GSK-3β (IC50 = 2.0 μM)

Cromoglycate sodium (Cromolyn disodium; FPL-670) is a chromone compound that operates by blocking the release of chemical mediators from sensitized mast cells. It is used for the preventive treatment of allergy and exercise-induced asthma but does not affect established asthma episodes.

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Cromolyn sodium was originally characterised as a mast cell stabiliser (Hoag 1991). However, it also inhibits neutrophil activation (Kay 1987), neutrophil chemotaxis (Bruijnzeel 1989), macrophage activation, tachykinin action, eicosanoid and cytokine release, and adhesion molecule expression (Yazid 2009). A more recent in vitro study (Yazid 2009) showed that Cromolyn sodium stimulates the anti‐inflammatory intracellular protein annexin‐A1 trafficking and release. Cromolyn sodium inhibits eicosanoid release due to inhibition of a phosphatase PP2A (phosphoprotein phosphatase; EC 3.1.3.16), which probably forms part of a control loop to limit annexin‐A1 release [3].

There were no alterations in ET-1 levels, damage scores, or inflammation in IIR mice treated with cromoglycate sodium (cromoglycate disodium; FPL-670) prior to ischemia (P>0.05, PreCr group vs. M group). In conclusion, by downregulating ET-1 and preventing persistent MC activation, the injection of Cromolyn (sodium) after reperfusion, but not before ischemia, attenuates IIRI [1]. The action of Cromolyn (sodium) is to prevent chronic lung disease (CLD). It is not advised to use cromolyn (sodium) to protect premature newborns from developing chronic lung illness [2].

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Stabilizing mast cells (MCs) can either inhibit or augment inflammation; however, how improved therapeutic benefits against small intestinal ischemia-reperfusion injury (IIRI) can be achieved by stabilizing MCs remains to be elucidated. The present study was designed to evaluate different treatments with Cromolyn sodium (CS, an MC stabilizer), which was administrated either prior to ischemia or after reperfusion. Kunming mice were randomized into a sham-operated group (SH), a sole IIR group (M), in which mice were subjected to 30 min superior mesenteric artery occlusion followed by 3 day or 3 h reperfusion, or IIR, treated with CS 15 min prior to ischemia or 15 min after reperfusion in the PreCr and PostCr groups. The survival rate and Chiu's scores were evaluated. The levels of ET-1, histamine, TNF-α and IL-6, and expression of MC protease 7 (MCP7), MC counts and myeloperoxidase (MPO) activity were quantified. IIR resulted in severe injury as demonstrated by significant increases in mortality and injury score. IIR also led to substantial elevations in the levels of ET-1, histamine, TNF-α and IL-6, expression of MCP7, MC counts and MPO activities (P<0.05, M vs. SH groups). All biochemical changes were markedly reduced in the PostCr group (P<0.05, PostCr vs. M groups), whereas pretreatment of IIR mice with CS prior to ischemia exhibited no changes of ET-1 levels, injury score and inflammation (P>0.05, PreCr vs. M groups). In conclusion, administration of CS after reperfusion, but not prior to ischemia, attenuates IIRI by downregulating ET-1 and suppressing sustained MC activation. [1]

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Cromolyn, tranilast and cetirizine ameliorate SIN-triggered local HRARs [2]
As SIN-triggered HRARs are mainly mediated by histamine release, we examined whether clinically available mast cell stabilizers and histamine receptor blockers could prevent SIN-induced HRARs. Hence, cromolyn, tranilast and cetirizine were employed in the experiments. The results demonstrated that cromolyn, tranilast and cetirizine significantly decreased the amount of Evans blue dye in the skin of SIN-treated animals (Fig. 4A and B) alongside with reduction of SIN-induced increase of mast cell numbers (Fig. 4C and D). Considering the critical role of IL-33 in SIN-triggered HRARs, we determined whether inhibition of IL-33 production contributed to the ameliorative effect of these three agents in the PCA model. Immunohistochemistry analysis revealed that cromolyn, tranilast and cetirizine inhibited SIN-induced IL-33 production in the skin of PCA rats (Fig. 4E), which is consistent with previous reports

