Nedocromil Research Articles

Nedocromil sodium and diphenhydramine HCl ameliorate exercise-induced arterial hypoxemia in highly trained athletes.

IntroductionExercise‐induced arterial hypoxemia (EIAH) has been observed in highly trained endurance athletes during near maximal exercise, which may be influenced by a histamine‐mediated inflammatory response at the pulmonary capillary‐alveolar membrane. In order to test this hypothesis, we examined whether the mast cell stabilizer nedocromil sodium (NS) and H1‐receptor antagonist diphenhydramine HCL (DH) would ameliorate EIAH and mitigate the drop in arterial oxyhemoglobin saturation (SaO2) during intensive exercise.MethodsSeven highly trained male cross country runners (age, 21 ± 2 years; V̇O2max, 74.7 ± 3.5 ml·kg−1·min−1) participated in the study. All subjects completed a maximal exercise treadmill test to exhaustion, followed by three 5‐min constant‐load exercise bouts at 70%, 80%, and 90% V̇O2max. Prior to testing, subjects received either placebo (PL), NS, or DH.ResultsCompared to PL, there was a significant treatment effect on SaO2 (p < 0.001) for both NS and DH during both constant‐load exercise and at V̇O2max. Post hoc tests revealed SaO2 values, compared to PL, were significantly higher at V̇O2max and during DH trials and higher with NS at constant‐load intensities except at 70% (p = 0.13).ConclusionThe findings provide further evidence that histamine contributes directly or indirectly to the development of EIAH during intense exercise in highly trained athletes.

Effects of vitamin E, methylprednisolone and nedocromil sodium on healing of rats with experimentally created intraabdominal adhesions

IntroductionIntraabdominal adhesions are a condition that can occur after many surgical procedures and may cause complications in a spectrum ranging from simple abdominal pain to ileus. For years, efforts have been made to prevent this complication. In this experimental study, the effects of methylprednisolone, vitamin E and nedocromil sodium on the improvement of intraabdominal adhesions in rats were investigated.Material and methodsTwenty Wistar Albino rats weighing 280 to 330 g were divided into four equal groups. 5 ml of 0.9% NaCl was given to the control group, 5 ml of methylprednisolone was given to group 2, 5 ml of vitamin E to group 3 and 5 ml of nedocromil sodium to group 4 were given intraabdominally. On the 14th postoperative day, all rats were sacrificed and re-laparotomy was performed. Intraabdominal adhesions were scored according to the Nair classification.ResultsWhen the groups were compared dyadically, the difference between group 1 and group 2 was found to be statistically significant (p = 0.011). The difference between group 1 and group 3 was statistically significant (p = 0.011). The difference between group 1 and group 4 was statistically significant (p = 0.007). There was no statistically significant difference between group 2 and group 3, and group 2 and group 4, and group 3 and group 4 (p &lt; 0.05).ConclusionsAs a result, methylprednisolone, vitamin E and nedocromil sodium have been shown to have a healing effect on adhesions.

Anti-allergic activities of 5,7-dimethoxy-3,4′-dihydroxyflavone via inhalation in rat allergic models

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.

Applicability of Bipolar Charge Analyzer (BOLAR) in Characterizing the Bipolar Electrostatic Charge Profile of Commercial Metered Dose Inhalers (MDIs).

To investigate the applicability of Bipolar Charge Analyzer (BOLAR), a new commercial instrument developed by Dekati Ltd., in simultaneously characterizing the bipolar electrostatic charge profile and measuring the size distribution of commercial metered dose inhalers (MDIs). Intal Forte(®) (sodium cromoglycate), Tilade(®) (nedocromil sodium), Ventolin(®) (salbutamol sulphate), and QVAR(®) (beclomethasone dipropionate) were used as model MDIs in this study. Three individual actuations of each MDI were introduced into the BOLAR at an air flow rate of 60l/min. Charge and mass profiles for each actuation were determined. The BOLAR was found to have better performance in collecting valid charge data (≥80%) than valid mass data (≥50%). In all tested products, both positively and negatively charged particles were found in five defined size fractions between zero and 11.6μm, with the charge magnitude decreased with increasing particle size. The net charge profiles obtained from the BOLAR qualitatively agreed with the results reported previously. In all suspension type MDIs, negligible masses were detected in the smallest size fraction (<0.95μm), for which the charge was most likely caused by the propellant and excipients. QVAR was the only solution MDI tested and the charge and mass profiles were significantly different from the suspension-type MDIs. Its mass profile was found to follow closely with the charge profile. Positively and negatively charged MDI particles of different size fractions and their corresponding charge-to-mass profiles were successfully characterized by the BOLAR.

Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis.

