The anti-allergic effects of FPL 52694

The substituted chromone carboxylic acid FPL 52694 inhibited models of IgE-mediated immediate hypersensitivity reactions in the rat by a mechanism similar to that of sodium cromoglycate. The compound was more potent than sodium cromoglycate but unlike cromoglycate was active following oral administration.     

Nedocromil sodium inhibits IgE- and IgG-related antigen-induced contraction in guinea-pig trachea

The effects of nedrocromil sodium and disodium cromoglycate were studied on the anaphylactic contraction of guinea-pig trachea in two models of active sensitization (IgE and IgG models). The influence of epithelial removal on the effects of nedocromil sodium and disodium cromoglycate was examined because several studies have shown that the epithelial layer can modulate agonist- or antigen-induced contractile responses. Disodium cromoglycate (10(-4) M) and nedocromil sodium (10(-4) M) provided significant protection against antigen-induced contractions of guinea-pig tracheal smooth muscle in the IgG model. But only nedocromil sodium had an effect at this concentration in the IgG model and was also effective at 10(-5) M in the epithelium-denuded tracheal strips. At this concentration, disodium cromoglycate lost its protective effect. Comparison with the results obtained with FPL-55712, AA-861 and mepyramine suggested that these drugs affect histamine and particularly leukotriene synthesis and/or release by mast cells or other immunocompetent cells. These findings indicate that nedocromil sodium inhibits the IgE- and IgG-related antigen-induced contraction in guinea-pig airways, whereas disodium cromoglycate inhibits only the IgG-related processes. This study supports the hypothesis that these drugs modulate antigen-induced mediator synthesis and/or release from immunocompetent cells.     

Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine

We have studied an aspect of the functional heterogeneity of human mast cells, namely responsiveness to the inhibitory effects of sodium cromoglycate and nedocromil sodium. The effects of these drugs were examined on the release of histamine and PGD2 from mast cells of human skin, lung, tonsils, adenoids and intestine. A high concentration, 1000 microM, of sodium cromoglycate was required to significantly inhibit histamine release from lung and tonsillar mast cells. Nedocromil sodium, 1000 microM, was more effective than sodium cromoglycate against histamine release from lung, tonsillar and adenoidal cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in adenoidal and intestinal mast cells. In contrast, in intestinal mast cells, the effect of nedocromil sodium was weaker and more variable than sodium cromoglycate. Skin mast cells differed from mast cells of the other anatomical sites in being unresponsive to sodium cromoglycate and nedocromil sodium. Our results confirm that high concentrations of sodium cromoglycate and nedocromil sodium are required to achieve even modest inhibition of mediator release from human mast cells under in vitro conditions. Notwithstanding this, the results also indicate that differences exist among skin, lung, tonsillar, adenoidal and intestinal mast cells with respect to their sensitivity to sodium cromoglycate and nedocromil sodium, thus extending our knowledge of functional heterogeneity within the human mast cell populations.     

Treating severe eye allergy

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.     

Double-blind group comparative study of 2% nedocromil sodium eye drops with 2% sodium cromoglycate and placebo eye drops in the treatment of seasonal allergic conjunctivitis

A 4 week, multicentre, double-blind, double dummy, placebo controlled group comparative study was carried out during the birch pollen season to compare the efficacy and tolerability of 2% nedocromil sodium eye drops (twice daily) and 2% sodium cromoglycate eye drops (four times daily). Participants with a history of seasonal allergic conjunctivitis (SAC) were randomized to receive nedocromil sodium (60), sodium cromoglycate (61) or placebo (64). Clinical assessment of SAC showed improvement with both active treatments compared to placebo but symptomatology was low and only changes in photophobia and grittiness reached significance (P < 0.05). Patient diaries showed significant control of itching by both active treatments, compared to placebo, with no differences between the active preparations. Patients' opinions indicated a marked placebo effect: 73% of this group reported full or moderate control of symptoms, compared with 75% in sodium cromoglycate and 80% in the nedocromil sodium group. Unusual symptoms were most common (27 patients) with nedocromil sodium eye drops: P < 0.05 vs. placebo (15 patients). There were no serious adverse events. Nedocromil sodium eye drops (b.d.) and sodium cromoglycate eye drops (q.i.d.) were both considered clinically more effective than placebo in controlling symptoms of SAC due to birch pollen.     

