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.

---

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].

---

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]

---

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

---

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.

---

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.

---

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
◉ Summary of Use during Lactation
Although no published data exist on the use of cromolyn during lactation, maternal milk levels are likely to be very low and it is expected to be poorly absorbed from the infant's gastrointestinal tract. An expert panel considers use of cromolyn to be acceptable during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Toxicity Summary
Cromolyn sodium is poorly absorbed and is low in toxicity. No severe toxicity reactions have been reported, and a specific toxic dose has not been established. Research verifying the efficacy or safety of cromolyn sodium is insufficient regarding use in pediatric patients younger than 2 years. However, acute life-threatening reactions have been reported.

In the event of a hypersensitivity reaction, patients should receive treatment with antihistamines with or without beta-agonists, corticosteroids, and epinephrine. In the case of a severe hypersensitivity reaction, oxygen, antihistamines, epinephrine, corticosteroids, electroencephalogram monitoring, and intravenous fluids should be administered. No specific labs or testing are necessary unless indicated. Management of mild to moderate toxicity is symptomatic and supportive. The clinician should correct any significant fluid and electrolyte abnormalities in patients with vomiting or diarrhea. Severe toxicity is not expected following an overdose, which should be managed with symptomatic and supportive treatment.

---

Adverse Effects
The frequency of adverse events in patients using cromolyn sodium remains unclear. Adverse events also vary depending on the administration route. The ophthalmic solution is associated with transient eye burning upon administration, and eye dryness, puffiness, irritation, itchiness, rash, and styes may be seen. Adverse events reported with the cromolyn sodium nasal spray were nasal congestion, sneezing, nasal itching, nosebleeds, rhinoconjunctivitis, and headaches. Adverse events reported with the inhalation solution were throat irritation and hoarseness, esophagitis, laryngeal and pharyngeal edema, drowsiness, dizziness, bronchial irritation, pulmonary infiltrates, and cough.

Most of the adverse events reported in patients with mastocytosis have been transient and can be symptoms of the disease. The most frequently reported adverse events in patients with mastocytosis who received oral cromolyn sodium solution in clinical studies were headache, diarrhea, pruritus, nausea, myalgia, abdominal pain, rash, and irritability. In addition, adverse events associated with oral solution include vomiting, constipation, erythema, photosensitivity, urticaria, and angioedema. Other reported adverse events, including reports of dyspepsia, constipation, glossitis, flatulence, stomatitis, vomiting, dysphagia, and esophagospasm, in clinical studies of patients with comorbid conditions as well as postmarketing patient experience were infrequent; attribution to cromolyn could not be determined.

---

27503 women TDLo oral 96 mg/kg/6D-I SKIN AND APPENDAGES (SKIN): DERMATITIS, ALLERGIC: AFTER SYSTEMIC EXPOSURE British Medical Journal., 289(470), 1984
27503 human TDLo oral 34 mg/kg/4W LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES British Medical Journal., 2(916), 1976
27503 rat LD50 oral >11 gm/kg Kiso to Rinsho. Clinical Report., 4(189), 1970
27503 rat LD50 intraperitoneal >4 gm/kg Kiso to Rinsho. Clinical Report., 4(189), 1970
27503 rat LD50 subcutaneous 6 gm/kg Kiso to Rinsho. Clinical Report., 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 that is the disodium salt of cromoglycic acid. It has a role as an anti-asthmatic drug and a drug allergen. It contains a cromoglycate(2-).
Cromolyn Sodium is the sodium salt form of cromolyn, a mast cell stabilizer with anti-inflammatory activity. Cromolyn sodium probably interferes with the antigen-stimulated calcium transport across the mast cell membrane, thereby inhibiting mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity reactions. Cromolyn sodium also inhibits eosinophil chemotaxis.
A chromone complex that acts by inhibiting the release of chemical mediators from sensitized mast cells. It is used in the prophylactic treatment of both allergic and exercise-induced asthma, but does not affect an established asthmatic attack.
See also: Cromolyn (has active moiety).

---

In conclusion, treatment of mice with CS at early reperfusion, but not prior to ischemia, displays promising therapeutic benefits against IIRI. Appropriate MC activation can suppress inflammation by degrading ET-1; however, sustained MC activation may exacerbate inflammation by releasing tryptase, histamine and pro-inflammatory cytokines.[1]

---

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and Cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN. [2]

---

Background: Chronic lung disease (CLD) frequently occurs in preterm infants and has a multifactorial aetiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis and may, therefore, have a role in the prevention of CLD.

Objectives: To determine the effect of prophylactic administration of Cromolyn sodium on the incidence of CLD, mortality or the combined outcome of mortality or CLD at 28 days of life in preterm infants at risk of CLD.

Search methods: The search strategy of the Cochrane Neonatal Review Group was used to identify studies. Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2009), MEDLINE, EMBASE, CINAHL up to and including July 2009, personal files and reference lists of identified trials. For this update the same data bases were searched on 12 April 2012. In addition, on the same date, abstracts from the Pediatric Academic Societies' Annual Meetings (2000 to 2012) were searched on the website PAS2View(TM) as was the Web of Science website using the two previously identified trials as starting points.

Selection criteria: Randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebuliser or metered dose inhaler with or without spacer device versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks' postmenstrual age (PMA), or the combined outcome mortality or CLD at 28 days.

Data collection and analysis: The standard method for The Cochrane Collaboration as described in the Cochrane Handbook for Systematic Reviews of Interventions was used. Risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. A fixed-effect model was used for meta-analysis. Heterogeneity was examined using the I(2) statistic.

Main results: Two eligible studies were identified with small numbers of infants enrolled. Prophylaxis with Cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality or CLD at 28 days; CLD at 28 days or at 36 weeks' PMA; or CLD in survivors at 28 days or at 36 weeks' PMA. Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotising enterocolitis, intraventricular haemorrhage, sepsis, and days of mechanical ventilation. No side effects were noted. Further research does not seem to be justified. Authors' conclusions: There is currently no evidence from randomised trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be 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.

---

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.

---

View More

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.

---

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