Seasonal/perennial allergic conjunctivitis is the most common allergic conjunctivitis, usually with acute manifestations when a person is exposed to allergens and with typical signs and symptoms including itching, redness, and tearing. The clinical signs and symptoms of allergic conjunctivitis are mediated by the release of histamine by mast cells. Histamine antagonists (also called antihistamines) inhibit the action of histamine by blocking histamine H1 receptors, antagonising the vasoconstrictor, and to a lesser extent, the vasodilator effects of histamine. Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals. Topical treatments include eye drops with antihistamines, mast cell stabilisers, non-steroidal anti-inflammatory drugs, combinations of the previous treatments, and corticosteroids. Standard treatment is based on topical antihistamines alone or topical mast cell stabilisers alone or a combination of treatments. There is clinical uncertainty about the relative efficacy and safety of topical treatment. The objective of this review was to assess the effects of topical antihistamines and mast cell stabilisers, alone or in combination, for use in treating seasonal and perennial allergic conjunctivitis. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 July 2014. We also searched the reference lists of review articles and relevant trial reports for details of further relevant publications. We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant-reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year. Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane. We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo. There were no reported serious adverse events related to the use of topical antihistamine and mast cell stabilisers treatment. It seems that all reported topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo in the short term. However, there is no long-term data on their efficacy. Direct comparisons of different antihistamines and mast cell stabilisers need to be interpreted with caution. Overall, topical antihistamines and mast cell stabilisers appear to be safe and well tolerated. We observed a large variability in outcomes reported. Poor quality of reporting challenged the synthesis of evidence.

The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35

Lack of high potency agonists has restricted analysis of the G protein-coupled receptor GPR35. Moreover, marked variation in potency and/or affinity of current ligands between human and rodent orthologs of GPR35 has limited their productive use in rodent models of physiology. Based on the reported modest potency of the antiasthma and antiallergic ligands cromolyn disodium and nedocromil sodium, we identified the related compounds lodoxamide and bufrolin as high potency agonists of human GPR35. Unlike previously identified high potency agonists that are highly selective for human GPR35, both lodoxamide and bufrolin displayed equivalent potency at rat GPR35. Further synthetic antiallergic ligands, either sharing features of the standard surrogate agonist zaprinast, or with lodoxamide and bufrolin, were also shown to display agonism at either human or rat GPR35. Because both lodoxamide and bufrolin are symmetric di-acids, their potential mode of binding was explored via mutagenesis based on swapping between the rat and human ortholog nonconserved arginine residues within proximity of a key conserved arginine at position 3.36. Computational modeling and ligand docking predicted the contributions of different arginine residues, other than at 3.36, in human GPR35 for these two ligands and were consistent with selective loss of potency of either bufrolin or lodoxamide at distinct arginine mutants. The computational models also suggested that bufrolin and lodoxamide would display reduced potency at a low-frequency human GPR35 single nucleotide polymorphism. This prediction was confirmed experimentally.

P.1.g.035 The role of P-glycoprotein in central sedative effects of H1-antihistamines

Medicinal chemical research in pulmonary and allergic diseases continues to focus on the role of leukotrienes (LTs) as major causative agents in bronchoconstriction, edema, and inflammation. Several potent orally active receptor antagonists and biosynthesis inhibitors have emerged as potential clinical candidates. In addition to eukotriene research, interest continues in selective phospholipase A2 inhibitors, non-sedating anti histamines, and phosphodi esterase inhibitors. This chapter discusses the above in detail. There are leukotrienes pharmacology and biochemistry of leukotrienes, synthesis of leukotrienes and related compounds, leukotriene receptor antagonists, inhibition of leukotrlene biosynthesis—phospholipases, xanthines and phosphodiesterase inhibitors, antihistamines and mediator release inhibitors. Recent studies show astemizole to blunt antigen-induced bronco-constriction in allergic asthmatics. Furthermore, both astemlzole and terfenadine were shown to be effective against exercise-induced asthma. Although the asthmatic response was not abolished in any of the studies cited, the results suggest that antihistamines (particularly the non-sedating agents) may have a role in the pharmacotherapy of bronchial asthma. The role of histamine in proucing the signs and symptoms of bronchial asthma was evaluated. Historically, H1-antihistamines have been only marginally effective in preventing antigen-induced bronchoconstriction, perhaps because the sedative effects of classical antihistamines limit their therapeutic utility, olr because histamine is not a primary mediator of allergic asthma. New topically and orally active MRIs continue to be reported, although the precise biochemical mechanism of action of this class of anti-allergic agents remains unknown. Nedocromil sodium and minocromil are topically active MRIs.

Is nedocromil sodium effective in preventing asthmatic attacks in patients with a history of asthma?

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Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

Background and PurposeAlthough the ‘cromones’ (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their ‘mast cell stabilising’ mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells.Experimental approachWe used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice.Key resultsCDMCs activated by IgE-FcRε1 crosslinking, released histamine and prostaglandin (PG) D2, which were inhibited (30–65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1–10 nM). In CDMCs cromones potentiated (2–5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3–5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect.Nedocromil (10 nM) also inhibited (40–60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRε1 cross-linking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present.Conclusions and ImplicationsWe conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.