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Cromolyn, tranilast and cetirizine block SIN-triggered systemic HRARs [2]
We further validated the effect of these mast cell stabilizers on the prevention of SIN-triggered systemic HRARs in rats, and the results demonstrated that cromolyn, tranilast and cetirizine could effectively reverse SIN-induced body temperature reductions, and animals treated with 200 mg/kg SIN exhibited an increase in body temperature from 35.0 °C to 35.9 °C, 36.0 °C and 36.2 °C, respectively (Fig. 5A). Additionally, cromolyn, tranilast, and cetirizine significantly reduced histamine concentrations in the plasma of animals treated with 200 mg/kg SIN from 5.5 μg/ml to 3.1, 1.0 and 0.9 μg/ml, respectively (Fig. 5B). Significant amelioration of lung injury was observed in animals treated with these mast cell stabilizers, exhibiting reduced immune cell infiltration in the lung tissues (Fig. 5C). Given that IL-33 is a critical cytokine in the initiation and exacerbation of inflammatory responses and histamine release in mouse mast cells, we further examined whether the inhibitory effect of three mast cell stabilizers on histamine release resulted from reduction of IL-33 secretion. As shown in Fig. 5D and E, the levels of IL-33 in plasma and lung tissues were significantly increased in animals treated with SIN intravenously, whereas co-treatment with SIN and cromolyn, tranilast, or cetirizine induced reductions in IL-33 levels in plasma or lung tissues of rats. Collectively, mast cell stabilizers are effective in preventing SIN-triggered systemic HRARs.

Experimental model of IIR and animal groups [1]
Four sets of healthy male Kunming mice weighing 20–22 g were anesthetized by intraperitoneal injection of 10% chloral hydrate (3.0 ml/kg) after they were fasted for 16 h prior to surgery. Animals had free access to water prior to surgery. After ensuring an adequate depth of anesthesia, the mice were fixed in the supine position. In the IIR group (M group), the abdomen was opened and the superior mesenteric artery (SMA) was identified and clamped for 30 min. The clamp was then released and reperfusion of the splanchnic region was maintained for 3 days to observe survival rates or maintained for 3 h to define early small intestinal injury. In the sham-operated group (SH group), the abdomen was opened and the SMA was isolated but not clamped. In the other two treatment groups, mice subjected to IIR in the PreCr group and PostCr group were injected intravenously with Cromolyn sodium/CS (25 mg/kg in 0.1 ml) through the caudal vein at 15 min prior to ischemia and 15 min after releasing of the clamp, respectively. Mice in the SH and M groups received the same volumes of normal saline at 15 min prior to ischemia. In addition, pre-warmed normal saline (0.033 ml/g body weight) was administered subcutaneously to avoid fluid loss following surgery. The dose of CS/Cromolyn sodium was selected in accordance with previous publications.

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Induction and measurement of local HRARs in rat skins [2]
SIN induced local HRARs in rats was performed according to the methods described previously with modifications. SD rats were randomly divided into different groups. As positive control, rats were intradermally injected in the dorsal skin with anti-DNP-IgE (500 ng in 100 μl PBS). After 24 h, rats were challenged intravenously with or without 1 μg DNP-HSA containing 1% Evans blue dye. SIN (10 mg in 100 μl PBS) or PBS (100 μl) was intradermally injected in the dorsal skin of rats challenged with 1% Evans blue dye after 2 h. Cromolyn and cetirizine were dissolved in PBS. Tranilast was dissolved in CMC-Na (sodium carboxylmethyl cellulose). Cromolyn (30 mg/kg) was administered intravenously once before the challenge with DNP-HSA or injection of SIN or PBS. Cetirizine (15 mg/kg) and tranilast (400 mg/kg) were administered orally 1 h or 30 min before the challenge with DNP-HSA or injection of SIN or PBS. Vascular permeability was visualized 2 h later based on blue staining of the injection sites on the reverse side of the skin. Skin samples were harvested, and Evans blue dye was extracted from the tissues upon incubation at 55 °C for 48 h with 2 ml of formamide and quantified by OD at 610 nm.

