Drug Disodium Cromoglycate Research Articles

Quercetin and Its Anti-Allergic Immune Response.

Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols. Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine. Quercetin is known for its antioxidant activity in radical scavenging and anti-allergic properties characterized by stimulation of immune system, antiviral activity, inhibition of histamine release, decrease in pro-inflammatory cytokines, leukotrienes creation, and suppresses interleukin IL-4 production. It can improve the Th1/Th2 balance, and restrain antigen-specific IgE antibody formation. It is also effective in the inhibition of enzymes such as lipoxygenase, eosinophil and peroxidase and the suppression of inflammatory mediators. All mentioned mechanisms of action contribute to the anti-inflammatory and immunomodulating properties of quercetin that can be effectively utilized in treatment of late-phase, and late-late-phase bronchial asthma responses, allergic rhinitis and restricted peanut-induced anaphylactic reactions. Plant extract of quercetin is the main ingredient of many potential anti-allergic drugs, supplements and enriched products, which is more competent in inhibiting of IL-8 than cromolyn (anti-allergic drug disodium cromoglycate) and suppresses IL-6 and cytosolic calcium level increase.

The anti-allergic activity of polyphenol extracted from five marine algae

Natural polyphenol has been widely believed to be effective in allergy remission. Currently, most of the natural polyphenol products come from terrestrial sources such as tea, grape seeds among others, and few polyphenols have been developed from algae for their anti-allergic activity. The aim of the study was to screen some commercial seaweed for natural extracts with anti-allergic activity. Five algae including Laminaria japonica, Porphyra sp., Spirulina platensis, Chlorella pyrenoidosa and Scytosiphon sp. were extracted with ethanol, and the extracts were evaluated for total polyphenol contents and anti-allergic activity with the hyaluronidase inhibition assay. Results showed that the total polyphenol contents in the ethanol extracts ranged from 1.67% to 8.47%, while the highest was found in the extract from Scytosiphon sp. Hyaluronidase inhibition assay showed that the extracts from Scytosiphon sp. had the lowest IC50, 0.67 mg mL−1, while Chlorella pyrenoidosa extract had the highest IC50, 15.07 mg mL−1. The anti-allergic activity of Scytosiphon sp. extract was even higher than the typical anti-allergic drug Disodium Cromoglycate (DSCG) (IC50 = 1.13 mg mL−1), and was similar with natural polyphenol from Epigallocatechin gallate (EGCG) (IC50 = 0.56 mg mL−1). These results indicated that the ethanol extract of Scytosiphon sp. contains a high concentration of polyphenol with high anti-allergic activity. Potentially Scytosiphon sp. can be developed to a natural anti-allergic compound for allergy remission.

Intranasal curcumin and its evaluation in murine model of asthma

Curcumin, a phytochemical present in turmeric, rhizome of Curcuma longa, has been shown to have a wide variety of pharmacological activities including anti-inflammatory, anti-allergic and anti-asthmatic properties. Curcumin is known for its low systemic bioavailability and rapid metabolization through oral route and has limited its applications. Over the recent decades, the interest in intranasal delivery as a non-invasive route for drugs has increased as target tissue for drug delivery since nasal mucosa offers numerous benefits. In this study, we evaluated intranasal curcumin following its absorption through nasal mucosa by a sensitive and validated high-performance liquid chromatography (HPLC) method for the determination of intranasal curcumin in mouse blood plasma and lung tissue. Intranasal curcumin has been detected in plasma after 15 min to 3 h at pharmacological dose (5 mg/kg, i.n.), which has shown anti-asthmatic potential by inhibiting bronchoconstriction and inflammatory cell recruitment to the lungs. At considerably lower doses has proved better than standard drug disodium cromoglycate (DSCG 50 mg/kg, i.p.) by affecting inflammatory cell infiltration and histamine release in mouse model of asthma. HPLC detection revealed that curcumin absorption in lungs has started after 30 min following intranasal administration and retained till 3h then declines. Present investigations suggest that intranasal curcumin (5.0 mg/kg, i.n.) has effectively being absorbed and detected in plasma and lungs both and suppressed airway inflammations at lower doses than the earlier doses used for detection (100-200 mg/kg, i.p.) for pharmacological studies (10-20 mg/kg, i.p.) in mouse model of asthma. Present study may prove the possibility of curcumin as complementary medication in the development of nasal drops to prevent airway inflammations and bronchoconstrictions in asthma without any side effect.