Anti-Inflammatory Gallic Acid and Wedelolactone Are G Protein-Coupled Receptor-35 Agonists

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.

Irreversible visual loss secondary to excessive topical steroid use in eczema

Topical steroids are invaluable in controlling numerous inflammatory skin conditions. However, they can produce significant adverse effects if used inappropriately and without supervision as illustrated in the case below. A 43-year-old male attended the ophthalmology department with a 2-week history of painless reduction in vision in his left eye. Past ophthalmic history included bilateral allergic conjunctivitis, primary open angle glaucoma (POAG) right eye, and ocular hypertension left eye, diagnosed on his first visit 18 months ago. Systemic enquiry revealed a history of asthma, hypertension, obesity, epilepsy, and atopic eczema. Current ophthalmic treatments included nedocromil sodium and latanoprost to both eyes. His only previous exposure to ophthalmic steroids was a 4-week course of dexamethasone 0.1% q.i.d. (standard practice) following uncomplicated left cataract surgery 8 months ago. Intraocular pressures (IOP) 6 weeks post-surgery were 23 and 18 mmHg right and left eye respectively. Ocular findings were as follows: Snellen acuity 6/9; hand movement with IOP of 46 and 56 mmHg in the right eye and left eye respectively (upper limit of normal IOP is 21 mmHg). Both …

Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells

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 H1, H2 and H4 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.

Mast Cell Stabilizers as Host Modulatory Drugs to Prevent and Control Periodontal Disease

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.

G-Protein-Coupled Receptor 35 Is a Target of the Asthma Drugs Cromolyn Disodium and Nedocromil Sodium

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.

Rethinking the Pathogenesis of Asthma

Asthma research has focused primarily on allergic pathways on the basis that the majority of asthma is associated with atopy, the recruitment of the Th2-type T cell, the cytokines, and the chemokines that are released on exposure to allergens, and the IgE pathway. However, despite considerable investment by industry, targeting these pathways has not resulted in new treatments being developed beyond blockade of cysteinyl leukotrienes and IgE and improvements in inhaled corticosteroids and beta(2)-adrenoceptor bronchodilators. Increasingly, it is recognized that asthma is a heterogeneous disorder, and while important, allergen sensitization is only one component of the disease, with many other environmental and genetic factors playing a role. In addition, these factors act locally on a susceptible airway epithelium that is both structurally and functionally deficient. It may be worthwhile to focus on increasing the resilience of the airways to environmental insults in addition to improving strategies that modify adaptive immunity or suppress inflammation.

Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1

Using biochemical, epifluorescence and electron microscopic techniques in a U937 model system, we investigated the effect of anti-allergic drugs di-sodium cromoglycate and sodium nedocromil on the trafficking and release of the anti-inflammatory protein Annexin-A1 (Anx-A1) when this was triggered by glucocorticoid (GC) treatment. GCs alone produced a rapid (within 5min) concentration-dependent activation of PKCα/β (Protein Kinase C; EC 2.7.11.13) and phosphorylation of Anx-A1 on Ser27. Both phosphoproteins accumulated at the plasma membrane and Anx-A1 was subsequently externalised thereby inhibiting thromboxane (Tx) B2 generation. When administered alone, cromoglycate or nedocromil had little effect on this pathway however, in the presence of a fixed sub-maximal concentration of GCs, increasing amounts of the cromoglycate-like drugs caused a striking concentration-dependent enhancement of Anx-A1 and PKCα/β phosphorylation, membrane recruitment and Anx-A1 release from cells resulting in greatly enhanced inhibition of TxB2 generation. GCs also stimulated phosphatase accumulation at the plasma membrane of U937 cells. Both cromoglycate and nedocromil inhibited this enzymatic activity as well as that of a highly purified PP2A phosphatase preparation. We conclude that stimulation by the cromoglycate-like drugs of intracellular Anx-A1 trafficking and release (hence inhibition of eicosanoid release) is secondary to inhibition of a phosphatase PP2A (phosphoprotein phosphatase; EC 3.1.3.16), which probably forms part of a control loop to limit Anx-A1 release. These experiments provide a basis for a novel mechanism of action for the cromolyns, a group of drugs that have long puzzled investigators.

Inhibition of tumour necrosis factor-alpha (TNF-alpha) release from mast cells by the anti-inflammatory drugs, sodium cromoglycate and nedocromil sodium.