Comparative study of the effects of nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) on adenosine-induced bronchoconstriction in asthmatic subjects

The effect of nedocromil sodium (4 mg; 7.8 × 10⁻⁶ m ) on adenosine-induced bronchoconstriction was compared with that of a higher dose of sodium cromoglycate (10 mg; 24.1 × 10⁻⁶ m ). Eleven allergic asthmatic patients (mean age 26.28 ± 12.21 years) were studied. Adenosine (0.03–4.00 mg) was administered as nebulized aerosol. The dose of adenosine producing a 20% change in FEV₁(PD₂₀) was calculated from the individual semi-logarithmic dose-response curves. Patients were studied on 4 separate days. On the first day the adenosine challenge was performed; on subsequent days patients were pretreated (20 min before challenge) with either placebo or test drug (nedocromil sodium 2 × 2 mg or sodium cromoglycate 2 × 5 mg) administered by pressurized aerosol in a randomized, double-blind manner. Statistical analysis was performed by two-way analysis of variance. Neither sodium cromoglycate nor nedocromil sodium showed a significant bronchodilator effect. In patients treated with placebo, inhalation of adenosine produced a dose-related bronchoconstriction with a geometric mean PD₂₀ of 0.42 mg. After drug administration the mean PD₂₀ values were 1.29 mg with sodium cromoglycate and 2.30 mg with nedocromil sodium. Both drugs produced a significant increase in mean PD₂₀ value in comparison with placebo and baseline ( P < 0.01). These results demonstrate that nedocromil sodium (4 mg) is significantly more potent than a larger dose of sodium cromoglycate (10 mg) in inhibiting adenosine-induced bronchoconstriction ( P < 0.05).     

Airway constriction by isocapnic hyperventilation of cold, dry air: comparison of magnitude and duration of protection by nedocromil sodium and sodium cromoglycate

The protective effect of 1,2 and 4 mg of nedocromil sodium against airway constriction induced by hyperventilation of cold, dry air was compared with 10 mg sodium cromoglycate and placebo in a double-blind randomized trial. On 5 days, twelve asthmatic subjects received one of the trial medications from a metered dose inhaler. Twenty minutes, 2.5 and 5 hr later, airway responsiveness to hyperventilation of cold, dry air was measured. At 20 min, there was significant protection by all four active medications when compared to placebo, with a trend towards a nedocromil dose relationship but there was no statistical difference between the four active medications. All four showed a similar progressive decrease in protection over 5 hr. The results of this study suggest that nedocromil gives protection against hyperventilation-stimulated airway constriction and that the magnitude and duration of effect for all three doses is similar to 10 mg of cromoglycate.     

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

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

New orally effective chromone derivatives for the treatment of asthma

Two new chromone derivatives have been identified which possess oral anti-allergic activity in the rat PCA model of immediate hypersensitivity. They may have a wider spectrum of anti-allergic activity than disodium cromoglycate (SCG) since they are effective in in vitro tests involving sensitized basophils, in which SCG is inactive. Both compounds, when given orally, provide relief from experimental and clinical asthma in man.Chemical Studies.Biological Studies.     

Nedocromil sodium and cromolyn (sodium cromoglycate) selectively inhibit antibody-dependent granulocyte-mediated cytotoxicity

Nedocromil sodium and cromolyn (sodium cromoglycate) are prophylactic agents in asthma which were initially found to be inhibitors of mast cell activation. Recent evidence has suggested that their effects on granulocyte-mediated reactions may contribute to their therapeutic effects. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the activity of granulocytes in antibody-dependent cell-mediated cytotoxicity (ADCC). Preincubation of purified neutrophils or eosinophils with nedocromil sodium or cromolyn partially inhibited their ability to mediate ADCC when stimulated by GM-CSF or TNF. Preincubation with nedocromil sodium did not alter the ability of neutrophils to produce superoxide or release lysozyme in response to soluble or phagocytic stimuli, and GM-CSF-enhanced superoxide production triggered by chemotactic peptide was not altered in such drug-treated neutrophils. After nedocromil sodium treatment, neutrophils showed no consistent changes in TNF-stimulated adherence to either plastic culture wells or umbilical vein endothelium. These findings demonstrate that nedocromil sodium and cromolyn directly and selectively affect the function of granulocytes in vitro. While drug-treated granulocytes were impaired in immune-directed cytotoxicity stimulated by GM-CSF or TNF, activation of other granulocyte functions by the same stimuli was intact.     