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Induction and measurement of systemic HRARs in rats [2]
The experiment protocol was modified according to the previous description. Briefly, rats were intravenously injected with PBS or SIN at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg. Cromolyn, cetirizine and tranilast were prepared as described above. Cromolyn (30 mg/kg) was administered intravenously once before injection of SIN or PBS. Cetirizine (15 mg/kg) and tranilast (400 mg/kg) were administered orally 1 h or 30 min before the injection of SIN or PBS. Changes in body temperature were monitored though rectal temperature every 30 min until recovery of normal body temperature. Plasma was collected in each experiment at different time intervals for different purposes. Rats were sacrificed 2 h later, and their lung tissues were collected for histological analysis or stored at −80 °C until later use. IL-4, IL-18, IL-33, and LTB4 production levels in the plasma were determined by ELISA according to the manufacturer’s instructions.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
While there is currently no published data on the use of Disodium cromoglycate during lactation, the concentration of Disodium cromoglycate in breast milk is likely very low, and poor absorption by the infant's gastrointestinal tract is expected. The expert panel considers the use of Disodium cromoglycate during lactation to be acceptable.
◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Toxicity Overview
Disodium cromoglycate is poorly absorbed and has low toxicity. No serious toxic reactions have been reported, nor have specific toxic doses been determined. There are currently insufficient studies to confirm the efficacy and safety of Disodium cromoglycate in children under 2 years of age. However, life-threatening acute reactions have been reported.
In case of hypersensitivity reactions, patients should receive antihistamines, with or without β-receptor agonists, corticosteroids, and epinephrine. In case of severe hypersensitivity, oxygen, antihistamines, epinephrine, corticosteroids, EEG monitoring, and intravenous fluid administration should be administered. No special laboratory tests or examinations are necessary unless indicated. Treatment for mild to moderate toxicity is primarily symptomatic and supportive. Clinicians should correct any significant fluid and electrolyte disturbances in patients experiencing vomiting or diarrhea. If serious toxicity is not anticipated after overdose, symptomatic and supportive treatment should be provided.

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Adverse Reactions
The frequency of adverse events in patients using Disodium cromoglycate is not well understood. The occurrence of adverse reactions also varies depending on the route of administration. A transient burning sensation in the eyes may occur after using the ophthalmic solution, and symptoms such as dry eyes, eyelid swelling, irritation, itching, rash, and styes may also occur. Adverse reactions reported with Disodium cromoglycate nasal spray include nasal congestion, sneezing, nasal itching, epistaxis, rhinoconjunctivitis, and headache. Reported adverse reactions to the inhaled solution include throat irritation and hoarseness, esophagitis, laryngeal and pharyngeal edema, drowsiness, dizziness, bronchial irritation, pulmonary infiltration, and cough. Most adverse reactions reported by patients with mastocytosis are transient and may be symptoms of the disease. In clinical studies, the most frequently reported adverse events in patients with mastocytosis treated with oral cromoglycate solution included headache, diarrhea, pruritus, nausea, myalgia, abdominal pain, rash, and irritability. Other adverse events associated with the oral solution include vomiting, constipation, erythema, photosensitivity, urticaria, and angioedema. In clinical studies of patients with other comorbidities and in post-marketing patient experience, the incidence of other reported adverse events (including dyspepsia, constipation, glossitis, abdominal distension, stomatitis, vomiting, dysphagia, and esophageal spasm) was low; it was not possible to determine whether these adverse events were related to cromoglycate.