Mast Cell Stabilizing Activity of Bauhinia variegata

The effect of Bauhinia variegata (Caesalpiniaceae) stem bark extracts on mast cell stabilizing activity was investigated to explore the scientific basis for the use of the decoction of its stem bark in the treatment of asthma and other respiratory complications in traditional Ayurvedic system of medicine. The authenticated plant material was defatted using petroleum ether and extracted with ethanol and distilled water to obtain ethanol (BVE) and aqueous (BVA) extract, respectively. The stabilization potential was studied on mouse mast cells and anti-anaphylactic activity was evaluated by determining the mortality rate of mice treated with toxicant (compound 48/80). The BVE (400 mg.kg−1) significantly protected mast cell from degranulation (71.18%) and reduced the mortality (50%) when compared to standard drug disodium cromoglycate (DSCG) used in the study. BVE possessed potent mast cell stabilizing activity, suggesting potential for use in the treatment of asthma.

X-ray analysis of disodium cromoglycate.

Abstract X-ray crystallographic studies have been made on the anti-asthmatic drug disodium cromoglycate. Interesting features of the structure are the non-coplanarity of the chromone (benzopyrone) rings, an apparent disorder in the position of one of the sodium atoms, and the occurrence of water-filled ‘channels’ in the crystal lattice.

In vitro Inhibitory Effects of Disodium Cromoglycate on Ionic Transports Involved in Sickle Cell Dehydration

Background: The antiallergic and antiasthmatic drug disodium cromoglycate (DSCG) has also demonstrated an activity against sickle cell disease, but the mechanism of this action still remains unknown. Methods: Na⁺ and K⁺ fluxes were studied in red cells obtained from 9 patients affected with sickle cell disease in the absence or in the presence of 1 mM of DSCG and deoxygenated under an N₂ flow during up to 24 h. Results: A significant inhibiting effect of DSCG on the intracellular K⁺ exit and the Na⁺ entry was observed. Conclusion: These results demonstrate that DSCG partially inhibits the abnormal K⁺ loss which is implicated in the dehydration of the sickle cell and the stimulation of sickling.

In vivo study of antiallergenicity of ethanol extracts from Sargassum tenerrimum, Sargassum cervicorne and Sargassum graminifolium turn

Food allergy has becoming the serious threat in the world for which the search of an effective anti-allergic drug is the demand of time. Keeping in view of the potentiality of seaweeds, the ethanol extracts from Sargassum tenerrimum (ST), Sargassum cervicorne (SC), and Sargassum graminifolium turn (SG) have been studied in vivo for its antiallergenicity through passive cutaneous anaphylaxis (PCA) and active cutaneous anaphylaxis (ACA) in female BALB/c mice. Intraperitoneal administration of these ethanol extracts inhibit mouse PCA and ACA in a dose-dependent manner using ovalbumin (OVA) and shrimp allergen as triggering agents to induce allergenicity over mice. The extract of ST containing phlorotannin has been found most active over the suppression of PCA triggered by OVA and shrimp with IC50 values of 25.64 and 40.98 mg/kg, respectively and an efficacy comparable to that of an anti-allergic drug disodiumcromoglycate. Similarly, ST inhibits ACA triggered by ova and shrimp allergen in the mouse, with 50% suppression at 25.5 and 43.53 mg/kg, respectively. The results presented here show that these extracts are active on the studied models among which ethanol extract of ST was the most potent, leading toward the promising development of a new class of anti-allergic drugs.

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.

Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox.

Hsp90 (heat-shock protein 90) alone can act to prevent protein aggregation and promote refolding in vitro, but in vivo it operates as a part of a multichaperone complex, which includes Hsp70 and cohort proteins. Since the physiological function of Hsp90 is not yet fully understood, the development of specific antagonists might open new lines of investigation on the role of Hsp90. In an effort to discover Hsp90 antagonists, we screened many drugs and found that the anti-allergic drugs DSCG (disodium cromoglycate) and amlexanox target Hsp90. Both drugs were found to bind directly wild-type Hsp90 via the N- and C-terminal domains. Both drugs strongly suppressed the in vitro chaperone activity of native Hsp90 towards citrate synthase at 1.5-3.0 microM. Amlexanox suppressed C-terminal chaperone activity in vitro, but not N-terminal chaperone activity, and inhibited the association of cohort proteins, such as cyclophilin 40 and Hsp-organizing protein, to the C-terminal domain of Hsp90. These data suggest that amlexanox might disrupt the multichaperone complex, including Hsp70 and cohort proteins, both in vitro and in vivo. Although DSCG inhibited the in vitro chaperone activity of the N-terminal domain, the drug had no effect either on the C-terminal chaperone activity or on the association of the cohort proteins with the C-terminus of Hsp90. The physiological significance of these interactions in vivo remains to be investigated further, but undoubtedly must be taken into account when considering the pharmacology of anti-allergic drugs. DSCG and amlexanox may serve as useful tools for evaluating the physiological significance of Hsp90.