Comparative Therapeutic Studies with Tilavist

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

LCB 2183 inhibits the inflammation associated with oxazolone-induced contact sensitivity

LCB 2183, an anti-allergic and potential anti-asthma compound, has been investigated for its ability to inhibit contact sensitivity in the mouse. The delayed response to epicutaneous hapten challenge in this model is a classical T-cell-mediated inflammatory reaction which is dependent on an early initiation phase. Both the early and late components of oxazolone-induced contact sensitivity were inhibited by oral administration of LCB 2183 in a dose-dependent manner. The drug appears to act on the efferent limb of the response since administration before hapten challenge was effective, while administration before the initial sensitization was not. LCB 2183 acts early in the cascade of events leading to inflammation, since the initiation phase of the response was inhibited; nonetheless, an effect of the drug on the late acting inflammatory cells cannot be ruled out. In comparison with oral prednisolone, which was also able to inhibit both the early and late components of the response, LCB 2183 was less active. Sodium cromoglycate and nedocromil sodium, which are poorly absorbed from the gastrointestinal tract, were tested by intraperitoneal administration. Neither of these agents significantly altered the delayed response and only nedocromil sodium had a limited inhibitory effect on the early initiation phase. Thus, in this model, LCB 2183 demonstrated more anti-inflammatory potential and resembled prednisolone more closely than either nedocromil sodium or sodium cromoglycate. The possible relevance of these effects in relation to the inflammation which characterizes human asthma is considered.     

Nedocromil sodium is more potent than sodium cromoglycate against AMP-induced bronchoconstriction in atopic asthmatic subjects

Nedocromil sodium is a new chemical entity which shows similar properties to sodium cromoglycate (SCG) and in addition exhibits a preferential activity in stabilizing mucosal mast cells. We have compared the effect of inhalation of nebulized placebo, SCG and nedocromil sodium on the bronchoconstrictor response to inhaled adenosine monophosphate (AMP) in eight atopic asthmatic subjects aged 25 yr (range 21-32 yr). The geometric mean provocation doses of AMP required to produce a 20% decrease in FEV1 (PD20FEV1) and a 40% decrease in Vmax30 (PD40 Vmax30) following placebo were 4.9 (0.3-14.2) and 1.8 (0.1-8.4) mumol respectively. Prior inhalation of both SCG and nedocromil sodium significantly inhibited the bronchoconstrictor response to AMP with PD20FEV1s of 36.6 (4.0-132.7) and 134 (12.4-560), and PD40 Vmax30 values of 20.5 (1.4-110) and 101.6 (5-560) mumol respectively (P less than 0.001). Nedocromil sodium was 3.9 (FEV1) and 8.0 (Vmax30) times more potent than SCG (P less than 0.001). In conclusion, both drugs inhibit the bronchoconstrictor response to inhaled AMP, and nedocromil is at least 4-8 times more potent than SCG.     

Neutrophils and mast cells: nedocromil sodium inhibits the generation of neutrophil-derived histamine-releasing activity (HRA-N).

The effect of nedocromil sodium on the generation of neutrophil-derived histamine-releasing activity (HRA-N) from human peripheral blood neutrophils and on the secretory effects of HRA-N and anti-IgE on rat basophil leukemia (RBL) cells was studied. Nedocromil sodium caused dose-related inhibition of HRA-N generation by human neutrophils (10(-7) to 10(-4) mol/L; inhibitory concentration of 50%, 1.5 x 10(-8) mol/L). In contrast, the presence of nedocromil sodium had no effect on HRA-N-mediated serotonin release from RBL cells. In five experiments, with one crude and four partially purified HRA-N preparations, serotonin release from RBL cells exposed to native HRA-N or HRA-N in the presence of nedocromil sodium (10(-4) mol/L) was 28% +/- 6% and 26% +/- 5%, respectively. Similar results were found with all concentrations of nedocromil sodium studied. Preincubation of RBL cells with nedocromil sodium (10(-4) mol/L) for 0 to 60 minutes also did not affect HRA-N-mediated serotonin release. Likewise, nedocromil sodium (10(-7) to 10(-4) mol/L) had no effect on anti-IgE-induced serotonin release from RBL cells. In 10 experiments, anti-IgE alone or in the presence of nedocromil sodium (10(-4) mol/L) induced 32% +/- 6% and 32% +/- 5% serotonin release, respectively. Preincubation of RBL cells with nedocromil sodium before anti-IgE exposure had no further effect. This is the first study of pharmacologic manipulation of the generation of a histamine-releasing factor. It is hypothesized that one possible mechanism whereby nedocromil sodium protects against asthma and allergic rhinitis is through inhibition of HRA-N generation.     