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27503 Female TDLo Oral 96 mg/kg/6D-I Skin and appendages (skin): Allergic dermatitis after systemic exposure. British Medical Journal, 289(470), 1984
27503 Human TDLo Oral 34 mg/kg/4W Lung, pleura or respiration: Respiratory depression; Lung, pleura or respiration: Other changes. British Medical Journal, 2(916), 1976
27503 Rat LD50 Oral >11 gm/kg. Kiso to Rinsho. Clinical Reports, 4(189), 1970
27503 Rat LD50 Intraperitoneal injection >4 gm/kg. Clinical Reports on Kiso to Rinsho, 4(189), 1970
27503 Subcutaneous LD50 in rats: 6 gm/kg Clinical Reports on Kiso to Rinsho, 4(189), 1970

[1]. Treatment of mice with cromolyn sodium after reperfusion, but not prior to ischemia, attenuates small intestinal ischemia-reperfusion injury. Mol Med Rep, 2013. 8(3): p. 928-34.

[2]. Sinomenine-induced histamine release-like anaphylactoid reactions are blocked by tranilast via inhibiting NF-κB signaling. Pharmacol Res. 2017 Aug 31. pii: S1043-6618(17)30796-X.

[3]. Ng, G. and A. Ohlsson, Cromolyn sodium for the prevention of chronic lung disease in preterm infants. Cochrane Database Syst Rev, 2012. 6: p. CD003059.

Disodium cromoglycate is an organic sodium salt, the disodium salt of cromoglycine. It is both an anti-asthmatic drug and a drug allergen. It contains a cromoglycate (2-) group. Disodium cromoglycate is the sodium salt form of Disodium cromoglycate, a mast cell stabilizer with anti-inflammatory activity. Disodium cromoglycate may interfere with the transport of antigen-stimulated calcium ions across the mast cell membrane, thereby inhibiting the release of histamine, leukotrienes, and other substances that induce hypersensitivity reactions from mast cells. Disodium cromoglycate also inhibits the chemotaxis of eosinophils. Disodium cromoglycate is a cromoglycate complex whose mechanism of action is through inhibiting the release of chemical mediators from sensitized mast cells. It is used to prevent allergic and exercise-induced asthma, but is ineffective against existing asthma attacks. See also: Disodium cromoglycate (containing the active ingredient). In summary, treatment of mice with CS during early reperfusion (rather than before ischemia) showed good therapeutic effects on ischemia-induced ischemia-reperfusion injury (IIRI). Appropriate mast cell (MC) activation can suppress inflammation by degrading endothelin-1 (ET-1); however, sustained MC activation may exacerbate inflammation by releasing trypsin, histamine and pro-inflammatory cytokines. [1]