Ca 2+ and phorbol ester effect on the mast cell phosphoprotein induced by cromolyn

Several phosphoproteins are involved in stimulus-secretion coupling. The β and γ subunits of immunoglobulin E binding protein (FcϵRI) and three other protein bands get phosphorylated during stimulation of mast cell secretion. These additional proteins of 42, 59 and 68 kDa are also phosphorylated when secretion is stimulated by compound 48/80 (C48/80). A 78 kDa band, however, is phosphorylated as secretion wanes after stimulation with C48/80 and by the anti-allergic drug disodium cromoglycate (cromolyn). Phosphorylation was blocked by protein kinase C inhibitors. We investigated the isozyme involved by first showing that a cation ionophore prevented the phosphorylation of the 78 kDa protein, while a Ca 2+ chelator did not affect phosphorylation even though it enhanced the inhibitory effect of cromolyn. This protein was identified as moesin by immunoprecipitation. Protein kinase C activators had no effect on 78 kDa protein phosphorylation either in the presence or absence of Ca 2+ ions, but prevented its phosphorylation by cromolyn. Protein phosphatase inhibitors prolonged the duration, but not the amount of phosphate incorporated in the 78 kDa protein band while cromolyn had no effect on protein phosphatase action in vitro. The insensitivity of the 78 kDa protein phosphorylation to calcium and protein kinase C activators suggests that an atypical protein kinase C isozyme may be involved. Western blot analysis identified the presence of isozymes α, β, δ and ζ, of which only the latter fits the profile suggested by the present findings.

Binding of disodium cromoglycate to human serum albumin

The binding of several benzopiranone derivatives to human serum albumin was determined. The antiallergic drug disodium cromoglycate binds weakly to serum albumin. However, its precursors, chromones of smaller size, were able to bind in a hydrophobic pocket in the protein, and are carried by serum albumin in blood.

ANTIALLERGIC/ANTIASTHMATIC ACTIVITY OF OLIGOPEPTIDE RELATED TO IgE

In spite of continuous research in the field of bronchial asthma, still no satisfactory drug is available. Recently a new class of oligopeptide exhibited antiallergic activity by inhibiting the synthesis of IgE antibody. The analogue of ADSDGK (94-335) has shown antiallergic activity in experimental models. The 94-335 inhibited the passive cutaneous anaphylaxis (PCA) reactions in rats in a dose-dependent manner (0.5–10 mg kg−1p.o.) by 47–90%. There was a 70–87% protection of mast cell degranulation induced by compound 48/80 with peptide 94-335 at 0.5–1.5 mg kg−1p.o. in rats. This peptide also inhibited antigen- induced contraction in sensitised guinea pig ileum. There was 18 and 72% protection to bronchoconstriction induced by histamine and egg albumin, respectively, in an aerosol test in guinea pigs. These effects of compound 94-335 were comparable with that of the clinically-used antiallergic drug disodium cromoglycate (DSCG). The results suggest that peptide 94-335 possesses potent antiallergic activity.

Characterization of the 78 kDa mast cell protein phosphorylated by the antiallergic drug cromolyn and homology to moesin

Mast cells (MC) can be stimulated to secrete by cross-linking immunoglobulin E bound to specific surface receptors, as well as in response to polycationic molecules such as substance P and compound 48 80 . The antiallergic drug disodium cromoglycate (cromolyn) inhibited MC secretion and rapidly incorporated phosphate into a 78 kDa protein, speculated to be its mode of action. This protein was purified by single and two-dimensional gel electrophoresis, and was shown to be phosphorylated primarily on serine residues by protein kinase C. Partial amino acid sequencing of two generated fragments was identical to that of portions of mouse moesin, a member of the band 4.1 superfamily of proteins, with no definitive function known to date. Polyclonal antibodies raised against the rat basophil leukemia cell moesin cDNA expressed in Escherichia coli immunoprecipitated the 78 kDa phosphoprotein quantitatively, and immunocytochemistry localized it to the plasma membrane. Reversible phosphorylation of this 78 kDa phosphoprotein could affect its possible cytoskeletal binding through which it may regulate stimulus-secretion coupling in MC.

Effect of the Antiallergic Drug Disodium Cromoglycate on Phosphodiesterase Activity

The antiallergic drug disodium cromoglycate and its non-antiallergic analogue dicoumarol, inhibit the enzymatic activity of phosphodiesterase with KI values of 0.8.10(-9) M and 1.6.10(-9) M, respectively. It seems that the dichromone group is responsible for this inhibition, independently of its antiallergic effect.

