium cromoglycate 2% eyedrops and enabled lower use of steroid rescue medication. Both drugs were well tolerated and without serious side-effects.

Chromones (sodium cromoglycate and sodium nedocromil) block cell swelling-activated Cl- channels in NIH-3T3 fibroblasts and endothelial cells. This has led to hypothesize that cell volume regulation might be involved in asthma pathogenesis. Using whole-cell patch-clamp experiments, we studied the effect of chromones on volume-sensitive Cl- currents in transformed human tracheal epithelial cells (9HTEo-) and in primary cultures of human bronchial epithelial cells (BE). Cl- currents activated by hypotonic shock were poorly blocked by extracellular nedocromil or cromoglycate. The block was voltage-dependent since it was observed only at positive membrane potentials. At the concentration of 5 mM, the current inhibition by both chromones at +80 mV was about 40% for 9HTEo- and only 20% for BE. Intracellular application of chromones elicited a voltage-independent inhibition in 9HTEo- cells. Under this condition, volume-sensitive Cl- currents were reduced at all membrane potentials (60 and 45% inhibition by 2 mM nedocromil and cromoglycate respectively). In contrast intracellular chromones were ineffective in BE cells. The relative refractoriness to chromones, in contrast with the high sensitivity shown by other Cl- channels, suggests that the epithelial volume-sensitive Cl- channel is not involved in asthma.

The effects of budesonide, nedocromil sodium and salmeterol on bronchial hyperresponsiveness were determined over a period of 3 weeks.Forty-three asymptomatic children (22 male, 21 female, aged 7-17 years) with mild-to-moderate asthma were evaluated. The study was placebo-controlled and double-blind. At the beginning the forced expiratory volume in 1 second (FEV1) was measured and a methacholine challenge was performed to determine PC20 (provocative concentration of inhaled methacholine required to reduce FEV1 by 20%). The patients in group I (n = 12), group II (n = 10), group III (n = 11), and group IV (n = 10) inhaled 200 micrograms of budesonide, 2 mg of nedocromil sodium, 25 micrograms of salmeterol and a placebo, respectively, twice a day over the period of 3 weeks. Then the methacholine PC20 values of all patients were measured again and the results were compared statistically with their previous values.The statistical data revealed that the methacholine doses in PC20 before and after treatment were different in group I (P0.01). However, these differences were not statistically significant in the other groups (P0.05).The short term usage of budesonide decreases bronchial hyperresponsiveness, but nedocromil sodium and salmeterol in the given dises do not affect bronchial hyperresponsiveness.

Airway inflammation is the most important component of asthma. Leukotrienes (LTB4, LTB-C4, LTB-D4, LTB-E4) and platelet-activating factor (PAF) play an important role in this inflammation. The pulmonary and peripheral leukocytes of asthmatics have a high potency of mediator-releasing activity after specific stimuli, and plasma levels of these are higher than in healthy controls. Nedocromil sodium (NES) is an inhaled anti-inflammatory drug and its inhibitory effect on inflammatory or epithelial cells has been demonstrated. The aim of this study was to determine whether inhaled NES affects plasma levels and release of PAF and leukotrienes from peripheral leukocytes of asthmatic children that were stimulated by house dust mites (as a specific allergen). Twenty-eight children (9 to 15 years of age) with atopic bronchial asthma were included in the study. They consisted of two age- and sex-matched groups (14 patients in the treatment group [group I]; 14 patients in the control group [group II]). Group I patien...