Regulation of IgE-dependent antiparasite functions of rat macrophages and platelets by nedocromil sodium

The IgE-dependent stimulation of mononuclear phagocytes and blood platelets can be measured by antiparasite cytotoxicity, oxygen-mediated chemiluminescence and, in macrophages, lysosomal enzyme activity. Using these parameters, the present study demonstrated an inhibition by nedocromil sodium of the IgE-mediated triggering of the nonmast cell inflammatory populations in the rat. These observations suggest that nedocromil sodium may be of value in the modulation of IgE-dependent cell activation inducing the release of inflammatory mediators.     

The development of a new agent for the treatment of inflammatory/allergic conditions

The search for new drugs for the treatment of reversible obstructive airways disease has been a major pursuit of the pharmaceutical industry for almost two decades. Little progress has been achieved. The acceptance that asthma is a multi-facetted disease state has led to the development of a new complex in vivo screen in the macaque monkey. This model is mediated through mast cells which stain positively with alcian blue/safranin. A new therapeutic agent, nedocromil sodium, was significantly more active than sodium cromoglycate in this primate model of airway disease. Extensive clinical trials have shown that this new agent is effective in the treatment of the reversible component of obstructive airways disease.     

Bronchial asthma due to spiramycin and adipic acid

Two cases of bronchial asthma due to spiramycin in workers of a pharmaceutical factory are reported. The subjects complained of cough, breathlessness and symptoms of asthma at work when coming into contact with spiramycin's powder. The symptoms cleared when away from work for more than 3 or 4 days. Inhalation challenge tests by aerosolization of solutions of spiramycin reproduced asthmatic reactions dual in type in both patients, the immediate component of the response has not been previously described for this antibiotic. Furthermore, one of the patients developed an immediate asthmatic reaction also after inhalation of a solution of adipic acid, and additive to bind spiramycin and diminish its irritant action. The reaction was obtained at a non-irritant concentration of the acid, was reproducible and inhibited by previous administration of sodium cromoglycate: this finding and the failure to elicit the reaction in the other patient suggest a hypersensitivity reaction to this substance.     

Mode of action of disodium cromoglycate, studies on immediate type hypersensitivity reactions using `double sensitization'' with two antigenetically distinct rat reagins

The mode of action of disodium cromoglycate has been investigated to determine at what stage in immediate type hypersensitivity reactions the compound is effective. In vitro studies using rat subcutaneous connective tissue sensitized with rat reagin revealed that the compound inhibited the allergic release of histamine if present during antigen challenge. The presence of the compound during sensitization had no effect on antigen-induced release of histamine provided the compound was removed prior to antigen challenge. Tissues which had undergone a primary antigen challenge in the presence of disodium cromoglycate did not release histamine when the compound was removed and the tissues rechallenged. These findings indicated that antigen/antibody interaction occurred in the presence of the compound resulting in desensitization to a subsequent antigen challenge. To corroborate the evidence of the in vitro studies in vivo passive cutaneous anaphylactic reactions (PCA) were undertaken using tissue sites sensitized with two reaginic antibodies which permitted a sequence of antigen challenges. Results from these in vivo reactions demonstrated that it was possible to desensitize tissue, without the release of the mediators of anaphylaxis, by an antigen challenge and disodium cromoglycate treatment. In these sites sensitized with two antibodies the immunological reactivity was maintained following a primary antigen challenge and disodium cromoglycate treatment, as a subsequent challenge with the dissimilar antigen produced a good PCA reaction. It would appear that disodium cromoglycate acts either directly or indirectly at a stage following antigen/antibody reaction but prior to the release of the mediators of anaphylaxis.     

Protection of nedocromil sodium on bronchoconstriction induced by inhaled neurokinin A (NKA) in asthmatic patients

Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 x 10(-9) mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects.     

Effect of nedocromil sodium on SO2-induced airway hyperresponsiveness and citric acid-induced cough in dogs

In anaesthetized dogs exposed to SO2, nedocromil sodium prevented the increase in bronchial responsiveness to histamine challenge and suppressed the cellular changes taking place in the lung. In conscious dogs challenged with citric acid, by inhalation, nedocromil sodium prolonged the time to onset of coughing and had an inhibitory effect on the total number of coughs in each episode. Nedocromil sodium has been observed to stimulate bronchial C fibers, and it is suggested that this activity may relate to the antitussive effect of the compound.