Effect of the antiallergic drug disodium cromoglycate and various derivatives on alkaline phosphatase.

Disodium cromoglycate (DSCG) inhibits alkaline phosphatase in a non-competitive manner, the enzyme undergoing a conformational change which is attenuated by the presence of calcium ions. The structurally related pyranone and benzoic acid are weak inhibitors of the enzyme and produce a similar conformational change. Coumarin does not induce any conformational change in the enzyme suggesting that the 4-oxo group in DSCG may be essential for its effect.

Some characteristics of the ATP-induced histamine release from and permeabilization of rat mast cells.

Extracellular adenosine 5'-triphosphate (ATP) induced a characteristic, dose-dependent release of histamine and prostaglandin D2 (PGD2) from rat peritoneal mast cells. The process was relatively slow, non-cytotoxic, maximal at physiological pH and dependent on external calcium. Strontium and barium ions were able to substitute for calcium, although higher concentrations were required for maximal release. Cells stimulated in the absence of calcium progressively lost the ability to respond to subsequent reintroduction of the cation. The secretion of histamine induced by ATP was largely unaffected by the anti-asthmatic drugs disodium cromoglycate and nedocromil sodium but was inhibited by structurally related flavonoids and by cAMP-active drugs. Importantly, the non-hydrolysable guanosine 5'-triphosphate (GTP) analogue, GTP-gamma-S, elicited a dose-dependent release of histamine when introduced into mast cells permeabilized with ATP in the absence of external calcium. ATP thus appears to be a useful cell permeabilizing tool with which to study the biochemical processes involved in mast cell activation.

Inhibitory effects of some natural products on the activation of hyaluronidase and their anti-allergic actions.

The anti-allergic drugs disodium cromoglycate (DSCG) and tranilast are strong inhibitors of hyaluronidase. In the development of new anti-allergic drugs, we studied the inhibitory effects of some natural products on the activation of hyaluronidase. Among the compounds tested, liquiritigenin, isoliquiritigenin and baicalein showed dose-related inhibitory effects. Anti-allergic activities of these compounds were evident from the facts that they inhibited the histamine release from rat peritoneal exudate cells induced by antigen, compound 48/80 and calcium ionophore A-23187, and from their inhibitory effect on Shultz-Dale reaction using sensitized guinea pig ileum.

Drugs affecting Trichophyton rubrum-induced neutrophil chemotaxis in vitro

Summary In Boyden-type experiments, it is shown that corticosteroid drugs inhibit T. rubrum-induced chemotaxis of polymorphonuclear cells (PMNs) in ng 1−1 concentrations; reference is made to reports showing such concentrations are therapeutically achieved by topically applied steroids to the skin under an occlusive dressing. The anti-asthma drugs disodium cromoglycate and ketotifen hydrogen fumarate and the anti-histamine, clemastine, all significantly reduced PMN migration at the ng 1−1 level. The results are discussed in relation to the inflammatory response of the skin in T. rubrum infections.

Effect of disodium cromoglycate on anti‐IgE induced early and late skin response in humans

The effect of the anti-allergic drug disodium cromoglycate (DSCG) on immediate and late responses to anti-human IgE was examined in thirteen healthy subjects. DSCG, 250 micrograms, applied intradermally together with anti-IgE had no effect on the immediate flare and weal response, whereas the following late phase response, 1-24 hr, was attenuated by 15% (P less than 0.05, at 6 hr P less than 0.01). This effect varied between individuals (P less than 0.01) and was reproduced in a second trial in DSCG-responders and non-responders (P less than 0.01, n = 8). The results support the view that DSCG has no effect on the immediate mast cell derived response in human skin but can inhibit the development of late reactions. This mechanism might account for some of the anti-allergic effects of the drug.

Possible role for a calcium-activated, phospholipid-dependent protein kinase in mode of action of DSCG

Ronit Sagi-Eisenberg suggests that the anti-allergic drug disodium cromoglycate (DSCG) exerts its inhibitory activity on mast cell degranulation by interacting with a Ca 2+- and phospholipid-dependent protein kinase C involved in the stimulus-secretion coupling of these cells. Her hypothesis is based on similarities between the conditions required to activate this kinase and those needed to evoke secretion. In addition, binding of DSCG of mast cells leads to protein phosphorylation; protein kinase C has been shown to play a dual role in the activation and termination of the secretory process in RBL-2H3 cells. Hence, the Ca 2+ phospholipid-dependent protein kinase C appears to be an attractive candidate for the protective action of DSCG.