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ZQFTN is a drug preparation derived from the medicinal plant Sinmenium acutum and is recognized in China as an effective drug for the treatment of rheumatoid arthritis (RA). However, histamine-releasing anaphylactic reactions (HRARs) often occur in some patients. Therefore, it is necessary to establish an effective clinical protocol to manage such HRARs. In this study, rat models of systemic anaphylactic reactions (HRARs) and local cutaneous anaphylactic reactions (HRARs) were established. Evans blue staining and histological methods were used to quantitatively analyze vascular permeability and mast cell number. The levels of histamine, leukotriene B4 (LTB4), and interleukin-33 (IL-33) in plasma were detected by ultra-high performance liquid chromatography-solid phase extraction-mass spectrometry (UHPLC-SPE-MS), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry, respectively. The results showed that simvastatin (SIN) could significantly induce systemic and local allergic reactions in rats, manifested as a significant decrease in body temperature, increased skin vascular permeability, lung tissue damage, and mast cell infiltration and elevated IL-33 expression in skin and lung tissue. Mechanistic studies have shown that tranilast can prevent simvastatin-induced allergic reactions by inhibiting H1 receptor gene expression and NF-κB signaling pathway. Our results indicate that mast cell membrane stabilizers and H1 receptor blockers can effectively prevent SIN-induced HRARs, while Disodium cromoglycate, cetirizine, and tranilast can be used for clinical treatment of ZQFTN-induced HRARs. [2] Background: Chronic lung disease (CLD) is common in premature infants and has a complex etiology, including inflammation. Disodium cromoglycate is a mast cell stabilizer that inhibits neutrophil activation and neutrophil chemotaxis, and therefore may play a role in the prevention of chronic lung disease (CLD).
Objective: To determine the effect of prophylactic use of Disodium cromoglycate on the occurrence of CLD, mortality, or a combined outcome of death and CLD within 28 days of birth in preterm infants at risk of CLD.
Search Methods: Relevant studies were identified using the Cochrane Neonatal Assessment Group search strategy. The Cochrane Central Registry of Controlled Trials (CENTRAL, Cochrane Library, Vol. 3, 2009), MEDLINE, EMBASE, CINAHL (as of July 2009), personal files, and reference lists of identified trials were searched. This update was performed on April 12, 2012, using the same databases. Additionally, on the same day, abstracts from the annual meetings of the Chinese Academy of Pediatrics (2000–2012) were searched on the PAS2View™ website and the Web of Science website, starting with two previously identified trials.
Inclusion Criteria: Randomized or quasi-randomized controlled clinical trials involving preterm infants. Disodium cromoglycate must be initiated within two weeks of birth. The intervention must include administration of Disodium cromoglycate using a nebulizer or metered-dose inhaler (with or without a spacer) and be compared to placebo or no intervention. Included studies must include at least one of the following outcome measures: overall mortality, 28-day incidence of chronic lung disease (CLD), CLD incidence at 36 weeks of gestation (PMA), or a composite outcome of 28-day mortality or CLD.
Data Collection and Analysis: Standard Cochrane Collaboration methods were used; see the Cochrane Manual of Interventions for details. For binary outcome measures, hazard ratios (RR) and risk differences (RD) and their 95% confidence intervals (CI) were reported; for continuous data, the weighted mean difference (WMD) was reported. Meta-analyses were performed using fixed-effects models. Heterogeneity was tested using the I² statistic.
Main Results: Two eligible studies were included, but the number of infants included was small. Prophylaxis with Disodium cromoglycate did not have a statistically significant effect on the composite outcome of 28-day mortality or CLD; chronic lung disease (CLD) occurring at 28 days or 36 weeks of gestational age; or CLD occurring in surviving infants at 28 days or 36 weeks of gestational age. Prophylaxis with Disodium cromoglycate did not show statistically significant differences in overall neonatal mortality, air leak incidence, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, and days of mechanical ventilation. No side effects were observed. Further research does not appear necessary. Authors’ Conclusion: There is currently no evidence from randomized trials that Disodium cromoglycate plays a role in the prevention of CLD. Disodium cromoglycate is not recommended for the prevention of CLD in preterm infants. [3]

C23H14NA2O11

512.3302

512.033

C, 53.92; H, 2.75; Na, 8.97; O, 34.35

15826-37-6

Cromolyn;16110-51-3

27503

White to off-white solid powder

752.3ºC at 760 mmHg

241-2420C (dec)

263.9ºC

1

11

6

36

824

0

C1=CC2=C(C(=C1)OCC(COC3=CC=CC4=C3C(=O)C=C(O4)C(=O)[O-])O)C(=O)C=C(O2)C(=O)[O-].[Na+].[Na+]

VLARUOGDXDTHEH-UHFFFAOYSA-L

InChI=1S/C23H16O11.2Na/c24-11(9-31-14-3-1-5-16-20(14)12(25)7-18(33-16)22(27)28)10-32-15-4-2-6-17-21(15)13(26)8-19(34-17)23(29)30;;/h1-8,11,24H,9-10H2,(H,27,28)(H,29,30);;/q;2*+1/p-2

disodium;5-[3-(2-carboxylato-4-oxochromen-5-yl)oxy-2-hydroxypropoxy]-4-oxochromene-2-carboxylate

CROMOLYN SODIUM; Sodium cromoglycate; Disodium cromoglycate; Sodium cromolyn; Gastrocrom; Cromolyn disodium salt; Cromoptic; ...; 15826-37-6;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~50 mg/mL (~97.59 mM)
DMSO : ~25 mg/mL (~48.80 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 50 mg/mL (97.59 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)