TNF-alpha is a cytokine thought to be involved in the pathogenesis of asthma and in several other inflammatory conditions. Given recent evidence that mast cells (MC) are an important source of TNF-alpha, we investigated the effects of two anti-inflammatory drugs, nedocromil sodium (NED) and sodium cromoglycate (SCG), on rat MC-derived TNF-alpha. We established that at least 2 h pretreatment with NED or SCG followed by washing was required to inhibit TNF-alpha-dependent cytotoxicity by rat peritoneal MC (PMC). A maximum inhibition of TNF-alpha occurred after 6 h treatment. The inhibitory effect of NED and SCG (10(-5)-10(-3)M) was concentration-dependent (20-37% for NED and 16-37% for SCG). The time-course analysis and the use of cycloheximide, an inhibitor of protein synthesis, provided strong evidence that new protein synthesis by the MC is required for this inhibitory effect. Furthermore, 24 h treatment with 1 mM NED inhibited the levels of mRNA for TNF-alpha by 59-83%. In addition to the effect on TNF-alpha-dependent cytotoxicity by MC, 20 min pretreatment with 10(-4) M NED and SCG inhibited antigen-stimulated TNF-alpha release (6h) by 42% and 48%, respectively. Interestingly, the functionally distinct intestinal mucosal MC (IMMC) is unresponsive to these drugs with regard to histamine secretion. However, as with PMC, 2h pretreatment with NED or SCG inhibited TNF-alpha-dependent cytotoxicity by IMMC. These effects may be important in the action of these drugs in vivo in the late phase reaction in asthma or other inflammatory conditions.

Effect of grinding on the dehydration behavior of nedocromil sodium hydrates

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.

Mast Cell Stabilizers in the Treatment of Allergic Rhinitis

Allergic rhinitis (AR) is caused by an immediate type hypersensitivity reaction in sensitized subjects after exposure to airborn allergens. The interaction of the allergen with a specific IgE antibody attached to the nasal mast cells leads to the local release of vasoactive and inflammatory mediators such as histamine, leukotriene C4 and prostaglandin D2. These mediators cause the nasal allergic symptoms complex of rhinorrhea, nasal obstruction, nasal itching and sneezing, which improve spontaneously or with treatment. Cromolyn sodium and nedocromil sodium are often termed ‘antiallergic drugs’, which are defined here as drugs capable of inhibiting both the early-phase response to challenge and chronic allergic inflammation. They act at the cell membrane levels. Intranasal and ocular formulations of cromones, such as cromoglycate, are available without medical prescription in many countries. Sodium cromoglycate or nedocromil have a good safety profile. They reduce the symptoms of AR, and should be used profilactically, but limited efficacy and the need for frequent dosing are disadvantages.

Inhaled corticosteroids compared to placebo for prevention of exercise induced bronchoconstriction

The pathogenesis of exercise induced bronchoconstriction is likely multifactorial and is not completely understood. Inflammation plays an important role in the pathogenesis of exercise induced bronchoconstriction in asthmatic subjects but the evidence seems less strong in non-asthmatic subjects. The management of exercise induced bronchoconstriction focuses on prevention, through both pharmacologic and non-pharmacologic interventions. The objectives of this review were to evaluate the use of inhaled corticosteroids in the treatment of exercise induced bronchoconstriction in a systematic way. Specifically, the review was designed to: determine whether inhaled corticosteroids (compared to placebo) has an attenuating effect on exercise induced bronchoconstriction in adult and pediatric asthmatic patients; estimate the magnitude of the attenuating effect. We searched the Cochrane Airways Review Group Specialised Register of trials, the Cochrane Central Register of Controlled Trials, review articles, textbooks and reference list of articles. Randomised trials in adults or children comparing inhaled corticosteroids with placebo to prevent bronchoconstriction in patients with exercise induced bronchoconstriction. Trial quality assessment and data extraction were conducted independently by two reviewers. The results from six randomised controlled trials involving 123 participants were analyzed (two trials involving adults and four involving children). Combining results from the two parallel studies with at least 4 weeks duration of inhaled corticosteroids, the use of inhaled corticosteroids significantly attenuated the percent fall index in forced expiratory volume in 1 second (WMD = 14.07%; 95% CI: 11.62% to 16.52%). The result from one crossover study with duration of inhaled corticosteroids of 4 weeks revealed significant attenuation of percent fall in forced expiratory volume in 1 second ( WMD = 6.90%; 95% CI: 1.40% to 12.40%) and the percent fall in peak expiratory flow ( WMD =11.50%; 95% CI: 6.31% to 16.69%). The small amount of data from placebo-controlled trials using a single treatment do not currently allow conclusions to be drawn. Inhaled corticosteroids used for 4 weeks or more before exercise testing significantly attenuated exercise-induced bronchoconstriction. The relative benefits of inhaled corticosteroids compared to other forms of exercise induced bronchoconstriction treatment (sodium cromoglycate, nedocromil sodium, salbutamol, and other anti-inflammatory agents) remains unclear.